Abstract: In the current study, we analysed the prognostic value of vascular endothelial growth factor receptor-1 (VEGFR-1) in clinically-localized prostate cancer (PCa). Forty patients who had undergone radical prostatectomy (RP) for clinically-localized PCa were included. Two groups were compared: 17 patients who experienced cancer progression following RP (group 1) and 23 patients who remained free of recurrence after intervention (group 2). Paraffin-embedded sections obtained from the RP specimens of the 40 patients were used to build tissue microarrays. The expression of VEGFR-1 was examined in the RP specimens using immunohistochemistry and was compared between the groups of patients. The two groups had similar tumor characteristics in terms of PSA, Gleason score and pathological stage of cancer. The median intensity score of VEGFR-1 expression was significantly higher in pT3 tumors than in pT2 tumors. Nevertheless, the intensity scores of VEGFR-1 expression were similar in the two groups of patients. Our results suggest that VEGFR-1 expression is not associated with the risk of cancer progression following RP. Therefore, VEGFR-1 may not be of prognostic value in clinically-localized PCa.
Abstract: AIM: The aim of this study was to determine the presence of the neuronal nitric oxide synthase (nNOS) in near full-term lambs with congenital diaphragmatic hernia (CDH) and its role in the modulation of pulmonary vascular basal tone. METHODS: We surgically created diaphragmatic hernia on the 85th day of gestation. On the 135th, catheters were used to measure pulmonary pressure and blood flow. We tested the effects of 7-nitroindazole (7-NINA), a specific nNOS antagonist and of N-nitro-L-arginine (L-NNA), a nonspecific nitric oxide synthase antagonist. In vitro, we tested the effects of the same drugs on isolated pulmonary vessels. The presence of nNOS protein in the lungs was detected by Western blot analysis. RESULTS: Neither 7-NINA nor L-NNA modified pulmonary vascular basal tone in vivo. After L-NNA injection, acetylcholine (ACh) did not decrease significantly pulmonary vascular resistance (PVR). In vitro, L-NNA increased the cholinergic contractile-response elicited by electric field stimulation (EFS) of vascular rings from lambs with diaphragmatic hernia. CONCLUSION: We conclude that nNOS protein is present in the lungs and pulmonary artery of near full-term lamb fetuses with diaphragmatic hernia, but that it does not contribute to the reduction of pulmonary vascular tone at birth.
Abstract: Although the impact of vascular endothelial growth factor (VEGF) is clearly established in advanced prostate cancer (PCa), its role in localized PCa remains to be determined. The aim of our study was to analyse the plasma levels of VEGF-A and the expression of VEGF-A in prostatic tissue in a population of patients with localized PCa. We measured the preoperative plasma levels of VEGF-A in 100 patients undergoing radical prostatectomy (RP) for clinically-localized PCa. After intervention, we determined the expression of VEGF-A in all RP specimens using immunohistochemistry. We found no association between plasma levels of VEGF-A and the established prognostic factors of PCa. Moreover, there was no association between plasma levels of VEGF-A and the expression of VEGF-A in prostatic tissue. On the contrary, there was a strong correlation between the expression of VEGF-A in PCa tissue and the Gleason score of cancer: the expression of VEGF-A was significantly higher in patients with a high Gleason score on RP specimen (p=0.01). Our results suggest that the expression of VEGF may have a prognostic impact in clinically-localized PCa.
Abstract: OBJECTIVE: To analyse the prognostic value of vascular endothelial growth factor (VEGF) in men with clinically localized prostate cancer. PATIENTS AND METHODS: Paraffin wax-embedded sections from the radical prostatectomy (RP) specimens of 40 men operated for clinically localized prostate cancer were used to build tissue microarrays. Of these patients, 17 had cancer progression and bone metastases after RP (group 1), and 23 remained free-of-tumour recurrence after RP (group 2). VEGF-A expression was examined in the RP specimens using immunohistochemistry. RESULTS: The groups had similar tumour characteristics in terms of prostate-specific antigen level, Gleason score, and pathological stage. VEGF-A expression was significantly higher in group 1 than in group 2 (P=0.046). In logistic regression analysis, VEGF-A expression was the most significant predictive factor of cancer progression after RP. CONCLUSION: VEGF-A expression in prostate cancer tissue is associated with the risk of cancer progression after RP. These results suggest that VEGF-A expression has a prognostic impact in clinically localized prostate cancer.
Abstract: The alveolar concentration of exhaled nitric oxide (CA,(NO)) is increased in patients with systemic sclerosis (SSc), but whether this increase is related to the severity of interstitial lung disease (ILD) in SSc has not yet been investigated. In total, 58 SSc patients prospectively underwent pulmonary function tests (PFTs), echocardiogram and fibrosis scoring on pulmonary computed tomography (CT). Patients were divided into two groups according to the presence (or not) of ILD. Measurements of CA,(NO) were assessed in all SSc patients and compared with those obtained in 19 healthy volunteers. Relationships were sought between CA,(NO) PFTs and CT scan fibrosis scores. Overall, CA,(NO) was significantly increased in SSc patients (median (range) 6.2 (3.8-9.9) ppb) as compared with controls (2.0 (1.2-3.0) ppb). Among SSc patients, CA,(NO) was significantly higher in patients with ILD compared with patients without ILD (n = 33, 7.5 (5.2-11.9) ppb versus n = 25, 4.9 (3.1-7.0) ppb, respectively). CA,(NO) was inversely related to total lung capacity (r = -0.34) and the diffusing capacity of the lung for carbon monoxide (r = -0.37) and was directly related to CT scan fibrosis scores (r = 0.36). An increased alveolar concentration of exhaled nitric oxide could, at least in part, either reflect or contribute to the severity of lung disease and could be used to noninvasively assess the extent of interstitial lung disease in systemic sclerosis.
Abstract: INTRODUCTION: Pulmonary arterial hypertension (PAH) is a disease of complex aetiology involving in varying degrees both genetic and environmental factors. BACKGROUND: Thanks to progress in biology over the past 15 years the physiological consequences of cellular and molecular abnormalities are much better understood. Recent work has allowed better understanding of the different cellular signalling pathways controlling pulmonary vascular tone and cell growth. It appears that these pathways form a dense and complex network involving several groups of molecules of which NO, cGMP, ET-1 and its receptors, are at the most important. VIEWPOINT: The pathophysiology of PAH may be regarded as a disorder of cellular signaling where molecular abnormalities disturb the balance between the different factors controlling vascular tone and cell proliferation. CONCLUSIONS: PAH may be viewed as a disease of cellular signalling where the molecular abnormalities not only affect a single signalling pathway but involve multiple cross-talks between groups of molecules controlling vascular smooth muscle tone and cell growth and differentiation.
Abstract: High mortality in newborn babies with congenital diaphragmatic hernia (CDH) is principally due to persistent pulmonary hypertension. ATP-dependent potassium (K(ATP)) channels might modulate pulmonary vascular tone. We have assessed the effects of Pinacidil, a K(ATP) channel opener, and glibenclamide (GLI), a K(ATP) channel blocker, in near full-term lambs with and without CDH. In vivo, pulmonary hemodynamics were assessed by means of pressure and blood flow catheters. In vitro, we used isolated pulmonary vessels and immunohistochemistry to detect the presence of K(ATP) channels in pulmonary tissue. In vivo, pinacidil (2 mg) significantly reduced pulmonary vascular resistance (PVR) in both controls and CDH animals. GLI (30 mg) significantly increased pulmonary arterial pressure (PAP) and PVR in control animals only. In vitro, pinacidil (10 microM) relaxed, precontracted arteries from lambs with and without CDH. GLI (10(-5) microM) did not raise the basal tone of vessels. We conclude that activation of K(ATP) channels could be of interest to reduce pulmonary vascular tone in fetal lambs with CDH, a condition often associated with persistent pulmonary hypertension of the newborn.
Abstract: OBJECTIVES: To analyze the correlation between serum levels of vascular endothelial growth factor (VEGF) and biopsy findings in patients with a suspicion of prostate cancer. METHODS: Serum levels of VEGF were measured on frozen, archival serum obtained before prostate biopsy in 47 patients with clinical and/or biologic suspicion of prostate cancer. VEGF-A levels were measured using an enzyme-linked immunosorbent assay. RESULTS: The prostate biopsies showed cancer in 27 patients (group 1) and benign tissue in the remaining 20 patients (group 2). No statistically significant difference was found between the two groups in age, digital rectal examination findings, total prostate-specific antigen (PSA) levels, free PSA levels, and complexed PSA levels. The mean prostate volume was significantly lower in group 1 (45.5 g versus 53.9 g; P = 0.04), and the mean percentage of free PSA (free PSA/total PSA) was significantly lower in group 1 (11.3% versus 19%; P = 0.0003). Serum VEGF-A levels were not significantly different between the two groups. The mean VEGF level was 90.6 pg/mL in group 1 and 107.9 pg/mL in group 2 (P = 0.55). Multivariate analysis showed that VEGF-A levels were not predictive of prostate cancer. CONCLUSIONS: Our findings suggest that serum VEGF-A is not helpful to predict prostate cancer in patients with clinical and/or biologic suspicion of prostate cancer.
Abstract: BACKGROUND: Inhaled nitric oxide (iNO) has been used for treatment of acute respiratory failure and pulmonary hypertension since 1991 in adult patients in the perioperative setting and in critical care. METHODS: This contribution assesses evidence for the use of iNO in this population as presented to a expert group jointly organised by the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists. CONCLUSIONS: Expert recommendations on the use of iNO in adults were agreed on following presentation of the evidence at the expert meeting held in June 2004.
Abstract: Major physical traumas provoke a systemic inflammatory response and immune dysfunction. In a model of thermal injury in rats, we previously showed that an overproduction of nitric oxide (NO) was responsible for the collapse of lymphoproliferative responses. In the present work, we performed a time-course analysis of cell proliferation and cell death parameters in order to establish the sequence of events triggered by the high NO output in Wistar/Han rat splenocytes activated with Con A, 10 days after burn injury. We demonstrate that activated T cells from burned rats never divided whereas normal T cells underwent four division cycles. However, T cells from both burned and normal rat entered the G1 phase as shown by increase of cell size, mitochondria hyperpolarization, and expression of cyclin D1. Burned rat T cells progressed to the late G1 phase as shown by expression of the nuclear Ki-67 antigen, but they never entered the S phase. They underwent apoptosis as shown by morphological parameters, disruption of transmembrane mitochondrial potential, and DNA fragmentation. Persistent accumulation of the p53 protein accompanied these phenomena. NO synthase inhibitors antagonize alterations of cell proliferation and cell death parameters in burned rat T cells and accelerated p53 turnover.
Abstract: The factors that mediate the postnatal fall in pulmonary vascular resistance, which is crucial for normal gas exchange, are not fully understood. The endothelium has been implicated in this phenomenon, through the release of vasorelaxant factors such as nitric oxide (NO). Human pulmonary expression of endothelial NO synthase increases up to 31 wk of gestation, together with vascular endothelial growth factor (VEGF), and both factors potently mediate pulmonary angiogenesis and vasorelaxation. During the perinatal period, when pulmonary vasodilatation is maximal, endothelial NO synthase and VEGF are weakly expressed. This raises the involvement of vasorelaxant factors other than NO at birth. One candidate is endothelial-derived hyperpolarizing factor, which induces smooth muscle cell hyperpolarization by activating K(ATP) channels. The marked vasorelaxation induced by activation of these channels in newborn animals, and their strong perinatal expression in the human lung, suggest their involvement during this phase. Another candidate is endothelin (ET)-1, together with its receptors ET-A and ET-B. ET-A receptors are located exclusively on smooth muscle cells and mediate vasoconstriction, whereas ET-B receptors mediate vasoconstriction when located on smooth muscle cells and vasodilatation when located on endothelial cells. ET-B receptors, which are strongly expressed in the human fetal lung both at the end of gestation and after birth, may be involved in perinatal pulmonary vasodilatation. Thus, in human fetal lung, K(ATP) channels and ET-B receptors could be important in mediating the perinatal pulmonary vasodilatation crucial for adapting the pulmonary circulation to extrauterine life.
Abstract: Nitric oxide (NO) plays a central role in many airway physiological functions, and its production appears to be related with progression of lung disease in patients with cystic fibrosis (CF). However, underlying mechanisms which specifically link NO and CF-related lung disease remain unclear. Following in vitro and animal studies suggesting a role for NO in ion transport in various epithelia, this work investigates the relationship between transepithelial baseline potential difference (BPD), an index of airway ion transport, and exhaled NO in the airways of adult patients with CF. Association with other phenotypic traits, lung function tests and CFTR genotype was also assessed. Using simple linear regression, F(E)NO and transepithelial BPD values were significantly inversely correlated (p<0.001, r=-0.53). Polynomial analysis evidenced an asymptotic relationship between F(E)NO and BPD values, yielding a plateau for absolute BPD values above 50 mV. This relation was not altered by adjustment for clinical and genetic characteristics of the patients. The relationship between exhaled NO and transepithelial BPD suggests that low NO concentrations likely worsens airway ion transport impairment resulting from CFTR defect. These results fit with experimental studies that suggest the inhibitory effect of NO on sodium absorption, which is the main determinant of airway basal transepithelial conductance.
Abstract: Pro PSA, the precursor of PSA, is an inactive 244-amino acid protein secreted by prostatic cells. Pro PSA, a distinct molecular form of free PSA in serum, includes native as well as several truncated forms. Clinical studies have recently provided evidence that pro PSA is associated with prostate cancer (PCa). The truncated (-2) pro PSA form accounts for only 6-19% of free PSA in the serum of patients without PCa, but it represents up to 25-95% of free PSA in that of PCa patients. In the PSA range of 2-10 ng/ml, it has been suggested that pro PSA may be useful to detect PCa, and to spare 10-20% of unnecessary prostate biopsies. However, only scant information about the role of pro PSA is available to date, and its real impact on PCa detection remains to be determined. Furthermore, it is questionnable whether pro PSA could be predictive of tumor recurrence of PCa after therapy. Prospective clinical studies with long term followup are needed to clarify this point.
Abstract: BACKGROUND: The severity of lung disease varies widely in patients with cystic fibrosis (CF) who have the same type of mutations of the cystic fibrosis transmembrane regulator (CFTR) gene, suggesting involvement of "modifier" genes. The nitric oxide synthase 1 (NOS1) gene is a candidate for this role because exhaled nitric oxide (NO) is reduced in patients with CF and NOS1 activity contributes to transepithelial ionic transport, immune defence, and non-specific inflammation of the airways. METHODS: Dinucleotide GT repeat polymorphism was studied in the 5' untranslated region of the NOS1 gene, immediately upstream from the transcription initiation site, in 59 patients with CF and 59 healthy controls. RESULTS: Nineteen alleles of the NOS1 gene were identified according to the number of GT repeats (from 18 to 36) in the 5 untranslated region. Exhaled NO levels were significantly correlated with the number of GT repeats. Patients with CF who had the NOS1 genotype associated with high NO production had a slower decline in lung function during the 5 year follow up period. There was no confounding effect of age, chronic bacterial colonisation of the airway, or CFTR genotype. CONCLUSIONS: These data suggest a possible link between the NOS1 gene locus and the rate of decline in lung function in patients with CF.
Abstract: The aim of this study was to assess pulmonary arterial blood flow changes induced by the creation of a systemic arteriovenous fistula (120 d gestation) in the fetal lamb using Doppler technique. Doppler echocardiographic assessment of the pulmonary artery blood flow performed 1, 6, and 14 d after surgery showed that mean pulmonary arterial blood flow in the left or right pulmonary artery was 224 +/- 58 mL/min at day 1 in the fistula group, significantly higher than in the control group (113 +/- 22 mL/min; p < 0.01, ANOVA test) whether no difference was found at days 6 and 14. The mean inner diameter of the left pulmonary artery measured on postmortem lung arteriograms compared favorably to the one measured on day 14 at the same level on ultrasound. The mean left pulmonary arterial blood flow, measured at birth on day 14 after surgery, using ultrasonic flow transducer, was not statistically different from the one measured by Doppler on day 14. Our data demonstrate that echocardiography allows accurate assessment of pulmonary arterial blood flow in utero, providing evidence suggesting transient high pulmonary blood flow that did not last >6 d after the creation of a systemic fistula.
Abstract: Several cases of systemic arteriovenous fistula diagnosed in the human fetus have been associated with the postnatal development of persistent pulmonary hypertension. The aim of this study was to determine the effects of a prenatally created systemic arteriovenous fistula on the structure and reactivity of the pulmonary circulation in the fetal lamb. A fistula between the jugular vein and carotid artery was created in fetal lambs at 119-124 days of gestation. At delivery (134-139 days), left pulmonary artery (LPA) pressure was increased in the fistula group (n = 12) compared with controls (n = 11, P < 0.01). The pulmonary vascular resistance was significantly higher in the fistula group (P < 0.05), whereas mean LPA blood flow was not statistically different between the two groups. Morphometric analysis of the pulmonary vascular bed revealed an increase in the number of peripheral muscular arteries, together with an increase in pulmonary arterial medial thickness in the fistula group. There was no difference in the relative number or size of intraacinar arteries. In vitro organ bath studies on pulmonary arterial rings showed impaired endothelium-dependent relaxation in the fistula group compared with controls. However, endothelial nitric oxide synthase protein expression was similar in both groups, whereas endothelium-independent relaxation to sodium nitroprusside was greater in the fistula group compared with controls. A systemic arteriovenous fistula leads to both structural and functional alteration of the pulmonary vasculature, which might lead to the development of persistent pulmonary hypertension after birth.
Abstract: We previously showed that an overproduction of nitric oxide (NO) by macrophages was responsible for the collapse of lymphoproliferative responses after burn injury in rats. First, we demonstrate here that 10 days post-burn, the inhibition of splenocyte response to concanavalin-A results from cytostatic, apoptotic, and necrotic effects of NO on activated T cells. This was evidenced by various criteria at the levels of DNA, mitochondria, and plasma membrane. Inhibition of NO synthase by S-methylisothiourea (10 microM) normalized all the parameters. Second, we show that two soluble guanylate cyclase (sGC) inhibitors, LY83583 and ODQ, restored the proliferative response in a concentration-dependent manner. LY83583 (0.5 microM) rescued T cells from apoptosis. Similar results were obtained with KT5823 (5 microM) a specific inhibitor of protein kinase G (PKG). In contrast, neither LY83583 nor KT5823 inhibited NO-induced necrosis. These results suggest that NO blocked T cells in the G1 phase and induced apoptosis through a sGC-PKG-dependent pathway and necrosis through an independent one.
Abstract: Nitric oxide (NO) is synthesized from l-arginine by the Ca(2+)/calmodulin-sensitive endothelial NO synthase (NOS) isoform (eNOS). The present study assesses the role of Ca(2+)/calmodulin-dependent protein kinase II (CaMK II) in endothelium-dependent relaxation and NO synthesis. The effects of three CaMK II inhibitors were investigated in endothelium-intact aortic rings of normotensive rats. NO synthesis was assessed by a NO sensor and chemiluminescence in culture medium of cultured porcine aortic endothelial cells stimulated with the Ca(2+) ionophore A23187 and thapsigargin. Rat aortic endothelial NOS activity was measured by the conversion of l-[(3)H]arginine to l-[(3)H]citrulline. Three CaMK II inhibitors, polypeptide 281-302, KN-93, and lavendustin C, attenuated the endothelium-dependent relaxation of endothelium-intact rat aortic rings in response to acetylcholine, A23187, and thapsigargin. None of the CaMK II inhibitors affected the relaxation induced by NO donors. In a porcine aortic endothelial cell line, KN-93 decreased NO synthesis and caused a rightward shift of the concentration-response curves to A23187 and thapsigargin. In rat aortic endothelial cells, KN-93 significantly decreased bradykinin-induced eNOS activity. These results suggest that CaMK II was involved in NO synthesis as a result of Ca(2+)-dependent activation of eNOS.
Abstract: BACKGROUND: We investigated the immunoinflammatory profile of patients successfully resuscitated after cardiac arrest, representing a model of whole-body ischemia/reperfusion syndrome. METHODS AND RESULTS: Plasma cytokine, endotoxin, and ex vivo cytokine production in whole-blood assays was assessed in 61, 35, and 11 patients, respectively. On admission, high levels of plasma interleukin (IL)-6, IL-8, IL-10, and soluble tumor necrosis factor (TNF) receptor type II could discriminate between survivors and nonsurvivors. Among nonsurvivors, the initial need for a vasopressor agent was associated with higher levels of IL-1 receptor antagonist, IL-10, and IL-6 on day 1. Plasma endotoxin was detected in 46% of the analyzed patients within the 2 first days. Endotoxin-induced TNF and IL-6 productions were dramatically impaired in these patients compared with healthy control subjects, whereas an unaltered production was observed with heat-killed Staphylococcus aureus. In contrast, IL-1 receptor antagonist productions were enhanced in these patients compared with healthy control subjects. The productions of T-cell-derived IL-10 and interferon-gamma were also impaired in these patients. Finally, using in vitro plasma exchange between healthy control subjects and patients, we demonstrated that the endotoxin-dependent hyporeactivity was an intrinsic property of patients' leukocytes and that an immunosuppressive activity was also present in their plasma. CONCLUSIONS: Altogether, the high levels of circulating cytokines, the presence of endotoxin in plasma, and the dysregulated production of cytokines found in these patients recall the immunological profile found in patients with sepsis.
Abstract: In order to investigate whether systemic arteriovenous fistula occurring during the fetal period could induce pulmonary hypertension at birth, a fistula was surgically created between the carotid artery and jugular vein of fetal lambs at 120 days' gestation. Mean pressures in the left pulmonary artery, aorta, atrium and ventricles were measured at birth in seven experimental animals and in five control animals. Mean left pulmonary pressure was significantly higher in the lambs with fistula as compared with the control group, suggesting that prenatal occurrence of systemic arteriovenous fistula may induce fetal pulmonary hypertension. The present study provides a new animal model that could be relevant for the study of mechanisms regulating pulmonary vascular tone in the perinatal period.
Abstract: Nitric oxide (NO) plays a major role in the modulation of perinatal pulmonary vascular tone. Congenital diaphragmatic hernia (CDH), a major cause of severe persistent pulmonary hypertension of the newborn (PPHN), is often refractory to inhaled NO. Alterations in NO/cyclic guanosine 3',5' monophosphate (cGMP)-mediated pulmonary vasodilatation may contribute to PPHN in CDH. We assessed NO/cGMP-mediated pulmonary vasorelaxation in vitro in 140-d gestational lamb fetuses with surgically created left CDH (term = 147 d) to age-matched controls. Relaxation of fourth generation intralobar pulmonary artery rings in response to the endothelium-dependent vasodilator, acetylcholine (ACh), and to the specific inhibitor of cGMP-phosphodiesterase (PDE), zaprinast, did not differ between the two groups. By contrast, relaxation in response to the calcium ionophore A23187 was impaired in CDH as compared with control animals. Relaxation in response to the NO donor sodium nitroprusside (SNP) (a direct activator of soluble guanylyl cyclase [sGC]) was also impaired in CDH animals as compared with controls. Repeating the challenge increased vasorelaxation in response to SNP in CDH as compared with control animals. Immunohistochemistry revealed the presence of endothelial NO-synthase in the endothelium of pulmonary arteries from both control and CDH animals. We conclude that endothelium-dependent vasodilatation in response to ACh and A23187 was differently affected in the fetal surgical CDH-lamb model. Furthermore, activity of sGC but not that of PDE was impaired in CDH animals. PPHN and decreased inhaled NO responsiveness in CDH may involve decreased sGC activity.
Abstract: Endothelial nitric oxide (NO) synthase (eNOS) is controlled by Ca(2+)/calmodulin and caveolin-1 in caveolae. It has been recently suggested that Na(+)/Ca(2+) exchanger (NCX), also expressed in endothelial caveolae, is involved in eNOS activation. To investigate the role played by NCX in NO synthesis, we assessed the effects of Na(+) loading (induced by monensin) on rat aortic rings and cultured porcine aortic endothelial cells. Effect of monensin was evaluated by endothelium-dependent relaxation of rat aortic rings in response to acetylcholine and by real-time measurement of NO release from cultured endothelial cells stimulated by A-23187 and bradykinin. Na(+) loading shifted the acetylcholine concentration-response curve to the left. These effects were prevented by pretreatment with the NCX inhibitors benzamil and KB-R7943. Monensin potentiated Ca(2+)-dependent NO release in cultured cells, whereas benzamil and KB-R7943 totally blocked Na(+) loading-induced NO release. These findings confirm the key role of NCX in reverse mode on Ca(2+)-dependent NO production and endothelium-dependent relaxation.
Abstract: A UNIVERSAL UBIQUITOUS PHENOMENON: Because it involves many different species, inflammation is a universal phenomenon. It is also an ubiquitous phenomenon because several organs may be involved within a given species. In humans, where it is involved in almost all pathological conditions, inflammation reaches its highest degree of complexity. FOUR STEPS: Despite the diversity of symptoms and the complexity of the molecular interactions, the sequence of events leading to an inflammatory reaction involves four steps. The first is the appearance of signals initiating inflammation. The second step involves a series of cellular reactions, the earliest reactions leading to surface phenomenon. Limitation, or on the contrary amplification, of the initial inflammatory response is the third step. Finally, healing or installation of chronic inflammation is the fourth step. Transcription factors which play a switching role in cell signaling can also be useful as therapeutic targets for anti-inflammatory agents. Two transcription factors play an important role in airway inflammation: nuclear factor NF-kappa B and activating protein 1 (AP-1). Apoptosis or programmed cell death involves a cascade of events leading to condensation of the chromatin and fragmentation of the deoxyribonucleic acid. Programmed cell death is required to resolve the inflammatory process. The principal factors involved in apoptosis can be schematically divided into pro-apoptotic factors and anti-apoptotic factors.
Abstract: In the vascular system, synthesis of the potent vasodilator nitric oxide (NO) is tightly regulated by the constitutively expressed endothelial NO synthase (eNOS). Activity of eNOS is controlled by Ca2+/calmodulin and various seryl/threonyl protein kinases. Less is known about the importance of phosphorylation and dephosphorylation of tyrosyl residues. Therefore the role of tyrosine phosphatase on the modulation of isolated rat pulmonary artery tone has been assessed. Inhibition of tyrosine phosphatase by sodium orthovanadate (SOV, 1x10(-6) M) significantly: 1) increased phenylephrine-induced vasoconstriction and 2) decreased endothelium-dependent relaxation to acetylcholine, but had no effect on endothelium-independent relaxation to the NO donor, sodium nitroprusside. In phenylephrine-precontracted pulmonary arterial rings, SOV (1x10(-7)-1x10(-5) M) had no effect on vascular tone but significantly relaxed rings which were pretreated with the NO-synthase inhibitor, N(omega)-nitro-L-arginine-methyl ester (L-NAME). SOV-induced relaxation in the presence of L-NAME was, however, abolished by glibenclamide. In conclusion, inhibition of tyrosine phosphatase altered pulmonary vascular tone by increasing vasoconstrictor response to phenylephrine and decreasing endothelium-dependent relaxation to acetylcholine. Furthermore, the tyrosine phosphatase inhibitor, sodium orthovanadate, exhibited original vasodilator properties which were only observed when nitric oxide synthesis was inhibited. Thus a new pathway involving the inhibitory effect of nitric oxide on a glibenclamide-sensitive diffusible relaxing factor, that might play an important role in the control of pulmonary vascular tone is described.
Abstract: The aim of our study was to find out, which are the thyroid linked mechanisms responsible for the changes in myosin isoform composition which accompany endurance training (ET) in rodents. We studied the interaction between ET and altered sedentary group with no thyroid treatment or Se group. Six groups of rats were compared: (1) a trained group with no thyroid treatment or T group; (2) a thyroid state in rats; (3) a sedentary group rendered hypothyroid with 6-n-propyl thio uracil (H); (4) a sedentary group rendered hyperthyroid with T3 (150 microg kg(-1) every other day for 4 weeks) (St); (5) trained rats rendered hyperthyroid with T3 (150 microg kg(-1) every other day for 4 weeks) (Tt) and (6) a trained group kept euthyroid with T3 (150 ng kg(-1) every other day for 4 weeks) (Te). In each group myosin isoform composition was determined in five muscles, three locomotor muscles: (1) extensor digitorum longus, (2) superficial lateral gastrocnemius, (3) deep medial gastrocnemius, (4) an antigravity muscle, the soleus and (5) a rhytmic respiratory muscle, the crural diaphragm. Different muscles responded in a specific way to variations of the thyroid state and training.
Abstract: The hepatopulmonary syndrome (HPS) is characterized by intrapulmonary vascular dilatations and an increased alveolar-arterial oxygen difference (AaPO(2)). Exhaled nitric oxide (NO) concentrations are elevated, suggesting that pulmonary NO overproduction may be the mechanism underlying HPS. We investigated whether common bile duct ligation in rats results in lung NO overproduction and whether normalization of NO synthesis by a 6-wk course of N(G)-nitro-L-arginine methyl ester (L-NAME) (5 mg x kg(-)(1) x d(-)(1)) prevents HPS. Untreated cirrhotic rats showed increases in AaPO(2) and in cerebral uptake of intravenous (99m)Tc-labeled albumin macroaggregates (indicating intrapulmonary vascular dilatations), with decreases in pulmonary vascular resistance and in pulmonary vasoconstriction induced by angiotensin II and hypoxia. Increases were found in exhaled NO; pulmonary total and calcium-dependent NO synthase (NOS) activities; and pulmonary expression of inducible and, to a lesser extent, endothelial NOS. Accumulation of intravascular macrophages accounted for the inducible NOS expression. L-NAME normalized AaPO(2), brain radioactivity, pulmonary vascular resistance, reactivity to hypoxia and angiotensin II, exhaled NO, and NOS activities. These findings suggest that HPS and the associated reduced response to pulmonary vasoconstrictors seen in untreated cirrhotic rats are related to increased pulmonary NO production dependent primarily on increases in the expression and activities of inducible NOS within pulmonary intravascular macrophages.
Abstract: Pharmacological evidence supports a role of a transient decreased endogenous nitric oxide (NO) synthesis in ovalbumin (OVA)-induced early airway hyperresponsiveness in guinea pigs. However, no data are available regarding the expression and activity of the constitutive NO synthases (cNOS; NOS1 and NOS3, nNOS and eNOS, respectively) in this model. Therefore, we evaluated cNOS activity (conversion of L-[3H]arginine to L-[3H]citrulline in the presence of Ca2+ and calmodulin), nitrate and nitrite (NOx) concentration (modified Griess method), and NOS1 and NOS3 protein expression (Western blot) in lung homogenates and in the tracheal smooth muscle from OVA-immunized and multiple aerosol-challenged guinea pigs (six challenges, once daily). The expression and activity of the inducible NOS isoform (NOS2), the levels of exhaled NO, and the in vivo airway reactivity were also determined. Constitutive NOS activity and NO(x) concentration were significantly lower 6 h after the last OVA challenge as compared with saline exposure, being similar at 24 h. Expression of NOS1 paralleled cNOS activity, which was reduced 6, but not 24 h after OVA challenge. The decrease in NOS1 expression was accompanied by a significant decrease in the amounts of exhaled NO and by a maximal airway hyperresponsiveness to histamine. The levels of NOS3 were not modified at the two time points evaluated, and no NOS2 expression and activity were found at any time point. Similar modifications were observed in the tracheal smooth muscle. We conclude that OVA stimulation in immunized guinea pigs induced a transient reduction in NOS1 protein expression and activity in the respiratory system, which probably participates in airway hyperresponsiveness.
Abstract: Congenital diaphragmatic hernia (CDH) is a major cause of refractory respiratory failure in the newborn. Besides pulmonary hypoplasia, the pathophysiology of CDH also includes surfactant deficiency. Vitamin A (vit A) is important for various aspects of lung development. We hypothesized that antenatal treatment with vit A would stimulate lung surfactant synthesis in experimental CDH induced in rats by maternal ingestion of the herbicide nitrofen (2,4-dichloro-phenyl-p-nitrophenyl-ether) on Day 12. Fetuses were assigned to six experimental groups: (1) controls from rats that received olive oil, the vehicle; (2) fetuses from rats that received olive oil on Day 12 and vit A orally (15,000 IU) on Day 14; (3) nitrofen (N)-exposed fetuses without diaphragmatic hernia (N/no DH); (4) N/no DH from rats given vit A on Day 14; (5 ) nitrofen-exposed fetuses with DH (N/+DH); (6) N/+DH from rats given vit A on Day 14. Fetuses were delivered by C-section at Day 21. Lung DNA content was lowered in the nitrofen group as compared with the controls group, but increased by subsequent vit A treatment. Lung surfactant disaturated phosphatidylcholine was reduced in the N/+DH group and restored to control level by vit A. The expression level of surfactant proteins (SP) -A and -C was decreased in vit A-treated control rats and in nitrofen-exposed fetuses with or without DH. Vit A restored SP-A and -C mRNA expression to control levels in N/+DH. SP-B expression was lowered in N/no DH and increased by vit A in this group. The proportion of type II cells assessed by SP-B immunolabeling was lowered in N/+DH and restored by vit A treatment. We conclude that antenatal treatment with vit A restores lung maturation in nitrofen-induced hypoplastic lungs with CDH. These findings point out vit A as a potential therapeutical agent for correcting surfactant deficiency in CDH.
Abstract: BACKGROUND: We previously reported that skin closure is improved by photoirradiation of the wound margins with an 815-nm diode laser system. OBJECTIVES: To determine whether the beneficial effects of laser treatment involve the overexpression of the inducible 72-kDa heat shock protein, Hsp70. METHODS: Expression of Hsp70 was investigated by immunocytochemistry in normal hairless rat dorsal skin and compared with its expression after laser photoirradiation. RESULTS: Constitutive expression of Hsp70 was mainly confined to the upper epidermal layer. Laser irradiation further increased epidermal expression of Hsp70 while inducing de novo synthesis of the protein in dermal structures, particularly around blood vessels, hair follicles and sebaceous glands. Laser-induced expression of Hsp70 was still present 7 days after photoirradiation. CONCLUSIONS: Laser-induced expression of Hsp70 might contribute to improved tissue regeneration and wound healing.
Abstract: Because inflammation stimulates the expression of inducible nitric oxide (NO) synthase (iNOS) with an associated increased local NO production, we hypothesized that patients with pneumonia would have increased excretion of NO into their airways. To test this hypothesis, NO was measured in the exhaled air and from the nasal cavities of 49 consecutively intubated and mechanically ventilated patients in our ICU. After excluding NO gas contamination in the inspiratory circuit, nasal NO and end-expiratory and mean exhaled tracheal NO levels and plasma nitrate concentrations were measured using a fast response chemiluminescence analyzer. Twenty-one patients (43%) presented with infectious pneumonia. End- expiratory exhaled NO concentrations were significantly higher in patients with pneumonia as compared with patients without pneumonia (5.9 +/- 1 ppb versus 3.2 +/- 0.5 ppb, p < 0.01). Similarly, mean nasal NO was higher in patients with pneumonia (1039 +/- 138 ppb versus 367 +/- 58 ppb, p = 0.003). Plasma nitrate levels did not differ between patient groups. Threshold values of tracheal or nasal NO were defined and subsequently validated in 60 other patients. Positive and negative values of a maximal tracheal level > 5 ppb for pneumonia were 74% and 89%, respectively. Thus tracheal and nasal NO levels may be of help in distinguishing patients with acute pneumonia from other causes. Furthermore, because these differences in airway NO levels were not paralleled in blood nitrite concentrations, we conclude that pneumonia per se is not associated with systemic NO production.
Abstract: The aim of this study was to assess the role of nitric oxide (NO) and endothelin (ET)-1 in the pathophysiology of persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created congenital diaphragmatic hernia (CDH). The pulmonary vascular response to various agonists and antagonists was assessed in vivo between 128 and 132 days gestation. Age-matched fetal lambs served as control animals. Control and CDH lambs had similar pulmonary vasodilator responses to acetylcholine, sodium nitroprusside, zaprinast, and dipyridamole. The ET(A)-receptor antagonist BQ-123 caused a significantly greater pulmonary vasodilatation in CDH than in control animals. The ET(B)-receptor agonist sarafotoxin 6c induced a biphasic response, with a sustained pulmonary vasoconstriction after a transient pulmonary vasodilatation that was not seen in CDH animals. We conclude that the NO signaling pathway in vivo is intact in experimental CDH. In contrast, ET(A)-receptor blockade and ET(B)-receptor stimulation significantly differed in CDH animals compared with control animals. Imbalance of ET-1-receptor activation favoring pulmonary vasoconstriction rather than altered NO-mediated pulmonary vasodilatation is likely to account for persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created CDH.
Abstract: The aim of this study was to determine which endothelial factors were involved in the decrease of pulmonary vascular resistance at birth, and how they changed with maturation. Response of intrapulmonary artery rings precontracted with prostaglandin F2alpha were studied from piglets aged <2 h, 2-3 day, 10 day and adult pigs for pharmacological responses to acetylcholine (ACh) and cromakalim (CMK) in the presence and the absence of the nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NA), the adenosine triphosphate sensitive potassium (K(ATP)) channel blocker, glibenclamide and the endothelin (ET)-A receptor antagonist, BQ123. In situ hybridization and immunochemistry studies were performed in lung tissues of the same animals in order to determine the expression of NOS and ET. There was a small contractile effect of ACh in the newborn. Relaxation to ACh, which was blocked by L-NA and reduced by glibenclamide, only appeared from the age of 3 days. The significantly greater relaxation to CMK in rings without endothelium (p<0.05) was abolished by BQ123 in the newborn, and then disappeared by 2 days of age. Glibenclamide had a greater inhibitory effect on relaxation induced by CMK at 10 days than in the newborn and 2 days old piglets. NOS expression was low in pulmonary arteries of the newborn and increased by 2 days of age whereas the converse was seen with ET expression. It is concluded that: 1) relaxant response to acetylcholine was absent at birth and appeared at 2 days; 2) the reduced relaxant response to cromakalin in rings with endothelium at birth could be blocked by BQ123; and 3) the expression of endothelin decreased whereas the expression of nitric oxide synthase increased from birth to 2 days of age.
Abstract: AIM OF THE STUDY: To assess the role of nitric oxide (NO) and its second messenger, cGMP, on the mechanisms underlying human ureteral smooth muscle relaxation. METHODS: Proximal segments of ureter were dissected from nephrectomy, then cut into rings and suspended in organ chambers. Isometric tone was recorded at baseline and after preincubation with KCl (120 mumol). The Increasing concentration (10-8-10-4 M) of NO donors, Sodium nitroprusside, (SNP) and molsidomine (SIN-1) and a type V phosphodiesterase inhibitor, Zaprinast were added to the organ chambers and a dose response curve was constructed from each experiment. RESULTS: Dose-dependent relaxation was seen with all compounds. This was, however, more pronounced with SNP as compared with SIN-1. Zaprinast alone had marginal relaxant effect but markedly potentiated the relaxing effect of the NO donor SNP (p < 0.05). Inhibition of NO synthesis by the arginine analogue L-NA increased electrical-induced contraction (98 +/- 4% vs 122 +/- 3%, p < 0.001). CONCLUSION: Activation of the soluble guanylate cyclase by NO donors markedly relaxed significantly human ureteral smooth muscle but inhibition of phosphodiesterase did not affect the in vitro relaxation. Our results suggest that cGMP is an important second messenger in the transduction signalling pathway leading to relaxation of human ureteral smooth muscle. By contrast, basal activity of phosphodiesterase seems to be marginal under physiological condition.
Abstract: The free radicals nitric oxide (.NO) and superoxide (O(2)(-).) react to form peroxynitrite (ONOO(-)), a highly toxic oxidant species. In this study we investigated the respective effects of NO and ONOO(-) in monocytes from healthy human donors. Purified monocytes were incubated for 6 or 16 h with a pure NO donor (S-nitroso-N-acetyl-DL-penicillamine, 0-2 mM), an.NO/ONOO(-) donor (3-morpholinosydnonimine chlorhydrate, 0-2 mM) with and without superoxide dismutase (200 IU/ml), or pure ONOO(-). We provide evidence that 3-morpholinosydnonimine chlorhydrate alone represents a strong stress to human monocytes leading to a dose-dependent increase in heat shock protein-70 (HSP70) expression, mitochondrial membrane depolarization, and cell death by apoptosis and necrosis. These phenomena were abolished by superoxide dismutase, suggesting that ONOO(-), but not.NO, was responsible for the observed effects. This observation was further strengthened by the absence of a stress response in cells exposed to S-nitroso-N-acetyl-DL-penicillamine. Conversely, exposure of cells to ONOO(-) alone also induced mitochondrial membrane depolarization and cell death by apoptosis and necrosis. Thus ONOO(-) formation may well explain the toxic effect generally attributed to.NO.
Abstract: Congenital diaphragmatic hernia (CDH) is a major cause of refractory respiratory failure in the newborn. Pulmonary hypoplasia often limits survival. Vitamin A (Vit A) is an important signal for lung growth. We hypothesized that antenatal treatment with Vit A would stimulate lung growth and decrease mortality in experimental CDH induced in rats by ingestion of the herbicide nitrofen (2, 4-dichlorophenyl-p-nitrophenyl ether). Nitrofen was administered to pregnant rats on day 12 of gestation (term 22 days). Rats were assigned to five groups: three groups received one dose of oral antenatal Vit A (15,000 IU) before (day 10), concomitant with (day 12), or after (day 14) nitrofen administration; one group received only nitrofen; and a control group received vehicle (olive oil). The incidence of CDH was markedly lower in all groups receiving Vit A (day 10, 44%; day 12, 20%; and day 14, 40%) compared with the nitrofen-treated group (84%; P < 0.05). The 72-h survival was higher in all 3 Vit A-treated groups (day 10, 40%; day 12, 58%; and day 14, 70%) compared with the nitrofen-treated group (16%; P < 0.05). Lung-to-body weight ratio and radial saccular count were significantly increased by Vit A. Antenatal treatment with Vit A lowers the incidence and severity of experimental CDH and increases lung growth and maturation.
Abstract: BACKGROUND: Single doses of zafirlukast attenuate exercise-induced bronchoconstriction (EIB), but previous studies have not measured zafirlukast's effects after regular dosing or its duration of effect beyond 4 hours. OBJECTIVE: The purpose of this study was to assess the effects of zafirlukast 20 mg and 80 mg twice daily compared with placebo on exercise challenges performed at 2 and 8 hours after the last dose of regular administration. METHODS: Twenty-four adult patients with stable asthma taking beta(2)-agonists, inhaled corticosteroids, or both received treatment with zafirlukast (20 mg and 80 mg) and placebo. The patients were treated twice daily for 14 days in a randomized, double-blind, 3-way cross-over fashion, with a 7-day washout period between each treatment. Exercise challenges were performed at 2 and 8 hours after the morning dose on day 14. FEV(1) was measured before exercise and at set intervals after exercise until it returned to within 7% of its baseline value. RESULTS: Both zafirlukast treatments significantly reduced EIB, as measured by the area under the FEV(1) time curve after the 2-hour (P <.001) and 8-hour (P <.001) exercise challenges and maximum fall in FEV(1) at the 2-hour challenge (P <.001). The comparison at 8 hours between treatments was affected by the unexpected finding that EIB was less in the placebo group after the 8-hour challenge than after the 2-hour challenge, as measured by the within-group change in the maximum fall in FEV(1) (P <.001) and the area under the FEV(1) time curve (P =.0023). CONCLUSION: Regular zafirlukast treatment protects against EIB for at least 8 hours after regular dosing. A refractory period, which may be caused by exercise-induced leukotriene release, may last for up to 6 hours after the initial response to exercise.
Abstract: Inhaled nitric oxide (NO) is used to treat various cardiopulmonary disorders associated with pulmonary hypertension. The rationale is based on the fact that NO, given by inhalation, only dilates those pulmonary vessels that perfuse well-ventilated lung units. As a result, pulmonary gas exchange is improved while pulmonary vascular resistance is reduced and pulmonary blood flow is increased. Inhaled NO has been successfully applied to treat persistent pulmonary hypertension of the newborn, reducing the need for extracorporeal life support. Although pulmonary hypertension and altered vasoreactivity contribute to profound hypoxaemia in adult and paediatric acute respiratory distress syndrome (ARDS), the benefit of inhaled NO still remains to be established in patients with ARDS. ARDS is a complex response of the lung to direct or indirect insults, leading to pulmonary vasoconstriction and various inflammatory responses. Recent randomized trials suggest that inhaled NO only causes a transient improvement in oxygenation. Whether this effect is important in the long-term management of ARDS remains to be established. NO, measured in the exhaled breath, is an elegant and non-invasive means to monitor inflammation of the upper and lower respiratory tract. In the normal upper airways, the bulk of exhaled NO originates from the paranasal sinuses. Exhaled NO is increased in nasal allergy and decreased in cystic fibrosis, nasal polyposis and chronic sinusitis. That NO production is increased in asthmatic airways is also well established. However, several questions still need to be addressed, in particular evaluation of the sensitivity and specificity of the measurement techniques, and assessment of the bronchodilator action of endogenous NO.
Abstract: In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascular smooth muscle cells in response to acetylcholine is dependent on the anatomical integrity of the endothelium. Endothelium-derived relaxing factor was identified 7 years later as the free radical gas nitric oxide (NO). In endothelium, the amino acid L-arginine is converted to L-citrulline and NO by one of the three NO synthases, the endothelial isoform (eNOS). Shear stress and cell proliferation appear to be, quantitatively, the two major regulatory factors of eNOS gene expression. However, eNOS seems to be mainly regulated by modulation of its activity. Stimulation of specific receptors to various agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine, thrombin) increases eNOS enzymatic activity at least in part through an increase in intracellular free Ca2+. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although the precise mechanisms activating the enzyme remain to be elucidated. Phosphorylation and subcellular translocation (from plasmalemmal caveolae to the cytoskeleton or cytosol) are probably involved in these regulations. Although eNOS plays a major vasodilatory role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production could be responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be promoted by several risk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty streak infiltration of the neointima). Several mechanisms probably contribute to this decrease in NO bioavailability. Finally, a defect in NO generation contributes to the pathophysiology of pulmonary hypertension. Elucidation of the mechanisms of eNOS enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology of endothelial dysfunction, and could provide insights for new therapies, particularly in hypertension and atherosclerosis.
Abstract: Nitric oxide (NO) exerts cytoprotective effects against hepatic ischemia-reperfusion damage. This study was designed to evaluate which isoform of NO synthase (NOS) is implicated in the generation of cytoprotective NO and to investigate whether NO effects are mediated by cyclic GMP (cGMP). After partial ischemia for 45 min, liver damage was estimated by the release into plasma of cytolytic enzymes. Ischemia-reperfusion induced marked increases in plasma creatine kinase and lactate dehydrogenase after 1 h of reperfusion and of aminotransferases after 6 h of reperfusion. The pretreatment of ischemic rats with 8-bromo-cGMP (16 mg/kg i.v. 30 min before ischemia) or with L-arginine (the endogenous precursor of NO, 100 mg/kg i.v.) significantly diminished the ischemia-reperfusion-induced release of all these enzymes. This demonstrates that cGMP possesses hepatoprotective properties. By immunohistochemistry, we observed, after 6 h of reperfusion, an increase in endothelial NOS-III immunoreactivity, particularly in the small arteries and sinusoids. This NOS-III accumulation in endothelial cells could protect the liver against ischemia-reperfusion by the local generation of NO probably via cGMP.
Abstract: Dexfenfluramine and fenfluramine greatly increase the risk of developing pulmonary hypertension (PHT). The mechanism of anorexigen-associated PHT (AA-PHT) and the reason PHT occurs in a minority of people exposed are unknown. Anorexigens are weak pulmonary vasoconstrictors, but they become potent when synthesis of the endogenous vasodilator nitric oxide (NO) is suppressed. We hypothesized NO deficiency predisposes affected individuals to develop AA-PHT. A prospective, case-control, study was performed on consecutive patients with AA-PHT (n = 9). Two sex-matched control groups were selected: patients with primary PHT (P-PHT, n = 8) and normal volunteers (n = 12). Lung NO production (VNO) and systemic plasma oxidation products of NO (NOx) were measured at rest and during exercise. AA-PHT developed 17 +/- 6 mo after a short course of anorexigen (6 +/- 2 mo) and was irreversible. VNO was lower in AA-PHT than in P-PHT and correlated inversely with PVR (p < 0.05). The apparent VNO deficiency may have resulted from increased oxidative inactivation of NO in patients with AA-PHT, as their NOx levels were elevated (p < 0.05) in inverse proportion to VNO (r2 = 0. 55; p < 0.02). In susceptible persons, anorexigens can cause an irreversible syndrome of PHT, hypoxemia, and systemic vascular complications after brief exposures. These patients have a relative NO deficiency years after discontinuing the anorexigen, perhaps explaining their original susceptibility.
Abstract: OBJECTIVE: To compare prostacyclin with an analogue, iloprost, in treatment of severe pulmonary hypertension. PATIENTS: Eight patients with severe pulmonary hypertension: primary in five, thromboembolic pulmonary hypertension in three. METHODS: All patients underwent right heart catheterisation. Mean (SEM) right atrial pressure was 9.9 (2.2) mm Hg, mean pulmonary artery pressure 67.4 (3.0) mm Hg, cardiac index 1.75 (0.13) l/min/m2 and mixed venous oxygen saturation 59.1(3.1)%. Continuous intravenous epoprostenol (prostacyclin, PGI2) or iloprost was given for phase I (three to six weeks); the patients were then crossed over to receive the alternate drug in an equivalent phase II. MAIN OUTCOME MEASURES: Exercise tolerance was measured at baseline and at the end of phase I and II with a 12 minute walk; distance covered, rest period, percentage drop in arterial oxygen saturation (delta Sao2%) and percentage rise in heart rate (delta HR%). RESULTS: Walking distance covered rose from (mean (SEM)) 407.5 (73) to 591 (46) m with PGI2 (p = 0.004) and to 602.5 (60) m while on iloprost (p = 0.008). Rest period decreased from 192 (73) seconds at baseline to 16 (16) seconds with PGI2 (p = 0.01) and to 58 (34) seconds with iloprost (p = 0.008). Delta HR% was 37.5(6)% at baseline, 35(3)% on PGI2, and 24(6)% on iloprost (p = 0.04). CONCLUSIONS: Both intravenous PGI2 and iloprost caused significant improvement in exercise tolerance. Iloprost offers an alternative to PGI2 treatment of severe pulmonary hypertension.
Abstract: Sampling arterialized earlobe blood is thought to be easier and less painful than direct arterial puncture, and to allow measurement of blood gas values during exercise without the need to insert an arterial cannula. However, arterialized earlobe oxygen tension (PO2) often underestimates arterial PO2 at rest, and is not fully validated during exercise. We have therefore conducted a prospective study to compare values of PO2 and carbon dioxide tension (PCO2) and the discomfort experienced by adult subjects undergoing the two methods of blood sampling during exercise. Seventy consecutive adult patients were studied. Blood samples were drawn simultaneously from the radial artery and arterialized earlobe of each patient during the last minute of an 8 min exercise. Values of PO2 and PCO2 were measured by means of blood gas electrodes. The correlation coefficients between the two samples were 0.92 for PO2 and 0.91 for PCO2. However, the bias and the limits of agreement between the two methods were wide for PO2 (mean+/-2SD of the differences between the two methods: 0.63+/-1.50 kPa (4.7+/-11.2 mmHg)). The bias and the limits of agreement were smaller for PCO2. Patients felt that the earlobe method was not associated with less discomfort than radial artery puncture. We conclude that arterialized earlobe blood oxygen tension is not a good substitute for arterial oxygen tension during exercise, and should not be used to assess arterial oxygen tension in adults during exercise.
Abstract: Inhaled nitric oxide (iNO) has been shown to improve oxygenation in severe persistent pulmonary hypertension of the newborn (PPHN). However, PPHN is often associated with various lung diseases. Thus, response to iNO may depend upon the aetiology of neonatal acute respiratory failure. A total of 150 (29 preterm and 121 term) newborns with PPHN were prospectively enrolled on the basis of oxygenation index (OI) higher than 30 and 40, respectively. NO dosage was stepwise increased (10-80 ppm) during conventional mechanical or high-frequency oscillatory ventilation while monitoring the oxygenation. Effective dosages ranged from 5 to 20 ppm in the responders, whereas iNO levels were unsuccessfully increased up to 80 ppm in the nonresponders. Within 30 min of iNO therapy, OI was significantly reduced in either preterm neonates (51+/-21 vs 23+/-17, P < .0001) or term infants with idiopathic or acute respiratory distress syndrome (45+/-20 vs 20+/-17, P < .0001), 'idiopathic' PPHN (39+/-14 vs 14+/-9, P < .0001), and sepsis (55+/-25 vs 26+/-20, P < .0001) provided there was no associated refractory shock. Improvement in oxygenation was less significant and sustained (OI=41+/-16 vs 28+/-18, P < .001) in term neonates with meconium aspiration syndrome and much less (OI=58+/-25 vs 46+/-32, P < .01) in those with congenital diaphragmatic hernia. Only 21 of the 129 term newborns (16%) required extracorporeal membrane oxygenation (57% survival). Survival was significantly associated with the magnitude in the reduction in OI at 30 min of iNO therapy, a gestational age > or =34 weeks, and associated diagnosis other than congenital diaphragmatic hernia. Conclusion, iNO improves the oxygenation in most newborns with severe hypoxaemic respiratory failure including preterm neonates. However, response to iNO is disease-specific. Furthermore, iNO when combined with adequate alveolar recruitment and limited barotrauma using exogenous surfactant and HFOV may obviate the need for extracorporeal membrane oxygenation in many term infants.
Abstract: Congenital diaphragmatic hernia (CDH) is still an unsolved problem. A disease which was, for a long time, thought to be merely a hole in the diaphragm appears today to be an intriguing malformation with a poorly understood pathogenesis and a complex pathophysiology. CDH results in various degrees of pulmonary hypoplasia and severe persistent pulmonary hypertension of the newborn. Despite antenatal ultrasound diagnosis and continuous improvement in neonatal intensive care, these features could not be overcome, and the overall mortality rate in CDH is still reaching 50%. Experimental works during the past 20 years suggest that CDH is a disease of impaired lung development associated with, but not caused by, a structural defect of the diaphragm. Furthermore, there is increasing evidence that the lung in CDH is not only small but that there are numerous disorders (e.g. surfactant deficiency, decreased anti-oxidant activity, increased vascular reactivity with decreased nitric oxide and increased endothelin 1 activity, and left heart hypoplasia) which may be associated with impaired lung development. Although antenatal diagnosis of CDH is feasible by ultrasound, there is no reliable predictor of pulmonary hypoplasia, the main prognostic factor in CDH. Whilst modern therapeutic strategies such as high-frequency oscillatory ventilation, exogenous surfactant or inhaled nitric oxide may be beneficial in selected subjects, most newborns with hypoplastic lungs will not survive despite these postnatal therapies. Perhaps these newborns would benefit from antenatal treatment directed at altering lung growth early in utero to minimize pulmonary hypoplasia. Therefore, research is needed to elucidate the aetiology and pathogenesis of CDH. Knowledge about the cellular control of proliferation, differentiation and programmed cell death (apoptosis) in the organogenesis should clarify our understanding of these processes and allow us to develop drugs that stimulate lung growth or even correct the anatomical defect. Furthermore, early and reliable assessment of prognosis for fetuses with CDH at risk of death will become increasingly important in the identification of fetuses most likely to benefit from antenatal therapies and may eventually lead to decreased mortality.
Abstract: Sleep-wake states were studied following withdrawal in 36 adult male wistar alcohol-dependent rats, after chronic administration of ethanol (10 g/kg/24 h) for 13 days. In the light phase of the withdrawal day, 12 alcohol-dependent rats received muscimol (0.25 mg/kg), 12 received homotaurine (140 mg/kg), and 12 received 0.9% physiological saline (10 ml/kg). The results have been compared with a control group of 36 rats that received water during the treatment phase of the experiment, and the 14th day received intraperitoneal muscimol or homotaurine. Muscimol significantly improves the alterations of sleep-wake states in alcohol-withdrawn rats, decreasing the percentage of active wakefulness and increasing the percentage of REMS, but without any action on the latency of appearance of REMS, which remains shortened. The effects of homotaurine are less important on the wakefulness, but it also increases the percentage of REMS without influencing its latency of appearance. The influence of these GABA(A) agonists is not identical during the whole period of survey in the light phase, as there are important differences in the temporal sequences for each of them. We conclude that the stimulation of GABA(A) receptors, of which the activity is decreased during alcohol withdrawal, significantly improves the disturbances in the sleep-wake states in the alcohol-dependent rats, in a time-related manner, and there are significant pharmacodynamic differences between muscimol and homotaurine.
Abstract: Hypoxia initiates pulmonary vasoconstriction (HPV) by inhibiting one or more voltage-gated potassium channels (Kv) in the pulmonary artery smooth muscle cells (PASMCs) of resistance arteries. The resulting membrane depolarization increases opening of voltage-gated calcium channels, raising cytosolic Ca2+ and initiating HPV. There are presently nine families of Kv channels known and pharmacological inhibitors lack the specificity to distinguish those involved in control of resting membrane potential (Em) or HPV. However, the Kv channels involved in Em and HPV have characteristic electrophysiological and pharmacological properties which suggest their molecular identity. They are slowly inactivating, delayed rectifier currents, inhibited by 4-aminopyridine (4-AP) but insensitive to charybdotoxin. Candidate Kv channels with these traits (Kv1.5 and Kv2.1) were studied. Antibodies were used to immunolocalize and functionally characterize the contribution of Kv1. 5 and Kv2.1 to PASMC electrophysiology and vascular tone. Immunoblotting confirmed the presence of Kv1.1, 1.2, 1.3, 1.5, 1.6, and 2.1, but not Kv1.4, in PASMCs. Intracellular administration of anti-Kv2.1 inhibited whole cell K+ current (IK) and depolarized Em. Anti-Kv2.1 also elevated resting tension and diminished 4-AP-induced vasoconstriction in membrane-permeabilized pulmonary artery rings. Anti-Kv1.5 inhibited IK and selectively reduced the rise in [Ca2+]i and constriction caused by hypoxia and 4-AP. However, anti-Kv1.5 neither caused depolarization nor elevated basal pulmonary artery tone. This study demonstrates that antibodies can be used to dissect the whole cell K+ currents in mammalian cells. We conclude that Kv2. 1 is an important determinant of resting Em in PASMCs from resistance arteries. Both Kv2.1 and Kv1.5 contribute to the initiation of HPV.
Abstract: OBJECTIVE: To assess the lung production of nitric oxide (NO) in patients with systemic sclerosis. METHODS: The NO concentration and its rate of production by the lungs were measured in the exhaled air in 14 patients with systemic sclerosis and in 12 healthy control subjects using the chemiluminescent method. RESULTS: The NO concentration and its rate of production were significantly increased in scleroderma patients (mean +/- SEM, 18.7 +/- 1.7 ppb and 5.8 +/- 0.5 nmol/min, respectively), as compared with control subjects (11.2 +/- 0.8 ppb and 4.3 +/- 0.4 nmol/min, p < 0.01 and p < 0.05, respectively). CONCLUSION: The pulmonary production of NO is increased in scleroderma patients, which might reflect and contribute to the inflammatory processes of the lungs in systemic sclerosis.
Abstract: Tobacco smoke (TS) induced in human monocytes the synthesis of both the classical heat shock proteins (HSP) (Hsp70, Hsp90, Hsp110) and the oxidation-specific stress protein (SP) heme oxygenase (HO). To determine the role of reactive oxygen species in SP induction by TS, we incubated the monocytes with various antioxidants before exposure to TS. Quercetin and N-acetylcysteine (NAC) both prevented the induction of HO by TS but not, or less so, than that of the classical HSP, while the nitric oxide synthase inhibitor L-nitroarginine had no effect. Thus, at least two mechanisms appear involved in SP induction by TS; (i) the induction of HO (oxidation-dependent), which was prevented by quercetin and NAC; and (ii) the induction of Hsp70, which was, at least in part, oxidation-independent. SP induction might represent an adequate biosensor for TS and other radical-mediated environmental exposures.
Abstract: Pulmonary vascular endothelium synthesizes and releases two groups of vasoactive substances, namely the endothelium-derived relaxing and contracting factors. Among the former, the effects of nitric oxide (NO), formerly known as endothelium-derived relaxing factor (EDRF), and those of the so-called endothelium-derived hyperpolarizing factor (EDHF) have been extensively investigated. Among the latter, endothelin is probably one of the most potent endogenous vasoconstrictors. NO is a free radical which can be readly inactivated by hemoglobin. NO has all the characteristics of a gas, whereas its pharmacological properties are consistent with those of an endogenous nitrovasodilator. Therefore, inhalation of the gas NO is now considered as one of the most promising means to treat persistent pulmonary hypertension of the newborn. EDHF relaxes vascular smooth muscle through activation of ATP-dependent potassium channels. Both the chemical nature and the physiological role of EDHF are still unclear. The pharmacological properties of endothelin are far from being unequivocal. It is a potent vasoconstrictor, when it directly acts on vascular smooth muscle. However, it can also induce the release of NO and EDHF, hence causing vasorelaxation. These effects of endothelin are mediated by various transduction pathways. Activations of ET-B receptors located on endothelium on the one hand, and ET-A receptors located on smooth muscle on the other hand, are responsible for relaxation and constriction of vascular smooth muscle, respectively. Such highly complex cellular mechanisms highlight the need for further insight into the physiology of the cell related to the pulmonary circulation. This, in turn, will help to better define the target upon which one can try to correct the abnormal function of the cell underlying the pathophysiological processes.
Abstract: Leukotrienes are newly formed mediators derived from arachidonic acid that are released from membrane phospholipids upon stimulation of phospholipases. As a result of their various paracrine effects, these mediators-among which the most important are leukotrienes B4, C4, D4 and E4 (LTB4, LTC4, LTD4 and LTE4, respectively)-are likely to play a central role in bronchial obstruction in asthma. Indeed, LTC4 et LTD4 act on all three effectors of bronchial obstruction, namely bronchial smooth muscle, vessels and mucus secretory cells, whereas LTB4 is a potent chemotactic factor recruiting neutrophils and, in a lesser extent, eosinophils. Urinary excretion of LTE4 is also increased during acute asthma and after bronchial provocation tests with various agonists. Increased production of leucotrienes, however, does necessarily imply they are directly involved in asthma. This is, nevertheless, likely according to results obtained from numerous clinical trials assessing the therapeutical effects of competitive antagonists of LTC4 and LTD4 and 5-lipoxygenase (5-LO) inhibitors. Pretreatment with various LTC4 antagonists and 5-LO inhibitors reduces bronchial obstruction induced by exercise, hyperventilation, aspirin and allergens. However, it is still necessary to wait for results of clinical trials looking at the effects of these drugs in a large group of individuals studied over a long period, before one can assess the real therapeutical benefit of suppressing either the production or the action of leucotrienes in asthma.
Abstract: BACKGROUND/AIMS: Hyporesponsiveness to vasoconstrictors in portal hypertension has been shown to involve increased production of nitric oxide in large arteries in vitro. Small arteries (diameter 50-500 microns) are partly responsible for peripheral resistance and probably have different regulatory mechanisms from large arteries. The purpose of this study was to investigate the hyporeactivity of small mesenteric resistance arteries in portal hypertensive rats and to determine the role of nitric oxide and prostaglandins in this hyporesponsiveness. METHODS: Third branch mesenteric arteries from normal and portal hypertensive rats obtained by portal vein ligation were isolated and suspended in myographs for isometric tension recording. Reactivity to vasoconstrictors was assessed by dose-responses to phenylephrine (Phe 10(-8) to 10(-3) M) and by potassium chloride (KCl 45 mM). Acetylcholine (Ach 10(-5) M) was administered in pre-contracted KCl 45 mM arterial rings to evaluate endothelium-dependent relaxation. Pre-incubations with N-nitro-L-arginine (L-NNA 10(-4) M, a specific inhibitor of nitric oxide synthase, or with indomethacin (10(-5) M), a specific inhibitor of cyclo-oxygenase, were performed to compare the individual roles of nitric oxide and prostaglandins in KCl 45 mM-induced contractions. RESULTS: Impaired responses to Phe (3731 +/- 851 microN and 5971 +/- 745 microN, respectively; p < 0.05) and to KCl (2197 +/- 251 vs 2804 +/- 222 microN, respectively; p < 0.05) were observed in mesenteric resistance arterial rings from portal hypertensive rats compared to rings from normal rats. Ach-dependent relaxation did not significantly differ between normal (-25.7 +/- 5.1%) and portal hypertensive (-17.3 +/- 3.3%) rats. Indomethacin induced a similar significant increase in KCl-induced contraction in normal (3472 +/- 400 microN) and portal hypertensive (3432 +/- 654 rats. Nitric oxide synthesis inhibition had no effect in normal rats (3032 +/- 368 microN) but significantly increased KCl-induced contraction in portal hypertensive rats (3331 +/- 551 microN). CONCLUSION: These results demonstrate the existence of a hyporesponsiveness to vasoconstrictors in small mesenteric resistance arteries of portal hypertensive rats, which seems to be due to increased production of nitric oxide.
Abstract: Nitric oxide (NO) is now considered as the endogenous nitrovasodilator which is mainly derived from vascular endothelial cells in physiological conditions. Biosynthesis of NO is controlled by a family of enzymes, the NO synthases (NOS), that can be divided into two major subgroups, namely the constitutive and the inducible NOS. The constitutive NOS is the principal isoform found in endothelial cells. Endothelial dysfunction, as seen in chronic hypoxic lung diseases, impairs endogenous production of NO, thereby causing and/or aggravating pulmonary hypertension. A logical means to reduce pulmonary hypertension would consist in supplying the patients with exogenous NO. Given by inhalation, NO is a selective pulmonary vasodilator, as it rapidly combines with haemoglobin, which inactives NO, and therefore prevents the occurrence of systemic hypotension. Increased production of NO resulting from induction of the inductible isoform of NOS also occurs in inflammatory disorders of the lung and the airways. Henceforth, it is possible to detect, and quantify, increased endogenous pulmonary synthesis of NO by measuring it in the exhaled air. Measuring exhaled NO could, therefore, represent a safe means to detect bronchial inflammation in patients. However, the importance of endogenous NO in the modulation of bronchial tone remains to be established. Current investigations include studies looking at regulatory mechanisms of cellular expression of various NOS isoforms on the one hand and, on the other hand, clinical evaluation of short- and long-term inhalation of NO in patients with primary and secondary pulmonary hypertension.
Abstract: The aim of this study was to see whether increased activity of nitric oxide (NO) might account for decreased pulmonary vascular tone seen in the hyperdynamic circulation of cirrhosis. We compared the pulmonary vascular reactivity of isolated pulmonary arteries (PA) from control rats (n = 10), and rats with biliary cirrhosis (n = 10) induced by chronic bile duct ligation (4 weeks). The responses of PA rings to cumulative concentrations of phenylephrine, acetylcholine, and sodium nitroprusside were studied, and also the effects of inhibition of synthesis of NO by the L-arginine analogue, N omega-nitro-L-arginine (L-NOARG) in PA rings challenged with cumulative concentrations of phenylephrine and acetylcholine. The contractile response to phenylephrine was significantly reduced in cirrhotic PA rings as compared with controls. Pretreatment with L-NOARG (10(-4) M) significantly increased the contractile response to phenylephrine in PA rings from cirrhotic rats but not in control PA rings. Furthermore, L-NOARG restored the response to phenylephrine in cirrhotic PA rings back to normal. There was no difference in the relaxation of PA rings from both groups in response to acetylcholine and sodium nitroprusside. We conclude that in vitro pulmonary artery ring hyporeactivity to phenylephrine results from increased nitric oxide production in the pulmonary circulation of cirrhotic rats and might account for the hepatopulmonary syndrome.
Abstract: It has been shown that endogenous nitric oxide (NO), measured in exhaled air, is increased in asthmatic subjects and after allergen challenge in sensitized animals. NO is also a paracrine molecule with some, though weak, bronchodilator effects. However, whether the amount of endogenous NO that originates in the lungs can reflect the degree of bronchial tone and airways calibre in asthmatic subjects has not yet been investigated. The aim of this study was, therefore, to determine whether NO production could be modified by acute changes of airways calibre in mild, nonatopic, asthmatic subjects. NO output was measured in the exhaled air of 14 steroid-free asthmatics, 8 steroid-treated asthmatics and 21 control subjects. In seven steroid-free asthmatics, exhaled NO was measured after methacholine challenge, and then after salbutamol-induced bronchial dilatation. Exhaled tidal breathing was collected for 30 s and NO in the exhaled air was measured with a chemiluminescence analyser. Both NO concentration and its output were significantly higher in the steroid-free asthmatic patients (15.6 +/- 1.5 parts per billion (ppb) and 6.3 +/- 0.7 nmol.min-1, respectively) as compared with the control subjects (8.9 +/- 1.0 ppb and 3.5 +/- 0.3 nmol.min-1, respectively; p < 0.001 for both) and with the steroid-treated asthmatic patients (11.3 +/- 3.3 ppb and 3.7 +/- 0.9 nmol.min-1, respectively; p < 0.05 for both). Neither methacholine-induced bronchial obstruction nor salbutamol-induced bronchial dilatation caused a significant change in exhaled NO. We conclude that NO production is higher in steroid-free than in steroid-treated asthmatics and in control subjects. Furthermore, NO production is not affected by acute pharmacologically-induced changes of airways calibre in asthmatic subjects. Our results suggest that NO production is a marker of airways inflammation rather than an endogenous modulator of bronchial tone in asthma.
Abstract: BACKGROUND: The short-term vasodilator response to prostacyclin (PGI2) in patients with primary pulmonary hypertension (PPH) is not only unpredictable but also extremely variable in magnitude. In this retrospective study, we attempted to evaluate in a nonselected population of patients with PPH the degree of vasodilatation achieved during short-term infusion of PGI2 and to investigate whether patients with PPH differed in terms of baseline characteristics and prognoses, according to the level of vasodilatation achieved during initial testing with PGI2. METHODS AND RESULTS: Between 1984 and 1992, 91 consecutive patients with PPH underwent catheterization of the right side of the heart with a short-term vasodilator trial with PGI2 (5 to 10 ng.kg-1.min-1). According to the level of vasodilatation achieved during PGI2 infusion, patients were divided into three groups: nonresponding (NR, n = 40), moderately responding (MR, n = 42), and highly responding (HR, n = 9) patients. All three groups were defined by a decrease in total pulmonary resistance index (TPRi) of < 20%, between 20% and 50%, and > 50%, respectively, relative to control values. Prolonged oral vasodilator therapy was subsequently started only in MR and HR patients. All patients had long-term oral anticoagulant therapy. The survival rate at 2 years (transplant recipients excluded) was significantly higher in HR patients compared with NR and MR patients (62% versus 38% and 47% survivors, respectively; P < .05). Comparisons between groups showed no significant differences in baseline hemodynamics or clinical characteristics except for a longer time between onset of symptoms and diagnosis (ie, first catheterization) of PPH in HR patients than in NR and MR patients (71 +/- 61 versus 35 +/- 34 and 21 +/- 21 months, respectively; P < .05). CONCLUSIONS: In this study, patients with PPH exhibiting a decrease in TPRi > 50% during short-term PGI2 challenge at the time of diagnosis had longer disease evolutions and better prognoses than patients with a lower vasodilator response.
Abstract: 1. The aim of this study was to assess the role of endothelial cells in the modulation of vasocontractile responses to endothelin-1 (ET-1) of human placental vasculature. 2. Isolated stem villi small arteries (diameter = 170-250 microns) were obtained from healthy parturients who underwent caesarean surgery during the 39th week of pregnancy for cephalo-pelvic disproportion. Isometric tension was measured in vascular rings mounted in a myograph system and challenged with ET-1 (10(-12) to 10(-6) M). 3. The vasocontractile response to ET-1 was significantly (P < 0.001) increased in endothelial-denuded (active tension = 1156 +/- 214 mN mm-1) as compared with endothelial-preserved vascular rings (active tension = 458 +/- 48 mN mm-1). This difference was significantly (P < 0.05) but only partly abolished by the NO synthase inhibitor N omega-nitro-L-arginine (L-NOARG, 10(-4) M). 4. In endothelial-preserved rings submaximally precontracted with 5-hydroxytryptamine (10(-6) M), ET-1 (10(-12) to 10(-9) M) induced dose-dependent relaxation (maximum relaxation = 70 +/- 7%) at 10(-9) M, which was followed, at higher doses (10(-8) to 10(-6) M), by a contraction. In contrast, no relaxation was seen in endothelial-denuded rings. The relaxation in rings with endothelium was significantly (P < 0.001) reduced by L-NOARG (10(-4) M. Moreover, it was totally abolished by combined pretreatment with L-NOARG (10(-4) M) and the sulphonylurea glibenclamide (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: BACKGROUND/AIMS: Endogenous pulmonary nitric oxide production may be increased in severe cirrhosis and contribute to pulmonary vasodilation. This study assessed pulmonary nitric oxide production by measuring nitric oxide in the exhaled air in patients with severe cirrhosis and examined the relationship between exhaled nitric oxide and pulmonary hemodynamics in these patients. METHODS: Nitric oxide concentrations and production were measured in the exhaled air in six Child-Pugh class C patients with cirrhosis and 21 non-smoking healthy controls. Systemic and pulmonary hemodynamics were measured in patients only. RESULTS: Nitric oxide concentration (32.0 +/- 1.7 (mean +/- SEM) vs. 8.9 +/- 1.0 ppb) and production (9.2 +/- 1.3 vs. 3.1 +/- 0.3 nmol/min) in exhaled air were significantly higher in patients than in controls. Patients had high cardiac output (8.5 +/- 0.9 l/min), low pulmonary and systemic vascular resistance (57 +/- 10 and 767 +/- 93 dyn.s.cm-5, respectively) under baseline conditions. A significant negative correlation was found between pulmonary vascular resistance and exhaled nitric oxide production (r=0.943, p=0.05) but not between cardiac output or systemic vascular resistance and nitric oxide measured in exhaled air. CONCLUSIONS: Endogenous pulmonary nitric oxide production measured from exhaled air is increased in patients with cirrhosis and liver failure. Increased in patients with cirrhosis and liver failure. Increased nitric oxide production may also contribute to cirrhosis-induced pulmonary vasodilatation.
Abstract: As feto-placental vessels in humans are not innervated, regulation of vascular tone in the fetal extracorporeal circulation most likely depends on either circulating hormones or local paracrine mechanisms. However, the latter have not yet been fully investigated. The aim of our study was to characterize vasomotor behaviour of resistance stem villi arteries when challenged with various constrictor and dilator agents, with special emphasis on the physiological importance of endothelium. The latter is poorly characterized in this particular vascular bed in humans. Villous stem arterial rings (internal diameter 182 +/- 6 microns) were isolated under microscopy from term human placentae obtained after cesarean section. The vessels were mounted as ring preparations in an isometric myograph for tension measurements. Endothelium was removed from some of the rings by gentle insertion of a knotted human hair into the vascular lumen. Of the three vasoconstrictors tested, endothelin-1 (ET-1) showed the greatest potency, being 1,000 times more potent than serotonin and phenylephrine. The classical endothelium-dependent vasodilators, acetylcholine, adenosine diphosphate (ADP) and histamine, caused dose-dependent relaxation of the rings; an effect which was completely abolished by the removal of endothelium. Pre-treatment with the nitric oxide (NO) synthase inhibitor, N omega-nitro-L-arginine, also markedly reduced the endothelium dependent relaxant responses to ADP. By contrast, the vasodilatory response to sodium nitroprusside was not affected by endothelial removal. We conclude that i) ET-1 is a potent vasoconstrictor of the human placental vascular bed and ii) placental villous endothelial cells synthesize and release relaxing factor(s) which could possibly be NO.
Abstract: The underlying mechanisms of bronchial obstruction in asthma are complex. Both bronchospasm and bronchial oedema are thought to play pivotal roles in asthma, but their respective importance in a given asthmatic individual is unknown. To address this question, we assessed the effects of pretreatment with inhaled methoxamine, a potent alpha 1-adrenoceptor agonist, on bronchial response to inhaled histamine in 10 asthmatic subjects. The study was conducted according to a double-blind, cross-over, randomized and placebo-controlled design. In each subject, dose-response curves for the effects on forced expiratory volume in one second (FEV1) of serially doubling doses of inhaled histamine were obtained on three different days, 15 min after pretreatment with either methoxamine (10 mg) or duplicated placebo. Histamine, first dose 100 micrograms (543 nmol), was delivered by a breath-activated dosimeter every 5 min. FEV1 was measured in triplicate after each dose and the largest value was retained. There was no difference in baseline and prechallenge FEV1 after placebo and methoxamine. Mean coefficient of variation of decrease in FEV1 induced by histamine on the two placebo days was 6.7 +/- 2%. On average, the bronchial responses to histamine were not modified by pretreatment with methoxamine as compared to placebo (delta FEV1 = 0.83 +/- 0.14 l on methoxamine versus 0.85 +/- 0.11 l and 0.86 +/- 0.13 l on the two placebo days).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Pulmonary hypertension is characterized by a poor prognosis which, therefore, justifies its treatment. Pulmonary vascular endothelium plays a pivotal role in the underlying mechanisms of different forms of pulmonary hypertension. Various paracrine factors, including nitric oxide, prostacyclin and endothelium-1, are synthesized by the endothelium. Nitric oxide and prostacyclin are powerful vasodilators, which also inhibit vascular smooth muscle proliferation and platelet aggregation. Endothelium-1 is probably one of the most potent vasoconstrictor known to date. The net effect of endothelial dysfunction results in increased vasoconstriction, platelet aggregation and occurrence of thrombosis, whereas vasodilatation is impeded. In primary pulmonary hypertension, acute pulmonary vasodilatation is currently sought using inhaled nitric oxide, oral calcium channel blockers or infused prostacyclin to predict the long-term effects of pulmonary vasodilators which might improve the quality of life and survival in some patients. Similar result could be obtained with anticoagulation. The most common cause of secondary pulmonary hypertension is alveolar hypoxia associated with chronic lung diseases. Long-term oxygen therapy improves survival and partially reverses the development of pulmonary hypertension. In chronic thromboembolic pulmonary hypertension, therapy includes anticoagulation and, in the case of lower limb venous thrombosis, inferior vena cava filtration. On the other hand, selected subsets of patients can undergo thromboendarterectomy. If the latter is contraindicated, lung transplantation is the only remaining curative treatment. However, lung transplantation should only be performed in end-stage diseased patients. Inclusion criteria are similar to those applied for primary pulmonary hypertension. The respective indications of heart-lung, double lung, and single lung transplantation, in primary or chronic thromboembolic pulmonary hypertension, remain to be evaluated.
Abstract: To determine whether inhaled nitric oxide (NO) affects pulmonary circulation, thereby improving right ventricular (RV) function in adult respiratory distress syndrome (ARDS), we studied 13 patients with both a lung injury severity score of 2.5 or more and a mean pulmonary artery pressure higher than 30 mm Hg. RV function was assessed by a thermodilution technique using a pulmonary artery catheter equipped with a rapid response thermistor before and 15 min after initiation of inhalation of NO (5 ppm). At baseline, stroke volumes were in a normal range (46 +/- 14 ml/m2), with a RV dilation (end-diastolic volume = 142 +/- 36 ml/m2). Inhaled NO was followed by an improvement in arterial oxygenation (PaO2/FIO2 = 103 +/- 47 versus 142 +/- 63, p < 0.05) and a drop in pulmonary artery pressure (36.1 +/- 4.5 versus 31.3 +/- 6.1 mm Hg, p < 0.01); stroke volumes and heart rates did not change. The resulting fall in pulmonary vascular resistance (211 +/- 43 versus 180 +/- 59 dyn-s/cm5, p < 0.05) was associated with an increase in RV, ejection fractions (32 +/- 5 versus 36 +/- 6%, p < 0.05), a trend toward decreased RV end-systolic (96 +/- 25 versus 85 +/- 19 ml/m2, NS) and end-diastolic (142 +/- 36 versus 131 +/- 27 ml/m2, NS) volumes, and a decrease in right atrial pressures (10.9 +/- 2.9 versus 9.6 +/- 3.2 mm Hg, p < 0.05). No relationship was seen between the improvement in arterial oxygenation and the decrease in pulmonary vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Nitric oxide inhalation can benefit newborn babies with right-to-left extrapulmonary shunt (EPS). Using doppler ultrasound, we compared the effects of nitric oxide on systemic oxygenation and mean pulmonary-blood-flow velocity (MPBFV) in severely hypoxic babies with or without EPS. With a median (interquartile range) dose of 20 (32) parts per million, oxygenation index decreased significantly in both groups (EPS, 49 [19] vs 11 [9]; non-EPS, 40 [11] vs 20 [13]). The decrease was significantly greater in the EPS group. MPBFV increased significantly in the EPS group (18 [4] vs 29 [8] m/s) only. Nitric oxide may improve systemic oxygenation in neonates with severe hypoxaemia secondary to EPS by increasing pulmonary blood flow, and in those without EPS by improving ventilation-perfusion matching.
Abstract: OBJECTIVE: To compare values of SvO2 obtained by reflectance spectrophotometry continuous monitoring with those obtained from blood samples measurements by transmission spectrophotometry (Co-Oximetry). DESIGN: Values of SvO2 recorded by three pulmonary artery catheters for continuous monitoring, SAT1, SAT2 and Oximetrix3 (OX3), were compared in a prospective manner to those measured on blood samples by a Co-Oximeter, using the statistical analysis of Bland and Altman. SETTING: Adult intensive care unit in an University Hospital. PATIENTS: 37 patients admitted for acute respiratory failure and/or shock who required hemodynamic monitoring. MAIN RESULTS: The bias (average under- or overestimation) was small for all comparative measurements: +1.3, -0.2 and +1.0 sat% for SAT1, SAT2 and OX3, respectively. However, limits of agreement were only acceptable for SAT2 (-8.3 to +7.9 sat%) and OX3 (-6.7 to +8.6 sat%), but not for SAT1 (-23.3 to +25.9 sat%). No significant drift during 24 h was found with the three catheters. However, in vitro calibration was only found acceptable for SAT2 and OX3. The results were not influenced by the numbers of wavelengths of the device (2 for SAT1 and SAT2, and 3 for OX3) nor did they correlate with any of the hemodynamic and biochemical variables tested. CONCLUSION: For usual monitoring in the ICU, SAT2 and OX3, gave SvO2 values which are in acceptable agreement with SvO2 measured on blood samples by Co-Oximetry.
Abstract: Nitric oxide (NO) is now considered as the endogenous nitrovasodilator which is mainly derived from vascular endothelial cells in physiological conditions. Biosynthesis of NO is controlled by a family of enzymes, the NO synthases (NOS), that can be divided into two major subgroups, namely the constitutive and the inducible NOS. The constitutive NOS is the principal isoform found in endothelial cells. Endothelial dysfunction, as seen in chronic hypoxic lung diseases, impairs endogenous production of NO, thereby causing and/or aggravating pulmonary hypertension. A logical means to reduce pulmonary hypertension would consist in supplying the patients with exogenous NO. Given by inhalation, NO is a selective pulmonary vasodilator, as it rapidly combines with haemoglobin, which inactivates NO, and therefore prevents the occurrence of systemic hypotension. Endothelial dysfunction resulting in reduced NO synthesis is also likely to account for various cardiovascular disorders, including essential hypertension and coronary atherosclerosis. However, the importance of endogenous NO in the modulation of bronchial tone remains to be established. Current investigations include studies looking at regulatory mechanisms of cellular expression of various NOS isoforms on the one hand and, on the other hand, clinical evaluation of short- and long-term inhalation of NO in patients with primary and secondary pulmonary hypertension.
Abstract: Hindrance to gas flow in the bronchi is affected not only by airway smooth muscle tone but also by airway circulation. Congestion and oedema increase airway wall thickness and act in series with airway smooth muscle contraction to reduce airway calibre, an effect which is more marked in small and intermediate bronchi. Many mediators, neuromediators, paracrine mediators produced by resident (epithelium) or migrant (inflammatory cells) cells share bronchomotor and vascular effects. In addition, contraction of airway smooth muscle and vascular phenomena are mechanically coupled. Contraction of airway smooth muscle facilitates vascular congestion and oedema because the diameter of the muscle ring is more reduced than the external diameter of the airways. In addition, a negative intrathoracic pressure, e.g. in asthma, increases the mechanical loading of both ventricles, thereby facilitating pulmonary and bronchial oedema. The effects of this mechanical coupling are enhanced by airway inflammation that facilitates both vascular congestion and leakage. Stimuli such as exercise and hyperventilation cause airway vasodilatation which, in turn, facilitates and, possibly, triggers the post-exercise asthma attack. Conversely, congestion and vasodilatation may have a protective effect through an increase in the clearance of bronchoconstrictor substances, or in reducing the amplitude of airway cooling and water loss in exercise-induced asthma. The relative role in bronchial hyperresponsiveness of airway smooth muscle contraction and vascular phenomena probably depends upon individual factors such as, for instance, both intensity and nature of inflammation of the airway walls.
Abstract: Inflammation results from the recruitment to a given tissue or organ and the activation of leucocytes, among which the monocytes-macrophages play a major role. These phagocytic cells produce high levels of reactive oxygen species (ROS) as well as cytokines. Whereas both ROS and cytokines have the potential to regulate the expression of heat shock (HS)/stress proteins (HSP), it appears that these proteins in turn have the ability to protect cells and tissues from the deleterious effects of inflammation. The mechanisms by which such protection occurs include prevention of ROS-induced DNA strand breaks and lipid peroxidation as well as protection from mitochondrial structure and function. In vivo, HS protects organs against a number of lesions associated with the increased production of ROS and/or cytokines. In an animal model for adult respiratory distress syndrome, an acute pulmonary inflammatory condition, HS completely prevented mortality. HSP (hsp70 in particular) may also exert protective effects in the immune system by contributing to the processing and presentation of bacterial and tumoral antigens. The analysis of the expression of hsp70 may prove of diagnostic and prognostic value in inflammatory conditions and therapeutical applications are being considered.
Abstract: Enoximone is a phosphodiesterase inhibitor that has both positive inotropic and systemic vasorelaxant activities. The latter are mediated by an increase in vascular smooth muscle concentration of cyclic 3'5' guanosine monophosphate. However, the effect of enoximone on pulmonary vasoreactivity is not established. The authors, therefore, have studied its effect on endothelium-dependent relaxation mediated by the endothelium-derived relaxing factor nitric oxide (NO), as well as endothelium-independent relaxation of isolated porcine pulmonary arteries. Enoximone (10(-7) to 10(-4) M) caused a dose-dependent relaxation in all pulmonary arterial rings. This relaxation neither required the presence of the endothelium nor was affected by the addition of the inhibitor of NO synthase omega-nitro-L-arginine methyl ester (10(-4) M). Also, the vasorelaxant response of the rings to the endothelium-dependent vasodilator adenosine diphosphate (10(-10) to 10(-5) M) was not affected by pretreatment with enoximone. The authors conclude that enoximone is a potent vasodilator that relaxes pulmonary vascular rings through mechanisms independent of the endothelium. This endothelium-independent vasodilatory effect of enoximone makes it a potentially valuable drug for the treatment of pulmonary hypertension. This particularly applies to diseases in man where NO production by the endothelial cells is impaired.
Abstract: The effects of alpha 1- and alpha 2-adrenoceptors stimulants on vascular tone of 188 isolated rings of pulmonary arteries from 24 pigs have been studied. The rings were pretreated with indomethacin, to inhibit cyclo-oxygenase. Isometric tension was recorded and concentrations of cyclic 3'5'-guanosine monophosphate (cGMP) and cyclic 3'5'-adenosine monophosphate (cAMP) were measured. Rings with endothelium contracted with phenylephrine (10(-5) M) (n = 41) and the alpha 1-adrenoceptor agonist methoxamine (10(-3) M) (n = 24). cGMP did not change with methoxamine, but rose with phenylephrine, peaking at 30 to 45 s. This preceded the maximum rise in tension with phenylephrine which occurred later at 120 to 360 s. The alpha 2-adrenoceptor agonist, clonidine (10(-5) M) (n = 33) and the muscarinic receptor agonist acetylcholine (10(-5) M) (n = 30) relaxed precontracted pulmonary arterial rings, minimum tension occurring after 120 s, whilst cGMP rose after 30-45 s. After removal of endothelium (n = 24), the tension after phenylephrine (10(-5) M) was higher and the rise in cGMP was abolished. The cAMP levels did not change with phenylephrine (10(-5) M), acetylcholine (10(-5) M), clonidine (10(-5) M) nor methoxamine (10(-3) M). Activation of alpha 1-adrenoceptors on pulmonary arteries smooth muscle cause contraction, whilst activation of alpha 2-adrenoceptors on endothelial cells cause relaxation probably through a release of nitric oxide and a rise in cGMP.
Abstract: Previous publications suggest that prolonged inhalation of frusemide (F) does not cause a fall in the nasal transepithelial potential difference (PD) whereas locally deposited F does. In an attempt to reconcile these observations, we have measured the effect of inhalation through the nose and local deposition of F, amiloride (A), bumetanide (B) and salbutamol (S) on nasal PD in 7 healthy male volunteers in a randomised, double blind study. Solutions of drugs ranging from 10(-6) M to 10(-3) M (3 x 10(-8) M to 3 x 10(-5) M for B) in phosphate buffered saline 0.5 ml (PBS) were sequentially deposited in both nostrils, and nasal PD was measured 5 min after each dose. In 10 further volunteers, 10(-2) M solutions of A, F and S (3 x 10(-4) M for B) 5 ml were nebulised through the nose for 15 min, when nasal PD was measured. Resting PD was similar in the left and right nostrils averaging -17.1 mV (lumen negative). Placebo, inhaled of deposited B and S, and inhaled F did not change nasal PD. Topically deposited F significantly lowered PDmax in a dose-dependent manner [10(-4) M, -12% from baseline; 10(-3) M, -24%] as did the more potent A [10(-5) M, -19%; 10(-4) M, -31%; 10(-3) M, -47%]. Nebulised A (10(-2) M) had the same effect on nasal PD as deposited A (10(-4) M). The effects of locally deposited F and A (10(-3) M) on nasal PD were additive.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: 1. Endothelium-dependent relaxation mediated by endothelium-derived relaxing factor (EDRF) or nitric oxide (NO), is impaired in pulmonary arteries (PA) of hypoxic patients with chronic obstructive lung disease (COLD). To determine the mechanisms responsible for this impairment, we compared the response of rings of isolated PA from 12 COLD patients and 8 controls to the endothelium-dependent vasodilators acetylcholine (ACh), adenosine diphosphate (ADP), and the calcium ionophore, A23187. The response of PA rings to the endothelium-independent nitro-vasodilator sodium nitroprusside (SNP) was also studied in both groups. The PA rings had been pre-contracted by the alpha-adrenoceptor agonist phenylephrine (PE). 2. Endothelium-dependent relaxation was significantly reduced in PA rings from COLD patients as compared with controls when tested with ACh (37.8 +/- 8.8% vs 73.4 +/- 7.9%), ADP (38.4 +/- 6.7% vs 80 +/- 5.6%), and the calcium ionophore, A23187 (35.8 +/- 6.1% vs 87 +/- 6.6%). Relaxation with SNP was, however, significantly greater in PA rings from COLD patients (99.4 +/- 0.6% vs 90.3 +/- 3.1%), as was the contractile response to PE (1.91 +/- 0.21 g vs 1.33 +/- 0.15 g). Pretreatment with the specific inhibitor of NO formation, NG-monomethyl-L-arginine (L-NMMA; 10(-4) M) significantly reduced the relaxation to ACh in all PA rings. This inhibition could be reversed by L-arginine (10(-3) M), the substrate for NO synthesis. Pretreatment with L-arginine alone, however, did not restore the impaired endothelium-dependent relaxation of PA rings from COLD patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: OBJECTIVE--To determine whether epoprostenol (prostacyclin, PGI2) or heart-lung transplantation (HLT), or both improves survival of patients with severe pulmonary hypertension. DESIGN--This was a prospective study where the effects of epoprostenol were compared with conventional treatment. Also, the benefits of epoprostenol and HLT were assessed by comparing survival in this group with that of 120 patients at the Mayo Clinic before HLT and epoprostenol treatment became available. PATIENTS AND INTERVENTIONS--Forty four patients were studied; 25 received continuous epoprostenol over a four year period (mean (SD) cardiac index 1.8 (0.4) 1 min-1 m-2 and mean (SD) pulmonary artery pressure (PAP) 70 (16) mm Hg) and 19 did not (cardiac index 2.1 (0.6) 1 min-1 m-2 and PAP 64 (13) mm Hg). Ten patients underwent HLT: seven had received epoprostenol, and three had not. RESULTS--The therapeutic intervention with epoprostenol, or HLT, or both improved survival compared with the Mayo clinic patients (p = 0.05). Most of the benefit was conferred by epoprostenol, which prolonged survival twofold from a median time of eight to 17 months and doubled the changes of successful HLT. The improved survival with epoprostenol was not related to its immediate capacity to cause pulmonary vasodilation. Those patients who had limited acute pulmonary vasodilation when treated with epoprostenol showed the greatest improvement in survival. CONCLUSIONS--These preliminary results indicate that those pulmonary hypertensive patients with the poorest chance of survival can be helped by epoprostenol and by HLT.
Abstract: Pulmonary endothelial cells normally synthesize prostacyclin (PGI2) and nitric oxide (NO), which are both potent vasodilators. Although PGI2 is largely used to treat patients with severe pulmonary hypertension, its role in the physiology and pathophysiology of the pulmonary circulation is still debated. NO, which is now considered as the endogenous nitrovasodilator, is perhaps more involved than PGI2 in the mechanisms that modulate pulmonary vascular tone in health and disease. There is evidence to suggest that background release of NO contributes to the normally low pulmonary vascular tone in normoxia. Although there are theoretical grounds to hypothesize that hypoxia reduces the synthesis of NO, lack of the latter does not seem to account for the acute hypoxic pulmonary vasoconstriction. Instead, there is evidence to suggest that NO activity is increased in order to modulate the pulmonary vasopressor response to acute alveolar hypoxia. However, more consistent, concerning the role of NO, are data gathered from studies performed in chronic hypoxic conditions. Both experimental data and studies performed in man demonstrate impairment of NO synthesis and/or release in chronic hypoxic pulmonary hypertension. The impaired NO production, whilst reducing the ability of the pulmonary vasculature to relax, also favours the occurrence of excessive pulmonary vasoconstriction. Lack of NO synthesis might also permit mitogenesis and proliferation of various cell types within the vascular wall. We hypothesize that functional alterations of pulmonary endothelium are likely to affect both reactivity and growth of pulmonary vessels. In this respect, NO probably has a pivotal role in modulating pulmonary vascular tone and controlling pulmonary vascular remodelling in health and disease.
Abstract: A prospective multicentre open study has been conducted in France in order to assess the efficacy and tolerability of an antimycobacterial regimen including rifabutin in the treatment of patients with pulmonary tuberculosis due to rifampicin and isoniazid resistant bacilli. Patients were treated with daily rifabutin (450-600 mg), associated with companion drugs to which the organisms remained susceptible; in most cases the regimen included a fluoroquinolone. The duration of treatment was initially scheduled for a minimum period of 12 months after sputum culture conversion. Thirty nine patients were enrolled, 23 of whom were treated for at least 12 months. Culture conversion was obtained at the end of the twelfth month in 14 out of 23 patients. Twenty one out of 39 patients experienced adverse events. These were, however, serious enough to discontinue treatment in only four patients. These results suggest that an antimycobacterial combination including rifabutin might contribute to the treatment of multi-resistant pulmonary tuberculosis.
Abstract: It is known that atrial natriuretic peptide (ANP) is synthesized, stored and released from the myocytes of mammalian heart, but the role of cardiac autonomic nerves in triggering the release of ANP has not been fully assessed. We have therefore measured plasma ANP concentrations in the right atrium and the main pulmonary artery, together with pulmonary haemodynamics in 10 heart transplant (HT) recipients who underwent graded submaximal bicycle exercise during right-heart catheterisation. Pulmonary arterial blood samples and haemodynamic measurements were obtained at rest, on peak of exercise, and after ten minutes of recovery. A radioreceptor of alpha-human ANP was used to measure ANP levels. Exercise significantly increased ANP levels in both the right atrium from 24 pM (resting values) to 48.5 pM, and the main pulmonary artery from 27.1 pM (resting values) to 58.4 pM. We conclude that HT recipients still retain the ability to increase ANP release in response to graded submaximal dynamic exercise, and that the mechanisms underlying ANP release depend on other factors than the integrity of cardiac innervation in man.
Abstract: Resistance to gas flow of an airway is a function of both airway smooth muscle tone and thickness of the airway wall internal to the outer ring of airway smooth muscle. Schematically, the increase in airway resistance caused by shortening of airway smooth muscle may be potentiated by a concomitant increase in airway wall thickness caused by vasodilation of the bronchial vessels and/or microvascular leakage. Conversely, bronchial vasoconstriction may limit to some extent the increase in resistance to gas flow caused by airway smooth muscle shortening and/or congestion and edema of the airway wall. Many endogenous paracrine mediators, putatively involved in asthma and bronchial hyperresponsiveness, have both bronchomotor and vascular effects. The overall effects on resistance to airflow of endogenous or exogenous agents depend not only upon pre-existing airway smooth muscle tone and pre-existing condition of bronchial vessels but also upon two factors that facilitate microvascular leakage, namely, inflammation of the airway wall and outflow pressure of the bronchial circulation, which is close to left atrial pressure.
Abstract: Endothelium-derived relaxing factors (EDRF) are paracrine vasodilator substances released by endothelial cells. There is compelling evidence to suggest that EDRF may play an important role in the modulation of vascular tone in the systemic circulation. However, the role of EDRF-mediated pulmonary relaxation in chronic lung disease is unknown. The authors have, therefore, investigated endothelium-dependent relaxation of isolated pulmonary arteries (PAs) obtained from 18 patients undergoing heart-lung transplantation for end-stage chronic hypoxic cor pulmonale (HCP). Control PAs were obtained from 10 patients, none of whom had evidence of HCP, and who underwent lobectomy for lung carcinoma. All vascular rings were studied immediately after lung excision. PA rings from control patients dose-dependently relaxed to cumulative doses of acetylcholine (ACh, 10(-10) to 10(-5) M), achieving a maximal relaxation of 73.2 +/- 4.4% from precontraction to phenylephrine. By contrast, PA rings from HCP patients achieved only 42.1 +/- 6.7% of maximal relaxation (p less than 0.01). Sodium nitroprusside (10(-4) M) relaxed all PA rings, with and without endothelium (carefully removed before study), obtained from both control and HCP patients. The endothelium-dependent maximal relaxation to ACh was positively related to pretransplant values of PaO2 (r = 0.59; p less than 0.01), but no relationship was found with either PaCO2 (r = -0.41) or FEV1 (r = -0.14). The authors conclude that pulmonary relaxation mediated by EDRF is impaired in human HCP and suggest that such impairment may be related to severity of the preexisting chronic hypoxemia.
Abstract: BACKGROUND. Endothelial cells release endothelium-derived relaxing factor (EDRF) in a variety of vascular beds, including the pulmonary circulation. However, the role of EDRF-mediated pulmonary-artery relaxation in chronic hypoxic lung disease is unknown. METHODS. We studied endothelium-dependent relaxation mediated by EDRF in vitro in pulmonary arteries that had been obtained from 22 patients undergoing heart-lung transplantation for end-stage chronic obstructive lung disease. Control pulmonary arteries were obtained from 15 patients undergoing lobectomy for lung carcinoma who did not have evidence of other chronic lung disease. The responses of all vascular rings (external diameter, 1.2 to 3.4 mm) to the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate were studied immediately after lung excision. RESULTS. Pulmonary arterial rings from the patients with chronic lung disease developed a greater tension (2.19 +/- 0.16 g) in response to phenylephrine (10(-6) M) than the rings from control patients (1.28 +/- 0.18 g, P less than 0.05). Inhibition of EDRF synthesis by treatment with NG-monomethyl-L-arginine (10(-4) M) eliminated this difference, increasing the tension in the rings from the controls (P less than 0.01) but not in those from the patients with chronic lung disease. Rings from control patients relaxed in response to cumulative doses (10(-10) to 10(-5) M) of acetylcholine (maximal relaxation, 81.3 +/- 3.9 percent) and adenosine diphosphate (maximal relaxation, 85.3 +/- 2.6 percent). By contrast, rings from patients with chronic obstructive lung disease achieved only 41.3 +/- 4.8 percent of maximal relaxation in response to acetylcholine (n = 32) and 49.4 +/- 5.5 percent in response to adenosine diphosphate (n = 24) (P less than 0.001, as compared with control rings). Rings from both the controls and the patients with chronic lung disease relaxed similarly in response to the endothelium-independent vasodilator sodium nitroprusside (10(-4) M). There was an inverse correlation between the degree of intimal thickening and the level of maximal relaxation of the rings from the patients with chronic lung disease (r = -0.60, P less than 0.001). Maximal relaxation was also related directly to the partial pressure of arterial oxygen before transplantation (r = 0.68, P less than 0.01) and inversely to the partial pressure of arterial carbon dioxide before transplantation (r = -0.55, P less than 0.01), but not to the forced expiratory volume in one second (r = 0.19, P not significant). CONCLUSIONS. Endothelium-dependent pulmonary-artery relaxation in vitro is impaired in arteries from patients with end-stage chronic obstructive lung disease. Such impairment may contribute to the development of pulmonary hypertension in chronic hypoxic lung disease.
Abstract: Endothelium-derived relaxing factor (EDRF) is probably identical to nitric oxide (NO) and is released by the vascular endothelium both in the basal unstimulated state and in response to a wide range of physical and chemical stimuli. Since it was first described 10 years ago, evidence is accumulating that it is an important modulator of vascular smooth muscle tone. EDRF acts on the pulmonary vascular bed as on the systemic circulation. EDRF release to pharmacologic stimuli is impaired in pulmonary arteries from patients with chronic hypoxemia. This impairment is associated with severity of respiratory failure and of structural change of vessel walls. Disturbance of EDRF activity may be important in the pathophysiology of pulmonary vascular disease. This brief review describes the current status of experimental studies concerning the possible role of EDRF on the pulmonary circulation in normal conditions and in the pathogenesis of pulmonary hypertension.
Abstract: The acute effects of inhaled nitric oxide (NO) (40 ppm in air) on pulmonary (PVR) and systemic (SVR) vascular resistance were compared with those of an intravenous infusion of prostacyclin (24 micrograms/h) in 8 patients with severe pulmonary hypertension and 10 cardiac patients with normal values of PVR. 10 healthy volunteers were studied non-invasively. In the patients with pulmonary hypertension, PVR fell significantly after inhaled NO and after prostacyclin. PVR also fell significantly in the cardiac patients after inhaled NO. Although SVR fell substantially after prostacyclin in patients with pulmonary hypertension, inhaled NO had no effect on SVR in any patient or volunteer. Inhaled NO therefore seems to be both a selective and effective pulmonary vasodilator.
Abstract: Pretreatment by inhalation with the alpha 1-adrenergic agonist methoxamine and the "loop" diuretic frusemide reduces the bronchial response to certain airway challenges in asthma. To test whether these drugs may act by altering airway epithelial ion and water transport, their effect on nasal potential difference (PD) when applied topically in eight normal volunteers was measured. For comparison, the effect of the Na(+)-channel blocking drug amiloride and the beta 2-adrenergic agonist salbutamol was also tested. Both methoxamine and frusemide significantly reduced PD: at the highest concentration given (10(-3) mol.l-1), there was a mean drop in PD from baseline of 39.5% following methoxamine treatment (p less than 0.05) and a mean drop of 30.2% following frusemide (p less than 0.05). Neither drug was as effective as amiloride, which caused a mean drop in PD of 27.5% from baseline at 10(-6) mol.l-1 and a drop of 71.6% at 10(-3) mol.l-1 (p less than 0.01 for each concentration). Salbutamol had no significant effect on PD (p greater than 0.05). We conclude that methoxamine and frusemide may derive their protective effect on some bronchial challenge, at least in part, from their effect on airway epithelial ion flux.
Abstract: Today heart-lung transplantation (HLT) probably provides the best means of studying the role of pulmonary innervation in human respiratory physiology. Outside the periods of postoperative complications ventilatory function, blood gases and exercise tolerance of HLT recipients are compatible with a normal sedentary life. Control of breathing in the waking state at rest, and when asleep, in HLT subject is not different from that of the healthy subject, which suggests that the pulmonary afferents play a negligible role in the control of breathing of adult humans at rest. The results of the ventilatory response to carbon dioxide and to exercise in HLT subjects are contradictory and do not enable any conclusion about the role of pulmonary innervation in these types of integrated responses. On the other hand, the existence of bronchial hyperreactivity to cholinergic stimulation is well established, and is attributed to an upregulation of bronchial muscarinic receptors. An increase in the bronchial response to distilled water observed in some HLT subjects seems on the other and related to episodes of lung rejection. The reflex theory of cough is supported by studies of HLT subjects. Results of studies of the effect of a deep inspiration on bronchomotor tone are far from concordant. Other studies including a large number of subjects and looking at the presence or the absence of reinnervation after transplantation are perhaps two supplementary means to further investigate the respiratory function of HLT patients. Knowledge of the latter would equally enable a better understanding of control mechanisms of human respiratory physiology.
Abstract: Primary pulmonary hypertension continues to present both diagnostic and therapeutic challenges to the physician, reflecting the lack of understanding about the basic mechanism of the disease. The natural history of the condition has been described only recently, and this has allowed a reasonably accurate prognosis for the individual patient to be determined. New treatments have been found effective, including heart-lung transplantation, which can now offer improved survival. Long-term intravenous infusion of prostacyclin has a place in the treatment of severely affected patients awaiting heart-lung transplantation. However, the major impact of prostacyclin has been, perhaps, to concentrate research upon the role of the endothelial cell in the development of this disorder, in particular the potential role of an impairment of release of the recently described endothelium-derived relaxing factor in certain forms of pulmonary hypertension. We have attempted in this review to focus on the problems of diagnosis and treatment together with current developments in the understanding of primary pulmonary hypertension.
Abstract: Endothelium-dependent vasorelaxation mediated by endothelium-derived relaxing factors (EDRF) has been extensively studied in animals but only limited studies in man are available. Demonstration of EDRF-mediated dilatation of human vessels is fundamental for understanding the mechanisms of vascular diseases in man. We have investigated endothelium-dependent relaxation of isolated human pulmonary arteries. Vascular segments, taken from uninvolved regions of resected lung from eight patients undergoing lobectomy for lung carcinoma, were cut into rings. In rings precontracted with phenylephrine, both acetylcholine (ACh) and adenosine diphosphate (ADP) induced dose-dependent relaxation in the presence of endothelium but not when the endothelium had been carefully removed. The rings without endothelium relaxed completely with sodium nitroprusside, a vasodilator agent acting directly on vascular smooth muscle. Pre-incubation with indomethacin, a cyclo-oxygenase inhibitor which blocks production of prostacyclin, did not alter the vasorelaxant responses to ACh and ADP, suggesting that one (or several) non-prostanoid EDRF(s) are responsible for the endothelium-dependent relaxation of isolated human pulmonary arteries.
Abstract: We compared the effects of pretreatment of 800 micrograms of inhaled Smith Kline & French (SK&F) 104353, a leukotriene receptor antagonist, and 120 mg of oral terfenadine on the bronchial responses to inhaled histamine in 12 subjects with asthma. The study took place on 3 different days and was conducted according to a double-blind, crossover, double-dummy, randomized, and placebo-controlled design. There was no difference in baseline and prechallenge FEV1 after placebo, SK&F 104353, and terfenadine administration. The median ratio of the provocative dose causing a 20% fall in FEV1 from baseline (PD20) with terfenadine over PD20 with placebo was 12.36 (range, 3.2 to 30.3; p less than 0.01) and that of PD20 with SK&F 104353 over PD20 with placebo was 1.51 (range, 0.8 to 5.9; not significant). Analysis of individual results demonstrated a shift toward the right of the dose-response curves to histamine with SK&F 104353 compared to that with placebo in three subjects, whereas the active compound did not exhibit any protective effect against histamine in the remaining nine subjects. We conclude that there is a leukotriene component to the bronchial responses to histamine in some, but not all, subjects. This component remains, however, small and does not appear to be clinically important in the population of subjects with asthma that was studied.
Abstract: We studied changes in lung volumes and in bronchial response to methacholine chloride (MC) challenge when antishock trousers (AST) were inflated at venous occlusion pressure in healthy subjects in the standing posture, a maneuver known to shift blood toward lung vessels. On inflation of bladders isolated to lower limbs, lung volumes did not change but bronchial response to MC increased, as evidenced by a greater fall in the forced expiratory volume in 1 s (FEV1) at the highest dose of MC used compared with control without AST inflation (delta FEV1 = 0.94 +/- 0.40 vs. 0.66 +/- 0.46 liter, P less than 0.001). Full inflation of AST, i.e., lower limb and abdominal bladder inflated, significantly reduced vital capacity (P less than 0.001), functional residual capacity (P less than 0.01), and FEV1 (P less than 0.01) and enhanced the bronchial response to MC challenge compared with partial AST inflation (delta FEV1 = 1.28 +/- 0.47 liter, P less than 0.05). Because there was no significant reduction of lung volumes on partial AST inflation, the enhanced bronchial response to MC cannot be explained solely by changes in base-line lung volumes. An alternative explanation might be a congestion and/or edema of the airway wall on AST inflation. Therefore, to investigate further the mechanism of the increased bronchial response to MC, we pretreated the subjects with the inhaled alpha 1-adrenergic agonist methoxamine, which has both direct bronchoconstrictor and bronchial vasoconstrictor effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Twenty-one patients were studied at rest and during exercise after heart transplantation to compare cardiac output measured by thermodilution and impedance cardiography. Exercise was performed on a bicycle ergometer over a limited range of work load (25 and 50 watt) whilst metabolic gas exchange was recorded. One patient was studied at rest whilst his circulation was maintained by a Jarvik-7 artificial heart. The values of cardiac output measured by impedance cardiography corresponded closely with the flow rate from the artificial heart. There was also close agreement between the impedance and thermodilution measurements of cardiac output at rest and during exercise. Both measurements followed the changes in heart rate and oxygen consumption. Both thermodilution and impedance cardiography methods elicited good reproducibility of cardiac output measurements at rest and during exercise. These observations suggest that the noninvasive and continuous record of cardiac output obtained by impedance cardiography can be used for the postoperative monitoring of heart transplant recipients.
Abstract: There are two types of non-prostanoid endothelium-derived vasoactive factors, one which relaxes and the other which contracts the vascular smooth muscle (EDRF and EDCF). These factors are released in response to stimulation of specific membrane receptors of the vascular endothelium by a large number of agonist substances and in response to physical stimuli to the vascular wall. It has been shown that EDRF is nitric oxide (NO) and EDCF has recently been identified as a peptide composed of 21 amino acids called endothelin. Other compounds may also act as EDRF or EDCF. EDRF (NO) induces relaxation of the underlying vascular smooth muscle by increasing intracellular concentration of cyclic guanosine monophosphate. The mechanisms of action of endothelin have not yet been clearly defined. It would seem that they depend, at least partially, on influx of extracellular calcium. The recent discovery of endothelin and the increased knowledge of the mode of action of EDRF on vascular smooth muscle has led to the suggestion that, vasomotor tone in humans is probably the result of an equilibrium between these two factors, each of which play a fundamental role, and very likely interact with each other in maintaining and regulating vascular tone in man.
Abstract: Non prostanoid endothelium-derived relaxing and contracting factors (EDRF and EDCF, respectively) are released by endothelial cells and act on the underlying vascular smooth muscle. It is now established that EDRF is nitric oxide (NO), whereas EDCF has been recently identified as a 21 residue peptide, called endothelin. However, circumstantial evidence suggests that there may be more than one EDRF and/or EDCF. EDRF (NO) induces relaxation of the underlying vascular smooth muscle by enhancing intracellular level of cyclic guanosine monophosphate. The mechanisms of action of endothelin are still to be defined. It seems however that influx of extracellular calcium may partly account for its action. Although important findings have been made recently, most of the hypotheseses, at our current stage of knowledge, about the respective roles of EDRF and EDCF in disease have still to be proved. However, it is preferable from now to think in terms of balance (or imbalance) between these two factors which, probably, have both a fundamental role and very likely interact with each other in maintaining and regulating vascular tone in man.
Abstract: A comparison has been made between the endothelium-dependent relaxation of pulmonary arteries (PA) obtained at heart-lung transplantation from 4 patients with Eisenmenger's syndrome and secondary pulmonary hypertension, and PA obtained at lobectomy from 4 patients with lung carcinoma, the controls. All vascular rings were studied immediately after lung excision. PA rings from control patients dose-dependently relaxed to cumulative doses of acetylcholine (ACh, 10(-10) to 10(-5) M), achieving a maximal relaxation of 80 +/- 5% (mean +/- s.e. mean) from precontraction with phenylephrine. By contrast, PA rings from Eisenmenger's syndrome patients achieved a maximal relaxation of only 34 +/- 12% (P less than 0.05, unpaired t test), with even paradoxical contraction at high doses of ACh (10(-6) to 10(-5) M). Sodium nitroprusside (10(-4) M) relaxed all PA rings, with and without endothelium (carefully removed before study), obtained from both control and Eisenmenger's syndrome patients. These results provide the first evidence that endothelium-dependent relaxation of PA mediated by endothelium-derived relaxing factors is impaired in Eisenmenger's syndrome patients with secondary pulmonary hypertension.
Abstract: The clinical and serological findings on 24 patients with pulmonary hypertension (PHT) seen at the Lupus Clinic of St. Thomas' Hospital, London are presented. Twenty-two patients had systemic lupus erythematosus (SLE), one other a primary antiphospholipid syndrome and another an SLE/progressive systemic sclerosis (PSS) overlap syndrome. In 21 of the 24 patients, the disease resembled the primary idiopathic variety with clear lung fields and no clinical evidence of pulmonary thromboembolism, although angiography and nuclear perfusion scans were not performed. Two patients clearly suffered from thromboembolic PHT, one with SLE and one with an antiphospholipid syndrome. One patient with SLE/PSS overlap syndrome developed pulmonary fibrosis. The frequency of antiphospholipid antibodies (lupus anticoagulant and antibodies to cardiolipin was 68% which appears to be higher than generally found in patients with SLE, and the clinical significance of this finding is unknown. Other associated features of the antiphospholipid syndrome in this group were uncommon. Death occurred in 13 of the 24 patients, 4 were lost to followup and 7 are known to be alive. The cause of death was circulatory failure in the majority; sudden death once this complication occurred was particularly common. One patient died from adult respiratory distress syndrome and one from hemorrhagic shock while undergoing heart/lung transplantation. Two patients underwent successful heart/lung transplantation. One, however, died of a mesenteric occlusion and bowel infarction following a second lung transplantation because of rejection of the first heart/lung transplantation after one year. The other patient is alive and well 2 years later.
Abstract: Bronchial smooth muscle contraction is not the only causative factor of airway narrowing in asthma. Other components, such as mucosal and submucosal oedema and mucosal inflammation, also intervene in the processes leading to bronchial obstruction. Re-analyzing the role of the tracheo-bronchial circulation is therefore necessary, since participation of the latter, through modification of bronchial blood flow and/or alteration of microvascular permeability, very likely modifies mucosal thickness of the bronchial wall and/or clearance of bronchoactive substances from the airways. This also implies that more attention should be paid on the vascular actions of compounds which are either currently prescribed or under development for future treatment of asthma.
Abstract: The effects of inhaled terbutaline, a beta 2-adrenergic agonist, administered via a 750-ml spacer device were studied in young asthmatic subjects with exercise-induced asthma. A double-blind, randomized, placebo-controlled study of the effects of inhaled 0.5 mg terbutaline and placebo was conducted in 10 asthmatic children (age range 6-16 years) with documented exercise-induced asthma. Forced expiratory volume in 1 s (FEV1) was measured at baseline, 15 min after inhaling terbutaline or placebo, and at intervals up to 60 min after exercising. Subjects exercised using a cycle ergometer for 5 min at a submaximal, constant work-load while breathing dry air at room temperature. Terbutaline induced bronchodilation at rest in all subject and fully prevented exercise-induced asthma in nine out of the 10 subjects; the exercise-induced fall in FEV1 was markedly reduced in the remaining subject. It is concluded that exercise-induced asthma can be inhibited by pretreatment with inhaled terbutaline, administered via a spacer, in a majority of young asthmatics.
Abstract: Endothelium-derived relaxing factor (EDRF) and endothelium-derived contracting factor (EDCF) are released by endothelial cells following stimulation by a wide range of chemical agonists acting on specific endothelial membrane receptors and by physical factors such as shear stress on the vascular wall. It has now been firmly established that EDRF is nitric oxide, whereas EDCF has been recently identified as a 21-residue peptide, endothelin. Circumstantial evidence, however, suggests that there may be more than one EDRF and/or EDCF. EDRF induces relaxation of the underlying vascular smooth muscle by enhancing intracellular cyclic GMP levels. This action is comparable to that of nitrovasodilators, and nitric oxide can, therefore, be regarded as an endogenous nitrovasodilator. The mechanism of action of endothelin is uncertain, but depends on influx of extracellular calcium. The respective roles of EDRF and EDCF in disease are still hypothetical. It is preferable to think in terms of balance (or imbalance) between these two factors which, probably, have a fundamental role, and very likely interact with each other in maintaining and regulating vascular tone in man.
Abstract: The respective prevalence of hypertension and asthma is sufficient for their combined existence to be far from rare. The effects of certain antihypertensive drugs, e.g., alpha 2-adrenoceptor agonists, on the bronchi may be either harmful or beneficial. When inhaled, alpha 2-agonists reduce the immediate bronchial response to allergens, whereas when ingested they aggravate the bronchial response to histamine and all the more so when their effect on the central nervous system is greater. Therefore, there has been much interest in agents such as the new oxazoline derivative, rilmenidine, which has less central effects than clonidine, an imidazoline compound of reference. Calcium antagonists inhibit smooth muscle contraction and release of mast cell inflammatory mediators. In asthmatic subjects, their short-term administration leads to a modest improvement in spontaneous bronchial obstruction, has only a partial protective action against various nonspecific or allergenic stimuli, and slightly reinforces the beneficial effect of beta 2-agonists. Beta-adrenoceptor antagonists aggravate bronchial obstruction and nonspecific bronchial hyperreactivity in asthmatic subjects. These harmful effects are dose-dependent, have even been reported after the administration of eyedrops, and are common to all beta-blockers. Angiotensin-converting enzyme inhibitors increase bronchial hyperreactivity in patients who develop cough during treatment and may, in certain cases, worsen or even induce asthma, probably by opposing inactivation by hydrolysis of tachykinins and of bradykinins.
Abstract: The role of sulfidopeptide leukotrienes in asthma alone or in association with other mediators is still debated. Sulfidopeptide leukotrienes (s-LT) C4, D4 and E4 are 5-lipoxygenase derivatives of membrane arachidonic acid. All s-LT contract bronchial smooth muscle in vitro and provoke an acute bronchial obstruction in vivo in both healthy and asthmatic subjects. Numerous cells, including mast cells, alveolar macrophages, polynuclear basophils and eosinophils, are capable of secreting s-LT following such diverse stimuli as allergen exposure, platelet activating factor and calcium ionophore A 23187. In addition to constricting bronchial smooth muscle, s-LT promote the occurrence of mucosal oedema increase micro-vascular permeability in the bronchial wall, and cause hypersecretion of mucus by tracheo-bronchial glands. These effects lead to worsening of airways obstruction. s-LT increase non specific bronchial hyper-responsiveness. Clinical trials aiming to test the efficacy of new anti-leukotrienes are currently under way. In general these products have a real antagonistic effect on exogenous s-LT. Their efficacy vis-a-vis other types of stimulus such as allergens, histamine and exercise does not seem to be constant and depends largely on the composition and perhaps the route of administration (inhaled versus oral). The contribution of s-LT as part of the therapeutic arsenal for the long term treatment of asthma remains to be established.
Abstract: In order to assess the role of the bronchial circulation in the pathogenesis of exercise-induced asthma (EIA), we conducted a double-blind, randomized study of the effects of pretreatment with an inhaled alpha 1-adrenergic agonist, methoxamine (Mx), in nine asthmatic teenagers with known EIA. Exercise consisted of 5 min cycle ergometry at a submaximal, constant work-load, while the subjects breathed dry air at ambient temperature. Forced expiratory volume in one second (FEV1) was measured at baseline, 15 min after pretreatment of either Mx or saline, and serially after exercise. Mx significantly reduced the exercise-induced fall of FEV1 without modifying baseline FEV1 in five of the eight subjects, had little or no effect in three and caused an acute asthmatic attack in the remaining subject. Mx has potent constrictor effects on both bronchial and vascular smooth muscles through stimulation of postjunctional alpha 1-adrenoceptors. Therefore, the protective effect of Mx on EIA may be attributed to vasoconstriction of tracheobronchial vessels opposing the hyperaemia and mucosal airway oedema that may cause, at least in part, the exercise-induced acute bronchial obstruction in EIA. Alternatively, Mx stimulates mucus, water and electrolyte secretion by airway epithelium and may, therefore, oppose the dehydration of airway surface that could be a causative factor of EIA.
Abstract: The respective prevalence of arterial hypertension and of asthma is sufficient that their association is far from unusual. Antihypertensive medications may have deleterious or beneficial effects on the bronchi. Calcium inhibitors oppose the contraction of smooth muscle and the liberation of inflammatory mediators from mast cells. In asthmatics, their acute administration has a modest beneficial effect on spontaneous bronchial obstruction, only exerts a partial protective action against numerous non-specific or allergic stimuli, and weakly reinforces the beneficial effects of beta-2 agonists. The antagonists of beta-adrenergic receptors worsen bronchial obstruction and non-specific bronchial hyperreactivity in asthmatics. These deleterious effects increase with the dose and have been observed even after administration of eye drops and apply to all beta blockers. Inhibitors of angiotensin converting enzymes increase bronchial hyperreactivity in patients developing cough during treatment and may indeed, even in a few cases, trigger an asthmatic attack, probably by opposing the inactivation by hydrolysis of tachykinins and bradykinins. The effects of alpha-2 adrenergics are controversial. Inhaled, they reduce the early allergic bronchial response, even when ingested they aggravate the bronchial response to histamine, all the more so as their effect on the central nervous system is greater. The alpha-1 adrenergic antagonists, frusemide and ketanserin have an overall beneficial effect.
Abstract: We assessed the effect of dry air (DA) nasal breathing on nasal clearance rate in healthy nonsmoking subjects. We measured saccharin nasal transit time (SNTT), an index of mucociliary clearance rate, in eleven normal subjects (six males, five females) breathing either room air (RA) or DA through the nose in random order on six different study days. On each study day, the trial was conducted at the same time, in the same nostril, using a patent airway. DA was breathed through a light-weight, tight-fitting, nasal mask (SEFAM, France) for 30 min and SNTT was then measured immediately. Saccharin (250 micrograms) was deposited on the anterior part of the inferior turbinate under visual control and saliva was swallowed every 30 s thereafter. SNTT was the time elapsed between deposition and first perception of saccharin taste. The group-average SNTT on DA was 18.5 +/- 8.6 min which was significantly longer than on RA (11.9 +/- 5.3 min). Our findings suggest that dry air breathing results in excessive water loss by the nasal mucosa, which may in turn reduce nasal mucociliary clearance rate through changes in the rheological properties or adhesiveness of nasal mucus and/or slowing of ciliary beating.
Abstract: 1. The effects of pretreatment with clonidine and rilmenidine, a new alpha 2-adrenoceptor agonist, on the bronchial responses to inhaled histamine were studied on 3 different days in a controlled, double-blind, randomized study in 12 asymptomatic asthmatic subjects. Clonidine and rilmenidine were orally administered as single and equipotent doses of 150 micrograms and 1 mg, respectively. All the subjects were non-smokers with normal lung function tests (forced expiratory volume in one second (FEV1) = 97 +/- 10% predicted FEV1). 2. Histamine (first dose = 543 nmol) was delivered by a breath activated dosimeter (DeVilbiss no. 646 nebulizer) every 5 min; FEV1 was measured in triplicate after each dose and the largest value was analyse. The three dose-response curves were compared by analysis of variance. 3. Both clonidine and rilmenidine decreased arterial blood pressure in all subjects. There was no difference in baseline values and pre-challenge values of FEV1 after placebo, clonidine and rilmenidine on the 3 study days. Compared with placebo, both rilmenidine and clonidine significantly increased the bronchial responses to histamine (P less than 0.05 and P less than 0.01 respectively) an effect which was significantly more marked with clonidine than rilmenidine (P less than 0.05). 4. We suggest that the enhancement of bronchial responsiveness to histamine by clonidine and rilmenidine may result from their effects on both central and peripheral alpha 2-adrenoceptors, and that the lesser aggravation of histamine-induced bronchial obstruction in asthmatic subjects on rilmenidine might be explained by its lesser central and/or greater peripheral effects than clonidine.
Abstract: Our aim was to examine the effects of clonidine (C), an agonist of central and peripheral alpha-2 adrenoceptors, on bronchomotor responsiveness to histamine (H). In a double-blind study, we compared on two different days the effects of pretreatment with placebo (P) and with 200 micrograms or 150 micrograms of C given orally, in ten normal (NS) and eight asymptomatic asthmatic subjects (AS) respectively, the response to inhalation of serially increasing doses of H. On each day, five doubling doses of H (first dose = 3.5 and 1.1 mumol in NS and AS, respectively) were administered every 5 min; forced expiratory volume in one second (FEV1) was measured after each dose. The dose-response curves were compared by an analysis of variance. Clonidine caused hypotension with bradycardia in all subjects. Baseline values and pre-challenge values of FEV1 after P and C were identical on the two study days. Compared to P, C did not modify the response to H in NS but significantly increased it in AS (p less than 0.01). Our results suggest that the neural control of the airways differs in AS compared to NS and could be explained either by a decrease in sympathetic inhibitory activity or a greater responsiveness of the airways to parasympathetic stimulation and/or a higher parasympathetic tone in AS.
Abstract: Exercise-induced asthma only differs from common asthma in its causative factor. It is a typical asthmatic attack which follows a strenuous and continuous physical exercise lasting 5 to 10 minutes, most often in cold and dry weather. The prevalence of exercise-induced asthma has not yet been firmly established; its pathophysiological mechanisms are still debated, and the respective roles of heat and water losses by the airways are not clearly defined. However, the influence of the type of exercise as a precipitating factor of exercise-induced asthma is now well-known. All things being equal, swimming generates less asthma than running and cycling. This enables the subjects to be directed towards the most suitable sports and encouraged to improve their physical fitness. Drug treatment of exercise-induced asthma must preferentially be preventive; it relies on cromoglycate and beta-2 adrenergic agonists, the latter being also capable of treating acute exercise-induced bronchial obstruction. Education of the patients and their family is also important.
