Abstract: Increased levels of extracellular superoxide dismutase (ecSOD) induced by preconditioning or gene therapy protect the heart from ischemia/reperfusion injury. To elucidate the mechanism responsible for this action, we studied the effects of increased superoxide scavenging on nitric oxide (NO) bioavailability in a cardiac myocyte-specific ecSOD transgenic (Tg) mouse. Results indicated that ecSOD overexpression increased cardiac myocyte-specific ecSOD activity 27.5-fold. Transgenic ecSOD was localized to the sarcolemma and, notably, the cytoplasm of cardiac myocytes. Ischemia/reperfusion injury was attenuated in ecSOD Tg hearts, in which infarct size was decreased and LV functional recovery was improved. Using the ROS spin trap, DMPO, electron paramagnetic resonance (EPR) spectroscopy demonstrated a significant decrease in ROS in Tg hearts during the first 20 min of reperfusion. This decrease in ROS was accompanied by an increase in NO production determined by EPR using the NO spin trap, Fe-MGD. Attenuated ROS in ecSOD Tg myocytes was also supported by decreased production of peroxynitrite (ONOO(-)). Increased NO bioavailability was confirmed by attenuated guanylate cyclase-dependent (p-VASP) signaling. In conclusion, attenuation of ROS levels by cardiac-specific ecSOD overexpression increases NO bioavailability in response to ischemia/reperfusion and protects against reperfusion injury. These findings are the first to demonstrate increased NO bioavailability with attenuation of ROS by direct measurement of these reactive species (EPR, reactive fluorescent dyes) with cardiac-specific ecSOD expression. This is also the first indication that the predominantly extracellular SOD isoform is capable of cytosolic localization that affects myocardial intracellular signal transduction and function.
Abstract: Nerve stimulation and ultrasound have been introduced to the practice of regional anesthesia mostly in the last two decades. Ultrasound did not gain as much popularity as the nerve stimulation until a decade ago because of the simplicity, accuracy and portability of the nerve stimulator. Ultrasound is now available in most academic centers practicing regional anesthesia and is a popular tool amongst trainees for performance of nerve blocks. This review article specifically discusses the role of ultrasonography for deeply situated nerves or plexuses such as the infraclavicular block for the upper extremity and lumbar plexus and sciatic nerve blocks for the lower extremity. Transitioning from nerve stimulation to ultrasound-guided blocks alone or in combination is beneficial in certain scenarios. However, not every patient undergoing regional anesthesia technique benefits from the use of ultrasound, especially when circumstances resulting in difficult visualization such as deep nerve blocks and/or block performed by inexperienced ultrasonographers. The use of ultrasound does not replace experience and knowledge of relevant anatomy, especially for visualization of deep structures. In certain scenarios, ultrasound may not offer additional value and substantial amount of time may be spent trying to find relevant structures or even provide a false sense of security, especially to an inexperienced operator. We look at available literature on the role of ultrasound for the performance of deep peripheral nerve blocks and its benefits.
Abstract: BACKGROUND: Adenosine is a soporific neuromodulator; aminophylline, which is clinically used as a bronchodilator, antagonizes the action of adenosine in the central nervous system. Thus, we tested the hypothesis that aminophylline delays loss of consciousness (LOC) and speeds recovery of consciousness (ROC) with propofol anesthesia, and that aminophylline increases the minimum alveolar concentration (MAC) of desflurane. METHODS: In this double-blind crossover study, volunteers were randomized to either aminophylline or saline on different days. Aminophylline 6 mg/kg was given IV, followed by 1.5 mg x kg(-1) x h(-1) throughout the study day. After 1 h of aminophylline or saline administration, propofol 200 mg was given at a rate of 20 mg/min. The bispectral index was continuously monitored, as were times to LOC and ROC. After recovery from propofol, general anesthesia was induced with sevoflurane and subsequently maintained with desflurane. The Dixon "up-and-down" method was used to determine MAC in each volunteer after repeated tetanic electrical stimulation. RESULTS: Eight volunteers completed both study days. Time to LOC was prolonged by aminophylline compared with saline (mean +/- SD) (7.7 +/- 2.03 min vs 5.1 +/- 0.75 s, respectively, P = 0.011). The total propofol dose at LOC was larger with aminophylline (2.2 +/- 0.9 vs 1.4 +/- 0.4 mg/kg, P = 0.01), and the time to ROC was shorter (6.18 +/- 3.96 vs 12.2 +/- 4.73 min, P = 0.035). The minimum bispectral index was greater with aminophylline (51 +/- 15 vs 38 +/- 9, P = 0.034). There was no difference in MAC. CONCLUSION: Aminophylline decreases the sedative effects of propofol but does not affect MAC of desflurane as determined by tetanic electrical stimulation.
Abstract: BACKGROUND: Inducible nitric oxide synthase (iNOS) is an obligatory mediator of the late phase of ischemic preconditioning, but the mechanisms of its cardioprotective actions are unknown. In addition, it remains unclear whether sustained elevation of iNOS in myocytes provides chronic protection against ischemia/reperfusion injury. METHODS AND RESULTS: Constitutive overexpression of iNOS in transgenic mice (alpha-myosin heavy chain promoter) did not induce contractile dysfunction and did not affect mitochondrial respiration or biogenesis, but it profoundly decreased infarct size in mice subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion. In comparison with wild-type hearts, isolated iNOS-transgenic hearts subjected to ischemia for 30 minutes followed by 40 minutes of reperfusion displayed better contractile recovery, smaller infarct size, and less mitochondrial entrapment of 2-deoxy-[(3)H]-glucose. Reperfusion-induced loss of NAD(+) and mitochondrial release of cytochrome c were attenuated in iNOS-transgenic hearts, indicating reduced mitochondrial permeability transition. The NO donor NOC-22 prevented permeability transition in isolated mitochondria, and mitochondrial permeability transition-induced NAD(+) loss was decreased in wild-type but not iNOS-null mice treated with the NO donor diethylene triamine/NO 24 hours before ischemia and reperfusion ex vivo. iNOS-mediated cardioprotection was not abolished by atractyloside. Reperfusion-induced production of oxygen-derived free radicals (measured by electron paramagnetic resonance spectroscopy) was attenuated in iNOS-transgenic hearts and was increased in wild-type hearts treated with the mitochondrial permeability transition inhibitor cyclosporin A. CONCLUSIONS: Cardiomyocyte-restricted expression of iNOS provides sustained cardioprotection. This cardioprotection is associated with a decrease in reperfusion-induced oxygen radicals and inhibition of mitochondrial swelling and permeability transition.
Abstract: BACKGROUND AND OBJECTIVE: Whereas the protective effect of anaesthetic and ischaemic preconditioning has been described for several organs, it is uncertain whether this mechanism is also effective in the kidney. We compared the effect of preconditioning with sevoflurane and preconditioning with short episodes of ischaemia on renal ischaemia/reperfusion injury in the rat in vivo. METHODS: Fourteen days after right-sided nephrectomy, anaesthetized male Wistar rats were randomly assigned to a sham-operated group (no arterial occlusion, n = 5) or underwent 45 min of left renal artery occlusion (control group, n = 9) followed by 3 days of reperfusion. Two further experimental groups of animals were preconditioned prior to ischaemia either by administering 1 MAC sevoflurane for 15 min followed by 10 min of washout (sevoflurane group, n = 10) or by subjecting the animals to three short episodes of renal ischaemia (ischaemia-preconditioned group, n = 8). Blood creatinine was measured during reperfusion and morphological damage was assessed by histological examination. RESULTS: Baseline creatinine values were similar in all four groups (0.7 +/- 0.2 mg dL-1; mean +/- SD) and remained unchanged in the sham-operated animals after 3 days (0.8 +/- 0.2 mg dL-1). Creatinine levels increased in the ischaemic preconditioning group (3.3 +/- 1.2 mg dL-1) and sevoflurane preconditioning group (4.0 +/- 1.1 mg dL-1) compared to the control group (1.6 +/- 0.6 mg dL-1). Morphological damage was less severe in the control group, i.e. in animals without preconditioning, than in both preconditioning groups. CONCLUSION: Neither sevoflurane nor ischaemic preconditioning preserves renal function or attenuates cell damage in the rat in vivo.
Abstract: PURPOSE: Frequency potentiation is the increase in force of contraction induced by an increased heart rate (HR). This positive staircase phenomenon has been attributed to changes in Ca2+ entry and loading of intracellular Ca2+ stores. Volatile anesthetics interfere with Ca2+ homeostasis of cardiomyocytes. We hypothesized that frequency potentiation is altered by volatile anesthetics and investigated the influence of halothane (H), sevoflurane (S) and desflurane (D) on the positive staircase phenomenon in dogs in vivo. METHODS: Dogs were chronically instrumented for measurement of left ventricular (LV) pressure and cardiac output. Heart rate was increased by atrial pacing from 120 to 220 beats x min(-1) and the LV maximal rate of pressure increase (dP/dt(max)) was determined as an index of myocardial performance. Measurements were performed in conscious dogs and during anesthesia with 1.0 minimal alveolar concentrations of each of the three inhaled anesthetics. RESULTS: Increasing HR from 120 to 220 beats x min(-1) increased dP/dt(max) from 3394 +/- 786 (mean +/- SD) to 3798 +/- 810 mmHg sec(-1) in conscious dogs. All anesthetics reduced dP/dt(max) during baseline (at 120 beats x min(-1): H, 1745 +/- 340 mmHg x sec(-1); S, 1882 +/- 418; D, 1928 +/- 454, all P < 0.05 vs awake) but did not influence the frequency potentiation of dP/dt(max) (at 220 beats x min(-1): H, 1981 +/- 587 mmHg x sec(-1); S, 2187 +/- 787; D, 2307 +/- 691). The slope of the regression line correlating dP/dt(max) and HR was not different between awake and anesthetized dogs. Increasing HR did not influence cardiac output in awake or anesthetized dogs. CONCLUSION: These results indicate that volatile anesthetics do not alter the force-frequency relation in dogs in vivo.
Abstract: BACKGROUND: 'Anaesthetic post-conditioning', that is administration of anaesthetics during early reperfusion, is known to have positive effects on several organs. For the kidney, however, the effects of post-conditioning by volatile anaesthetics are not well researched. We examined renal function and morphology after post-conditioning by desflurane. METHODS: Anaesthetized rats were subjected to 30 or 45 min of renal ischaemia 14 days after contralateral nephrectomy. Post-conditioning was achieved by administration of 1 MAC desflurane (6.7 vol%) for 15 min during early reperfusion (all groups n=8). Cystatin C (CyC), creatinine clearance (Cl(Cr)) and fractional sodium excretion (FE(Na)) were measured in the awake rats over 3 days. Cell damage was graded from 1 to 4 in histological sections. Functional variables [mean (SD)] were compared statistically by a one-way anova followed by Bonferroni's multiple comparison test and histological scores (median and range) by Kruskal-Wallis test followed by Dunn's multiple comparison test. RESULTS: Pre-ischaemia function did not differ between the groups, but was markedly reduced after ischaemia. After 30 min ischaemia, the area under the curve (AUC) for Cl(Cr) was smaller in the desflurane than in the control group [21.5 (5.0) vs 31.6 (5.1) ml min(-1) h, P<0.05]. After 45 min desflurane reduced the AUC compared with the control group for both CyC [15 (4) vs 21 (3) mg litre(-1) h] and FE(Na) [1054 (221) vs 1570 (572)% h, both P<0.05). Morphological differences were greater between the 30 min groups [control: 2.75 (2.0-3.5) vs desflurane: 1.5 (1.0-2.5); P<0.05] than between the 45 min groups [control: 3.5 (3.0-4.0) vs desflurane: 3.0 (1.5-4.0)]. CONCLUSION: Desflurane post-conditioning protects renal function and tissue. This protection was greater after the short episode than after the long episode of ischaemia.
Abstract: Increasing numbers of elderly patients with severe co-existing medical diseases undergo major surgery. With these patients there is also an accompanying risk of age-related cardiovascular complications such as life-threatening myocardial ischaemia. We present a patient who suffered a myocardial infarction after a hemicolectomy and suffered a cardiac arrest in the recovery room. The therapeutic options available (e.g. coronary artery bypass grafting, acute percutaneous coronary angioplasty and peri-operative thrombolysis) are discussed and the successful management of the case by coronary angioplasty and stent implantation is described.
Abstract: BACKGROUND AND OBJECTIVES: Salt-water aspiration results in pulmonary oedema and hypoxia. We tested the hypothesis that partial liquid ventilation has beneficial effects on gas exchange and rate of survival in acute and extended salt water-induced lung injury. METHODS: Anaesthetized, ventilated rats (tidal volume 6 mL kg(-1), PEEP 5 cmH2O) received a tracheal salt-water instillation (3%, 8 mL kg(-1) body weight) and were randomly assigned to three groups (n = 10 per group). While lungs of Group 1 were gas-ventilated, lungs of Group 2 received a single perfluorocarbon instillation (30 min after the injury, 5 mL kg(-1) perfluorocarbon) and lungs of Group 3 received an additional continuous perfluorocarbon application into the treachea (5 mL kg(-1) h(-1)) Arterial blood gases were measured with an intravascular blood gas sensor. RESULTS: Salt-water instillation resulted in a marked decrease in PaO2 values within 30 min (from 432 +/- 65 to 83 +/- 40 mmHg, FiO2 = 1.0, P < 0.01). Arterial oxygenation improved in all three groups irrespective of treatment. We observed no significant differences between groups in peak PaO2 and PaCO2 values. CONCLUSIONS: Our results suggest that partial liquid ventilation has no additional beneficial effects on gas exchange after life-threatening salt water-induced lung injury when compared to conventional gas ventilation with positive end-expiratory pressure.
Abstract: BACKGROUND: Volatile anaesthetics precondition the heart against infarction, an effect partly mediated by activation of the epsilon isoform of protein kinase C (PKCepsilon). We investigated whether cardioprotection by activation of PKCepsilon depends on the isoflurane concentration. METHODS: Anaesthetized rats underwent 25 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups (n=10 in each group): isoflurane preconditioning induced by 15 min administration of 0.4 minimal alveolar concentration (MAC) (0.4MAC), 1 MAC (1MAC) or 1.75 MAC (1.75MAC) followed by 10 min washout before ischaemia. Each protocol was repeated in the presence of the PKC inhibitor staurosporine (10 microg kg(-1)): 0.4MAC+S, 1MAC+S and 1.75MAC+S. Controls were untreated (CON) and additional hearts received staurosporine without isoflurane (S). In a second set of experiments (n=6 in each group) hearts were excised before the infarct inducing ischaemia, and phosphorylation and translocation of PKCepsilon were determined by western blot analysis. RESULTS: Isoflurane reduced infarct size from a mean of 61(SEM 2)% of the area at risk in controls to 20(1)% (0.4MAC), 26(3)% (1MAC) and 30(1)% (1.75MAC) (all P<0.01 vs CON or S). This protection was partially reversed by administration of staurosporine in the 0.4MAC+S group (30[2]%; P<0.05 vs 0.4MAC) group, but not after administration of 1 MAC or 1.75 MAC isoflurane (26[2]% and 31[2]%, respectively). Thus 0.4MAC increased PKCepsilon phosphorylation, and this effect was blocked by staurosporine. Higher concentrations of isoflurane did not change PKCepsilon phosphorylation. PKCepsilon was translocated to the membrane fraction after administration of 0.4 MAC isoflurane, but not after 1.0 or 1.75 MAC. CONCLUSIONS: Although isoflurane preconditioning resulted in a reduction in infarct size at all concentrations used, the protection was mediated by phosphorylation and translocation of PKCepsilon only at 0.4 MAC.
Abstract: Volatile anesthetics induce myocardial preconditioning and can also protect the heart when given at the onset of reperfusion-a practice recently termed "postconditioning." We investigated the role of mitochondrial KATP (mKATP)-channels in sevoflurane-induced cardioprotection for both preconditioning and postconditioning alone and whether there is a synergistic effect of both. Rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Infarct size was determined by triphenyltetrazolium staining. The following protocols were used: 1) preconditioning (S-Pre, n = 10, achieved by 2 periods of 5 min sevoflurane administration (1 MAC) followed by 10 min of washout); 2) sevoflurane postconditioning (1 MAC of sevoflurane given for 2 min at the beginning of reperfusion; S-Post, n = 10); 3) administration before and after ischemia (S-Pre + S-Post, n = 10). Protocols 1-3 were repeated in the presence of 5-hydroxydecanoate (5HD), a specific mKATP-channel-blocker (S-Pre + S-Post + 5HD, S-Pre + 5HD: n = 10; S-Post + 5HD: n = 9). Nine rats served as untreated controls (CON) or received 5HD alone (5HD, n = 10). Both S-Pre (23% +/- 13% of the area at risk, mean +/- sd) and S-Post (18% +/- 5%) reduced infarct size compared with CON (49% +/- 11%, both P < 0.05). S-Pre + S-Post resulted in a larger reduction of infarct size (12% +/- 5%, P = 0.054 versus S-Pre) compared with administration before or after ischemia alone. 5HD diminished the protection in all three sevoflurane treated groups (S-Pre + 5HD, 35% +/- 12%; S-Post + 5HD, 44% +/- 12%; S-Pre + S-Post + 5HD, 46% +/- 14%;) but given alone had no effect on infarct size (41% +/- 13%). Sevoflurane preconditioning and postconditioning protects against myocardial ischemia-reperfusion injury. The combination of preconditioning and postconditioning provides additive cardioprotection and is mediated, at least in part, by mKATP-channels.
Abstract: Delta1-opioid receptor agonists can induce cardioprotection by early and late preconditioning (LPC). Morphine (MO) is commonly used for pain treatment during acute coronary syndromes. We investigated whether MO can induce myocardial protection by LPC and whether a nuclear transcription factor kappaB (NF-kappaB)-dependent intracellular signaling pathway is involved. Rats were subjected to 25 min of regional ischemia and 2 h of reperfusion 24 h after treatment with saline (NaCl; 0.9% 5 mL), lipopolysaccharide of Escherichia coli (LPS; 1 mg/kg), or MO (3 mg/kg). LPS is a trigger of LPC and served as positive control. Naloxone (NAL) was used to investigate the role of opioid receptors in LPC and was given before NaCl, LPS, or MO application (trigger phase) or before ischemia-reperfusion (mediator phase). Infarct size (percentage area at risk) was 59% +/- 9%, 51% +/- 6%, or 53% +/- 10% in the NaCl, NAL-NaCl, and NaCl-NAL groups, respectively. Pretreatment with MO reduced infarct size to 20% +/- 6% after 24 h (MO-24h), and this effect was abolished by NAL in the trigger (NAL-MO, 53% +/- 14%) and in the mediator (MO-NAL, 60% +/- 8%) phases. Pretreatment with LPS reduced infarct size to 23% +/- 8%. NAL administration in the trigger phase had no effect on infarct size (NAL-LPS 30% +/- 16%), whereas NAL during the mediator phase of LPC abolished the LPS-induced cardioprotection (LPS-NAL 54% +/- 8%). The role of NF-kappaB in morphine-induced LPC was investigated by Western blot and electrophoretic mobility shift assay. Morphine and LPS treatment increased phosphorylation of the inhibitory protein kappaB, leading to an increased activity of NF-kappaB. Thus, MO induces LPC similarly to LPS and it is likely that this cardioprotection is mediated at least in part by activation of NF-kappaB. Opioid receptors are involved as mediators in both MO- and LPS-induced LPC but as triggers only in MO-induced LPC. IMPLICATIONS: Like lipopolysaccharide, morphine induces late preconditioning and activation of nuclear transcription factor-kappaB. Opioid receptors are involved as mediators in both morphine- and lipopolysaccharide-induced late preconditioning but as triggers only in morphine-induced late preconditioning.
Abstract: Xenon is an anesthetic with minimal hemodynamic side effects, making it an ideal agent for cardiocompromised patients. We investigated if xenon induces pharmacological preconditioning (PC) of the rat heart and elucidated the underlying molecular mechanisms. For infarct size measurements, anesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Rats received either the anesthetic gas xenon, the volatile anesthetic isoflurane or as positive control ischemic preconditioning (IPC) during three 5-min periods before 25-min ischemia. Control animals remained untreated for 45 min. To investigate the involvement of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK), rats were pretreated with the PKC inhibitor calphostin C (0.1 mg kg(-1)) or the p38 MAPK inhibitor SB203580 (1 mg kg(-1)). Additional hearts were excised for Western blot and immunohistochemistry. Infarct size was reduced from 50.9+/-16.7% in controls to 28.1+/-10.3% in xenon, 28.6+/-9.9% in isoflurane and to 28.5+/-5.4% in IPC hearts. Both, calphostin C and SB203580, abolished the observed cardioprotection after xenon and isoflurane administration but not after IPC. Immunofluorescence staining and Western blot assay revealed an increased phosphorylation and translocation of PKC-epsilon in xenon treated hearts. This effect could be blocked by calphostin C but not by SB203580. Moreover, the phosphorylation of p38 MAPK was induced by xenon and this effect was blocked by calphostin C. In summary, we demonstrate that xenon induces cardioprotection by PC and that activation of PKC-epsilon and its downstream target p38 MAPK are central molecular mechanisms involved. Thus, the results of the present study may contribute to elucidate the beneficial cardioprotective effects of this anesthetic gas.
Abstract: Studies on lung injury and its treatment options are often performed on small animals like rats. Because conventional blood gas analyses may not detect rapid changes in gas exchange during respiratory distress syndrome and intermittent blood withdrawal can result in hypo-volaemia and anaemia, we tested the applicability and accuracy of a continuous intravascular blood gas monitor (Paratrend 7+). Anaesthetized and ventilated rats with a body weight of 398 +/-45 g (n =22) had a 20-gauge cannula inserted in both carotid arteries. A photochemical blood gas sensor for continuous measurement (Paratrend 7+) was advanced into the aorta via the left carotid artery. Blood was sampled for intermittent blood gas analysis by means of the right carotid artery. Arterial pO(2) was varied by applying different inspiratory oxygen concentrations, and arterial pCO(2) by applying different respiratory rates. Paired blood gas measurements (n =136) were analysed over a wide range of pO(2) values (5.3-76.8 kPa). We found an acceptable correlation for pO(2) (r(2)=0.98), pCO(2) (r(2)=0.96) and pH (r(2)=0.92). The calculated bias and imprecision for pO(2) was -1.0 +/- 3.3 kPa, for pCO(2) 0.04 +/- 0.28 kPa and for hydrogen ion concentration -0.05 +/-2.2 nmol/l. We conclude that in rats, continuous blood gas monitoring with a photochemical blood gas sensor provides pO(2), pCO(2) and pH measurements with acceptable accuracy.
Abstract: BACKGROUND: Lidocaine is frequently used as an agent to treat ventricular arrhythmias associated with acute myocardial ischaemia. Lidocaine is a potent blocker not only of sodium channels, but also of ATP-sensitive potassium channels. The opening of these channels is a key mechanism of ischaemic preconditioning. We investigated the hypothesis that lidocaine blocks the cardioprotection induced by ischaemic preconditioning. METHODS: Isolated rat hearts (n=60) were subjected to 30 min of no-flow ischaemia and 60 min of reperfusion. Control hearts (CON) underwent no further intervention. Preconditioned hearts (PC) received two 5-min periods of ischaemia separated by 10 min of reflow before the 30 min ischaemia. In three groups, lidocaine was infused at concentrations of 2, 10 or 20 microg ml(-1) for 5 min before the preconditioning ischaemia. Left ventricular developed pressure (LVDP) and infarct size (IS) (triphenyltetrazolium choride staining) were measured as variables of ventricular function and cellular injury, respectively. RESULTS: PC reduced IS from 24.8 (sem 4.1) % to 4.0 (0.7) % of the area at risk (P<0.05). Adding 2 or 10 microg ml(-1) lidocaine had no effect on IS compared with PC alone (3.7 (0.7) %, 6.9 (1.8) %). Adding 20 microg ml(-1) lidocaine increased IS to 14.1 (2.5) % compared with PC (P<0.05). Baseline LVDP was similar in all groups (111.4 (2.1) mm Hg). Compared with CON, PC improved functional recovery (after 60 min of reperfusion; 52.3 (5.9) mm Hg vs 16.0 (4.0) mm Hg, P<0.01). The improved ventricular function was not influenced by addition of 2 or 10 microg ml(-1) lidocaine (47.3 (5.7) mm Hg, not significant; 45.3 (7.3) mm Hg, not significant), but was blocked by the infusion of 20 microg ml(-1) lidocaine (22.5 (8.0) mm Hg, P<0.01 vs PC). CONCLUSIONS: Lidocaine blocks the cardioprotection induced by ischaemic preconditioning only at supratherapeutic concentrations.
Abstract: OBJECTIVE: Partial liquid ventilation can improve respiratory functions in acid-induced lung injury. We studied the effects of the interval between induction of injury and initiation of partial liquid ventilation on survival, gas exchange, and pulmonary neutrophil accumulation. MATERIAL AND METHODS: Anesthetized rats were randomly assigned to one of five groups ( n = 6 per group). Group 1 served as the control group, in the other groups an extended lung injury was induced by intratracheal instillation of hydrochloric acid. Whereas lungs of group 2 were gas-ventilated, group 3 received an early partial liquid ventilation (5 min after acid instillation) and group 4 a delayed partial liquid ventilation (30 min after acid instillation, 5 ml/kg perfluorocarbon). Group 5 received an additional continuous perfluorocarbon application of 5 ml x kg(-1) x h(-1) (30 min after acid instillation). Blood gases were measured with an intravascular blood gas sensor. RESULTS: Acid instillation resulted in a marked decrease in PO(2)-values within 30 min (from 481+/-37 mmHg to 128+/-71 mmHg, FiO(2) 1.0). Survival rate of the study period (12 h) was higher with early partial liquid ventilation. We observed no differences between groups in peak PO(2)-values during treatment. Histopathological examination, however, showed less pulmonary neutrophil accumulation in lungs of the early partial liquid ventilation group when compared to the delayed partial liquid ventilation group. CONCLUSIONS: Our results suggest that early partial liquid ventilation increases survival after extended acid-induced lung injury. While effects on arterial oxygenation appear not to predict acute survival we observed less intrapulmonary neutrophil accumulation with early partial liquid ventilation.
Abstract: BACKGROUND: Activation of protein kinase C epsilon (PKC-epsilon) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) are important for cardioprotection by preconditioning. The present study investigated the time dependency of PKC-epsilon and ERK1/2 activation during desflurane-induced preconditioning in the rat heart. METHODS: Anesthetized rats were subjected to regional myocardial ischemia and reperfusion, and infarct size was measured by triphenyltetrazoliumchloride staining (percentage of area at risk). In three groups, desflurane-induced preconditioning was induced by two 5-min periods of desflurane inhalation (1 minimal alveolar concentration), interspersed with two 10-min periods of washout. Three groups did not undergo desflurane-induced preconditioning. The rats received 0.9% saline, the PKC blocker calphostin C, or the ERK1/2 inhibitor PD98059 with or without desflurane preconditioning (each group, n = 7). Additional hearts were excised at four different time points with or without PKC or ERK1/2 blockade: without further treatment, after the first or the second period of desflurane-induced preconditioning, or at the end of the last washout phase (each time point, n = 4). Phosphorylated cytosolic PKC-epsilon and ERK1/2, and membrane translocation of PKC-epsilon were determined by Western blot analysis (average light intensity). RESULTS: Desflurane significantly reduced infarct size from 57.2 +/- 4.7% in controls to 35.2 +/- 16.7% (desflurane-induced preconditioning, mean +/- SD, P < 0.05). Both calphostin C and PD98059 abolished this effect (58.8 +/- 13.2% and 64.2 +/- 15.4% respectively, both P < 0.05 versus desflurane-induced preconditioning). Cytosolic phosphorylated PKC-epsilon reached its maximum after the second desflurane-induced preconditioning and returned to baseline after the last washout period. Both calphostin C and PD98059 inhibited PKC-epsilon activation. ERK1/2 phosphorylation reached its maximum after the first desflurane-induced preconditioning and returned to baseline after the last washout period. Calphostin C had no effect on ERK1/2 phosphorylation. CONCLUSIONS: Both, PKC and ERK1/2 mediate desflurane-induced preconditioning. PKC-epsilon and ERK1/2 are both activated in a time dependent manner during desflurane-induced preconditioning, but ERK1/2 activation during desflurane-induced preconditioning is not PKC dependent. Moreover, ERK1/2 blockade abolished PKC-epsilon activation, suggesting ERK-dependent activation of PKC-epsilon during desflurane-induced preconditioning.
Abstract: BACKGROUND AND OBJECTIVE: The effects of desflurane and sevoflurane on the failing myocardium are still uncertain. We investigated the effects of different concentrations of sevoflurane, desflurane and halothane in dogs with pacing induced chronic heart failure. METHODS: Global (left ventricular pressure, left ventricular dP/dt, Konigsbergtransducer) and regional myocardial function (systolic segment length shortening, ultrasonic crystals) were measured in chronically instrumented dogs with tachycardia induced severe congestive heart failure. Measurements were performed in healthy dogs and after induction of heart failure in the awake state and during anaesthesia with 0.75, 1.0, 1.25 and 1.75 minimum alveolar concentration (MAC) of halothane, sevoflurane or desflurane. RESULTS: The anaesthetics reduced dP/dtmax in a dose-dependent manner in healthy dogs (dP/dtmax decreased to 43-53% of awake values at 1.75 MAC). Chronic rapid left ventricular pacing increased heart rate and left ventricular end-diastolic pressure and decreased mean arterial pressure, left ventricular systolic pressure and dP/dtmax. The reduction in contractility was similar in the failing myocardium (to 41-50% of awake values at 1.75 MAC). Segmental shortening was reduced during anaesthesia by 50-62% after pacing compared with 22-44% in normal hearts. While there were similar effects of the different anaesthetics on diastolic function in healthy dogs, after induction of heart failure a more pronounced increase of the time constant of isovolumic relaxation and a greater decrease of dP/dtmin was observed with sevoflurane than with desflurane, indicating a stronger depression of diastolic function. CONCLUSIONS: While the negative inotropic effects of sevoflurane and desflurane were similar in normal and in the failing myocardium in vivo, desflurane led to a better preservation of diastolic function in the failing myocardium.
Abstract: PURPOSE: Volatile anesthetics can protect the heart against reperfusion injury. When sevoflurane is given for the first 15 min of reperfusion, a concentration corresponding to one minimum alveolar concentration (MAC) provides a maximum protective effect. The present study addresses the question of how long sevoflurane has to be administered to achieve the best cardioprotection. METHODS: Chloralose anesthetized rats were subjected to a 25-min occlusion of a major coronary artery, followed by 90 min of reperfusion. During the initial phase of reperfusion, an end-tidal concentration of 2.4 vol.% of sevoflurane (1 MAC) was given for two (n = 8), five (n = 8) or ten minutes (n = 7). Seven rats served as untreated controls. We measured left ventricular (LV) pressure, mean aortic pressure and infarct size (triphenyltetrazolium staining). RESULTS: Administration of sevoflurane for two minutes resulted in the greatest reduction of infarct size to 15% (8-22 [mean (95% confidence interval)] of the area at risk compared with controls [51 (47-55) %, P < 0.001]. Five or ten minutes of sevoflurane administration reduced infarct size to 26 (18-34) and 26 (18-35) % [P < 0.05], respectively. The cardiodepressant effect of sevoflurane varied with the duration of its administration: LV dP/dt was reduced from 6332 mmHg x sec(-1) (5771-6894) during baseline to 4211 mmHg x sec(-1) (3031-5391), 3811 mmHg x sec(-1) (2081-5540) and 3612 mmHg x sec(-1) (2864-4359) after two, five and ten minutes of reperfusion, respectively. CONCLUSION: Administration of 1 MAC sevoflurane for the first two minutes of reperfusion effectively protects the heart against reperfusion injury in rats in vivo. A longer administration time had lesser cardioprotective effects in this experimental model.
Abstract: Volatile anaesthetics protect the heart against reperfusion injury. We investigated whether the cardioprotection induced by sevoflurane against myocardial reperfusion injury was concentration-dependent. Fifty-eight alpha-chloralose anaesthetized rats were subjected to 25 min of coronary artery occlusion followed by 90 min of reperfusion. Sevoflurane was administered for the first 15 min of reperfusion at concentrations corresponding to 0.75 (n=11), 1.0 (n=11), 1.5 (n=13), or 2.0 MAC (n=12). Eleven rats served as untreated controls. Left ventricular peak systolic pressure (LVPSP, tipmanometer) and cardiac output (CO, flowprobe) was measured. Infarct size (IS, triphenyltetrazolium staining) was determined as percentage of the area at risk. Baseline LVPSP was 131 (126-135) mm Hg (mean (95% confidence interval)) and CO 33 (31-36) ml min(-1), similar in all groups. During early reperfusion, sevoflurane reduced LVPSP in a concentration-dependent manner to 78 (67-89)% of baseline at 0.75 MAC (not significant vs controls 99 (86-112)%), 71 (62-80)% at 1 MAC (P<0.05), 66 (49-83)% at 1.5 MAC (P<0.05) and 56 (47-65)% at 2 MAC (P<0.05). CO remained constant. While 0.75 MAC of sevoflurane had no effect on IS (34 (27-41)% of the area at risk) compared with controls (38 (31-45)%, P=0.83), 1.0 MAC reduced IS markedly to 23 (17-30)% (P<0.05). Increasing the concentration to 1.5 MAC (23 (17-30)%) and 2 MAC (23 (13-32)%, both P<0.05 vs controls) had no additional protective effect. One MAC sevoflurane protected against myocardial reperfusion injury. Increasing the sevoflurane concentration above 1 MAC resulted in no further protection.
Abstract: The aim of the present study was to investigate whether the non-peptide angiotensin II type 1 (AT1) receptor antagonist irbesartan (SR 47436, BMS 186295, 2-n-butyl-3 [2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-diaza-spiro [4,4]non-1-en-4-one) has myocardial protective effects during regional myocardial ischemia/reperfusion in vivo. Eighteen anesthetized open-chest dogs were instrumented for measurement of left ventricular and aortic pressure (tip manometer and pressure transducer, respectively), and coronary flow (ultrasonic flowprobes). Regional myocardial function was assessed by Doppler displacement transducers as systolic wall thickening (sWT) in the antero-apical and the postero-basal wall. The animals underwent 1 h of left anterior descending coronary artery (LAD) occlusion and subsequent reperfusion for 3 hours. Irbesartan (10 mg kg(-1), n = 9) or the vehicle (KOH, control, n = 9) was injected intravenously 30 min before LAD occlusion. Regional myocardial blood flow (RMBF) was measured after irbesartan injection and at 30 min LAD occlusion using colored microspheres. Infarct size was determined by triphenyltetrazolium chloride staining after 3 h of reperfusion. There was no recovery of sWT in the LAD perfused area in both groups at the end of the experiments (systolic bulging, -15.1+/-6.1% of baseline (irbesartan) vs. -12.3+/-3.0% (control), mean+/-SEM). Irbesartan led to an increase in RMBF in normal myocardium (2.47+/-0.40 vs. 1.35+/-0.28 ml min(-1) g(-1), p<0.05), and also to an increase in collateral blood flow to the ischemic area (0.27+/-0.04 vs. 0.17+/-0.02 ml min(-1) g(-1), P = <0.05). Infarct size (percent of area at risk) was 24.8+/-3.2 % in the treatment group compared with 26.9+/-4.8% in the control group (P = 0.72). These results indicate that a blockade of angiotensin II AT1 receptors with irbesartan before coronary artery occlusion led to an increase in RMBF, but did not result in a significant reduction of myocardial infarct size.
Abstract: Left stellate ganglion block (LSGB) results in acute sympathetic denervation of the left ventricular (LV) posterobasal wall. We investigated the effects of LSGB in chronically instrumented awake dogs before and after the induction of pacing-induced congestive heart failure. Twelve dogs were instrumented for measurement of global hemodynamics [LV pressure (LVP)], its first derivative (dP/dt), cardiac output (CO), and regional myocardial function (systolic posterobasal segment length shortening, mean velocity [SLmv]). Before the induction of heart failure (n = 12), LSGB did not affect CO [3.2+/-1.4 (control, mean +/- SD) vs. 3.3+/-1.6 L/min (LSGB, P = 0.45)] and SLmv (11.1+/-4.0 vs. 10.8+/-4.0 mm/s, P = 0.16), but slightly reduced LVP (130+/-12 vs. 125+/-14 mm Hg, P = 0.04), dP/dt(max) (3614+/-755 vs. 3259+/-644 mm Hg/s, P = 0.003) and dP/dt(min) (-3153+/-663 vs. -2970+/-725 mm Hg/s, P = 0.03). During heart failure (n = 8), global hemodynamics [CO (2.8+/-1.2 vs. 2.7+/-1.2 L/min, P = 0.04), LVP (119+/-6 vs. 112+/-9 mm Hg, P = 0.01), dP/dt(max) (1945+/-520 vs. 1824+/-554 mm Hg/s, P = 0.03) and dP/dt(min) (-2402+/-678 vs. -2243+/-683 mm Hg/s, P = 0.04)], as well as regional myocardial function, were significantly different after LSGB [SLmv] (8.0+/-3.8 vs. 6.9+/-3.4 mm/s, P = 0.02)]. In conclusion, even during heart failure, the hemodynamic changes after LSGB are small, confirming its broad margin of safety.
Abstract: A prolongation of the intracellular acidosis after myocardial ischemia can protect the myocardium against reperfusion injury. In isolated hearts, this was achieved by prolongation of the extracellular acidosis. The aim of this study was to investigate whether regional reperfusion with acidotic blood after coronary artery occlusion can reduce infarct size and improve myocardial function in vivo. Anesthetized open-chest dogs were instrumented for measurement of regional myocardial function, assessed by sonomicrometry as systolic wall thickening (sWT). Infarct size was determined by triphenyltetrazolium staining after 3 h of reperfusion. The left anterior descending coronary artery (LAD) was perfused through a bypass from the left carotid artery. The animals underwent 1 h of LAD occlusion and subsequent bypass-reperfusion with normal blood (control, n = 6) or blood equilibrated to pH = 6.8 by using 0.1 mM HCl during the first 30 min of reperfusion (HCl, n = 5). Regional collateral blood flow (RCBF) at 30-min occlusion was measured by using colored microspheres. There was no difference in recovery of sWT in the LAD-perfused area between the two groups at the end of the experiments [-2.8+/-1.2% (HCl) vs. -4.4+/-2.5% (control); mean +/- SEM; p = NS]. RCBF was comparable in both groups. Infarct size (percentage of area at risk) was reduced in the treatment group (12.8+/-2.8%) compared with the control group (26.2+/-4.8%; p < 0.05). These results indicate that reperfusion injury after coronary artery occlusion can be reduced by a prolonged local extracellular acidosis in vivo.
Abstract: It is known that volatile anaesthetics protect myocardial tissue against ischaemic and reperfusion injury in vitro. In this investigation, we have determined the effects of the inhalation anaesthetics, enflurane, isoflurane, sevoflurane and desflurane, administered only during early reperfusion, on myocardial reperfusion injury in vivo. Fifty chloralose-anaesthetized rabbits were subjected to 30 min of occlusion of a major coronary artery followed by 120 min of reperfusion. Left ventricular pressure (LVP, tip-manometer), cardiac output (CO, ultrasonic flow probe) and infarct size (triphenyltetrazolium staining) were determined. During the first 15 min of reperfusion, five groups of 10 rabbits each received 1 MAC of enflurane (enflurane group), isoflurane (isoflurane group), sevoflurane (sevoflurane group) or desflurane (desflurane group), and 10 rabbits served as untreated controls (control group). Haemodynamic baseline values were similar between groups (mean LVP 106 (SEM 2) mm Hg; CO 281(7) ml min-1). During coronary occlusion, LVP and CO were reduced to the same extent in all groups (LVP 89% of baseline; CO 89%). Administration of inhalation anaesthetics during early reperfusion further reduced both variables, but they recovered after discontinuation of the anaesthetics to values not different from control animals. Infarct size was reduced from 49 (5)% of the area at risk in the control group to 32 (3)% in the desflurane group (P = 0.021), and to 36 (2)% in the sevoflurane group (P = 0.097). In the enflurane group, infarct size was 39 (5)% (P = 0.272). Isoflurane had no effect on infarct size (48 (5)%, P = 1.000). The results show that desflurane and sevoflurane markedly reduced infarct size and therefore can protect myocardium against reperfusion injury in vivo. Enflurane had only a marginal effect and isoflurane offered no protection against reperfusion injury in vivo. These different effects suggest different protective mechanisms at the cellular level.
Abstract: In addition to having anti-ischaemic effects, halothane can protect isolated rat hearts and isolated cardiomyocytes against reperfusion injury of the "oxygen paradox" type. The aim of this study was to investigate if halothane can also protect against myocardial reperfusion injury in vivo. Twenty-two rabbits anaesthetized with alpha-chloralose underwent 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Seven animals received 1 MAC of halothane for the first 15 min of reperfusion (halothane group), and eight animals served as untreated controls (controls group). In seven additional animals, the haemodynamic effects of halothane were antagonized by an i.v. infusion of noradrenaline (halothane-noradrenaline group). We measured cardiac output (CO) by an ultrasonic flow probe around the ascending aorta, left ventricular pressure (LVP) by a tip manometer and infarct size by triphenyltetrazolium staining. Baseline LVP was mean 92 (SEM 4) mm Hg and CO was 289 (16) ml min-1. During coronary occlusion, LVP was reduced to 86 (4)% of baseline and CO to 84 (4)% (similar in all groups). During halothane administration at reperfusion, LVP declined further to 55 (6)% of baseline and CO to 66 (9)% (P < 0.05 halothane group vs control group). Noradrenaline prevented the reduction in LVP (halothane-noradrenaline group 87 (5)% of baseline, control group 84 (6)% and reduction in CO (halothane-noradrenaline group 89 (5)%, control group 83 (6)%. Infarct size was 49 (6)% of the area at risk in controls and was reduced markedly by administration of halothane to 32 (3)% in the halothane group (P < 0.05) and to 30 (3)% in the halothane-noradrenaline group (P < 0.05). Treatment with halothane during the early reperfusion period after myocardial ischaemia protected the myocardium against infarction in vivo, independent of the haemodynamic effect of halothane.
