Abstract: Pulse wave analysis was performed in apparently normal volunteers (n=164) and in essentially hypertensive patients without cardiovascular complications (n=171) using a newly developed non-invasive pulse wave measurement device (HEM-9010AI). Our results suggest that early wave reflections measured by radial augmentation index (AIr) are enhanced in volunteers with systolic blood pressure (SBP) >or= 160 mm Hg compared with the volunteers with their SBP<160 mmHg (98+/-18 vs 88+/-12, P<0.05). Furthermore, AIr is lower in hypertensive patients with long-term antihypertensive treatment than in those with short-term treatment (84+/-10 vs 89+/-13, P<0.01).

Abstract: BACKGROUND: Cardiovascular diseases constitute major causes of death in patients with chronic kidney diseases. An increase in arterial stiffness predicts the presence of cardiovascular diseases; however, non-invasive arterial stiffness parameters such as pulse wave velocity are confounded by blood pressure. METHODS: A new arterial stiffness parameter beta for the arterial tree, cardio-ankle vascular index (CAVI), was measured. To examine the usefulness of CAVI to screen for the presence of cardiovascular diseases, cross-sectional studies were performed on 68 patients undergoing chronic hemodialysis. RESULTS: Stepwise regression analysis indicated that CAVI significantly correlated to age (beta=0.05, p<0.01) but not blood pressure. In addition, CAVI was higher in diabetics than non-diabetics (8.39+/-0.37 vs 7.63+/-0.57, p<0.05). Furthermore, CAVI was markedly elevated in patients with a history of cardiovascular diseases (8.69+/-0.23 vs 6.66+/-0.28, p<0.01). Analysis using the ROC curve has demonstrated that CAVI of 7.55 constitutes the cut-off value for the presence of cardiovascular diseases with both sensitivity and specificity of 0.79. CONCLUSION: The present findings suggest that CAVI can be used as a screening test to detect for the presence of cardiovascular diseases in patients undergoing hemodialysis.

Abstract: Our previous data indicated that various subtypes of connexin (Cx) were expressed in the juxtaglomerular apparatus. Experiments were performed to characterize the effects on renal autoregulation of specific mimetic peptides that inhibit these Cx subtypes in Wistar-Kyoto rats. Intrarenal infusion of (Cx37,43)GAP27 increased autoregulatory index of renal plasma flow (0.06 +/- 0.05 to 0.47 +/- 0.06, n = 6, P < 0.05) and glomerular filtration rate (GFR; 0.01 +/- 0.07 to 0.49 +/- 0.07, P < 0.05). The additional administration of 8-cyclopentyl- 1,3-dipropylxanthine (CPX) produced a further elevation of autoregulatory index of RPF (0.86 +/- 0.07, P < 0.05) and GFR (0.88 +/- 0.09, P < 0.05), compared with (Cx37,43)GAP27 alone. However, the addition of pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid (PPADS) to (Cx37,43)GAP27 did not. Combined treatment with CPX and PPADS markedly worsened autoregulatory index of RPF (0.04 +/- 0.10 to 0.81 +/- 0.06, n = 6 P < 0.01) and GFR (0.05 +/- 0.08 to 0.79 +/- 0.05, P < 0.01). (Cx40)GAP27 induced similar changes to (Cx37,43)GAP27. Renal autoregulation was preserved in the presence of (Cx43)GAP26. Our results indicate that the inhibition of gap junction impaired renal autoregulation. Furthermore, the present data provide evidence that both adenosine and purinergic receptors contribute to glomerular autoregulation. Finally, our findings suggest that gap junctions, at least in part, transduce purinergic signals mediating renal autoregulation.

Abstract: Cardiovascular diseases constitute major cause of death in chronic kidney diseases (CKDs). We examined the effects of angiotensin inhibition either with angiotensin-converting enzyme inhibitor or with angiotensin receptor blocker on patient prognosis and heart-ankle pulse wave velocity (haPWV) in CKDs. Randomized controlled study was performed on 102 patients with non-diabetic CKDs. Patients were divided into two groups with or without angiotensin inhibition, and followed until death, creatinine clearance was halved or starting renal replacement therapy, whichever occurred first. For 4 years, haPWV was assessed repeatedly in the surviving patients. While both groups showed well blood pressure control throughout 4 years (129+/-1 to 131+/-2/71+/-1 to 73+/-2 mm Hg), renal prognosis was better in angiotensin inhibition group (P<0.05). In addition, angiotensin inhibition reduced cardiovascular and renal death (P<0.05). Age, sex, heart rate, systolic blood pressure and proteinuria were correlated to haPWV (R(2)=0.76, P<0.0001). Although haPWV was similar between two groups at the start of the study (1098+/-31 vs 1094+/-37 cm/s), it was higher in patients without angiotensin inhibition than that with angiotensin inhibition 4 years later (1034+/-38 cm/s (n=28) vs 1242+/-37 cm/s (n=23), P<0.01). The present results provided the evidence that angiotensin inhibition arrested a time-dependent elevation of haPWV in non-diabetic CKDs, conferring organ protection. Furthermore, our data indicated that angiotensin inhibition improved patient prognosis in non-diabetic chronic kidney diseases with mild-to-moderate renal dysfunction.

Abstract: Gap junctions are present in the juxtaglomerular apparatus enabling intercellular communication. Our study determined the location of different connexin subtypes within the juxtaglomerular apparatus of the rat, and the role of these subtypes in renal hemodynamics through the use of specific mimetic peptides. Immunohistochemical analysis showed connexins 37 and 40 expression in the endothelial and renin-secreting cells of the afferent arteriole, while connexin 40 was also found in extra- and intraglomerular mesangial cells. In contrast, connexin 43 was weakly expressed in endothelial cells of the afferent arteriole and within the glomerulus. Intra-renal infusion of the peptides (GAP) reported to block specific gap junctions ((Cx37,43)GAP27 or (Cx40)GAP27), elevated blood pressure, plasma renin activity, and angiotensin II levels, while decreasing renal plasma flow without a significant change in the glomerular filtration rate. Subsequent restoration of blood pressure reduced both renal plasma flow and glomerular filtration rate. In contrast, (Cx43)GAP26 reduced glomerular filtration rate without alterations in blood pressure, renal plasma flow, plasma renin activity, or angiotensin II levels. Hence, connexins 37 and 40 are expressed in the rat juxtaglomerular apparatus and these proteins control, in part, the renin-angiotensin system and renal autoregulation.

Abstract: BACKGROUND: Cardiovascular disease is the leading cause of mortality in patients with kidney failure treated with hemodialysis (HD). Although angiotensin receptor blockers (ARBs) reduce cardiovascular disease (CVD) events in patients with diabetes and chronic kidney disease, their effect in patients with kidney failure on HD therapy is not known. STUDY DESIGN: Open-labeled randomized trial. SETTING & PARTICIPANTS: Patients aged 30 to 80 years receiving HD 2 to 3 times weekly for 1 to 5 years at 5 university-affiliated dialysis centers. INTERVENTIONS: Treatment with ARBs (valsartan, candesartan, and losartan) versus without ARBs after stratification by sex, age, systolic blood pressure, and diabetes. OUTCOMES: The primary end point is the development of fatal and nonfatal CVD events, defined as the composite of CVD death, myocardial infarction, stroke, congestive heart failure, coronary artery bypass grafting, or percutaneous coronary intervention. The secondary end point is all-cause death. RESULTS: 366 subjects initially were randomly assigned to an ARB or no ARB (control), but after a run-in phase, 180 were retained in each group. Mean age was 60 years, 59% were men, 51% had diabetes, and mean predialysis systolic blood pressure was 154 mm Hg. There were 93 fatal or nonfatal CVD events (52%); 34 (19%) in the ARB group and 59 (33%) in the non-ARB group. After adjustment for age, sex, diabetes, systolic blood pressure, and center, treatment with an ARB was independently associated with reduced fatal and nonfatal CVD events (hazard ratio, 0.51; 95% confidence interval, 0.33 to 0.79; P = 0.002). There were 63 deaths (35%); 25 (14%) in the ARB group and 38 (21%) in the non-ARB group. After adjustment, all-cause mortality differed between the 2 groups (hazard ratio, 0.64; 95% confidence interval, 0.39 to 1.06; P = 0.1). LIMITATIONS: Because of the small sample size of this trial, the large effect may be a spurious finding. Use of an open-label design and 3 different agents in the ARB group might have influenced results. CONCLUSION: Use of an ARB may be effective in reducing nonfatal CVD events in patients undergoing long-term HD. A larger study is required to confirm these results.

Abstract: AIM: Cardiovascular disease constitutes a major cause of death in patients with chronic kidney diseases and is related to enhanced arterial stiffness. It has been reported that daytime hemodialysis patients show better prognosis than evening hemodialysis patients. METHODS: Aortic augmentation index (AI) and radial AI were measured in 20 non-diabetic hemodialysis patients, using SphygmoCor (PWV Medical) and HEM-9010AI (Omron Healthcare) as markers of arterial stiffness. Cardiovascular prognosis was followed for two years. RESULTS: Mean age, blood pressure, pulse rate, and aortic and radial AI were 52 +/- 4 y/o, 142 +/- 6/74 +/- 4 mmHg, 78 +/- 4 bpm, 21 +/- 2, and 71 +/- 4%, respectively, in 10 daytime hemodialysis patients, and they averaged 52 +/- 3 y/o, 146 +/- 6/76 +/- 4 mmHg, 74 +/- 3 bpm, 26 +/- 2, and 73 +/- 3% in 10 evening hemodialysis patients, respectively. Thus, aortic AI was higher in evening hemodialysis patients (p < 0.05). In all, one patient was hospitalized due to cardiovascular complications in daytime hemodialysis patients, as well as three patients from those dialyzed in the evening. CONCLUSION: Although a larger scale study is required to draw a definite conclusion, our findings suggest that a better prognosis in daytime hemodialysis non-diabetic patients is related to the lower AI.

Abstract: BACKGROUND: Intracellular Ca(2+) ([Ca(2+)](i)) may be a factor of importance to hypertension in spontaneously hypertensive rats (SHR). Platelet hyperactivity caused by increased [Ca(2+)](i) may contribute to atherothrombotic cardiovascular events. In a genome scan, we have recently demonstrated that a candidate quantitative trait locus (QTL) for [Ca(2+)](i) in platelets is located near the sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase (Serca) II gene locus on chromosome 12 in backcrossed rats derived from SHR and normotensive Fischer 344 rats (F344). METHODS: Congenic substitution mapping was performed for the chromosomal region including the Serca II gene locus. The segment including the Serca II gene locus was transferred from F344 onto the genetic background of the progenitor SHR. Systolic blood pressure (SBP), platelet aggregation, and ratio of heart weight to body weight (HW/BW) as well as [Ca(2+)](i) responses in platelets were compared between SHR and the congenic strain. RESULTS: Among the parental strains, thrombin-stimulated and thapsigargin-induced peak values of [Ca(2+)](i) in platelets, platelet aggregation, SBP, and HW/BW were significantly greater in SHR than in F344 and F(1) rats. The heterozygous congenic rats for the Serca II gene segment had significantly attenuated [Ca(2+)](i) responses and platelet aggregation compared with SHR. Furthermore, they demonstrated significantly lower SBP and HW/BW. CONCLUSION: Congenic substitution mapping clarified that a chromosomal segment including the Serca II gene locus was responsible for attenuated [Ca(2+)](i) responses and platelet aggregation in the heterozygous congenic rats. Therefore, this chromosomal region may contribute to the development of hypertension and cardiac hypertrophy by augmenting Ca(2+) signaling in SHR.

Abstract: Salt is essential and important for maintaining life. Excess salt intake produces an increase in blood pressure. In several subpopulations of patients with hypertension, such as those with obesity, post-menopausal women, and patients with chronic kidney diseases, for example, salt sensitivity is based on a pressure-natriuresis mechanism. In this mechanism, neuro-humoral regulation is mainly responsible for sodium handling. In addition, NO has a powerful effect on the pressure-natriuresis mechanism. Based on this mechanism, progression of chronic kidney disease is governed by salt uptake. Moreover, a genetic component for salt sensitivity is important in normotensive subjects with a family history of hypertension. In these regards, modulation of salt is of utmost importance in the fields of hypertension and nephrology.

Abstract: Insulin resistance prevails not only among diabetic patients but also among hypertensive and obese patients. The relationship between insulin resistance and cardiovascular diseases was investigated in hemodialysis (HD) patients. Eighty-one maintenance HD patients were enrolled. The homeostasis model assessment of insulin resistance (HOMA-IR) method was used to assess insulin resistance. The relationship of HOMA-IR with cardiovascular and all-cause events was assessed. Compared with nondiabetic patients (n = 55), diabetic patients (n = 26) showed higher HOMA-IR (2.5 +/- 0.3 vs 1.4 +/- 0.2, P < .05), lower ankle-brachial pressure index (ABI, 0.85 +/- 0.09 vs 1.12 +/- 0.02, P < .01), and shorter HD duration (3 +/- 1 vs 9 +/- 1 years, P < .01), although their body mass index was similar (22.3 +/- 0.5 vs 21.5 +/- 0.4 kg/m(2)). Nondiabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 36) had lower HOMA-IR (1.2 +/- 0.2 vs 1.8 +/- 0.4, P < .05) and higher ABI (1.18 +/- 0.02 vs 1.02 +/- 0.05, P < .01) than those without (n = 17). Cardiovascular events were less common in HD patients with normal HOMA-IR (P < .05) or ABI (P < .01). Our data indicate that 69% of diabetic and 27% of nondiabetic patients have HOMA-IR greater than 1.6, implying reduced insulin sensitivity in HD patients. The present results provide evidence that angiotensin inhibition improves insulin resistance, possibly preventing vascular injury in HD patients. Finally, our findings suggest that insulin resistance is prognostic of cardiovascular events in HD patients.

Abstract: Bisphenol A (BPA) and phthalate diesters, two well-described endocrine-disrupting substances (EDSs), were shown to elute out of the dialysis tubing used by patients who underwent hemodialysis (HD) and peritoneal dialysis (PD). Since these patients require dialysis for survival, they may be exposed to potentially harmful levels of these compounds. In this study, serum BPA levels were quantified in HD (n = 45) and PD (n = 43) patients, and healthy controls (n = 12) using an enzyme-linked immunosorbent assay (ELISA) kit. Our results showed that serum BPA levels were significantly elevated in both HD (5.3 +/- 0.3 ng/mL) and PD (3.8 +/- 0.2 ng/mL) patients compared to controls (2.6 +/- 0.1 ng/mL; P < 0.05); levels in the HD patients were significantly greater than in the PD patients (P < 0.05). To investigate the potential effects of these higher serum BPA levels, the patients' serum samples were examined for their effects on estrogen receptor gene transcription levels using a luciferase assay system. MCF-7 cells that were transfected with estrogen response element (ERE) cDNA were cultured with our patients' sera or a solution of BPA. Our results showed that our patients' sera induced higher levels of ERE transcription than did the same dose of BPA; this higher expression may have been due to the presence of other EDSs in the dialysis patients, such as phthalate diesters (DEHP), though this remains to be determined.

Abstract: Experiments were performed to characterize renal hemodynamics in Thy-1 nephritic rats. A monoclonal antibody against Thy-1 was intravenously injected to induce mesangiolysis in rats, and 2 days later renal hemodynamic responses to variations in blood pressure were determined. In the first series of experiments, autoregulation of renal plasma flow (RPF) or glomerular filtration rate (GFR) was impaired in nephritic rats. In response to a reduction in blood pressure (98 +/- 2 to 80 +/- 1 mmHg), both RPF (4.17 +/- 0.63 to 3.20 +/- 0.45 ml x min(-1) x g kidney wt(-1), P < 0.05, n = 6) and GFR (0.88 +/- 0.05 to 0.75 +/- 0.06 ml x min(-1).g kidney wt(-1), P < 0.05) were decreased in nephritic rats. Intravenous administration of furosemide and 30% albumin, both of which inhibit tubuloglomerular feedback, diminished renal autoregulation in control but not nephritic rats. In the second studies, the infusion of 5'-nucleotidase, an enzyme expressed on mesangial cells, into a renal artery ameliorated the magnitude of autoregulatory decrements in GFR in nephritic rats (-16 +/- 5 to -6 +/- 2%, P < 0.05, n = 6), but this enzyme failed to alter renal autoregulation in control rats. In the third studies, the effects of indomethacin were examined in nephritic rats. Inhibition of prostaglandin synthesis reduced RPF (4.07 +/- 0.30 to 1.54 +/- 0.22 ml x min(-1) x g kidney wt(-1), P < 0.05, n = 5) and GFR (1.03 +/- 0.18 to 0.69 +/- 0.13 ml x min(-1) x g kidney wt(-1), P < 0.05) in nephritic rats. However, cyclooxygenase inhibition failed to restore renal autoregulation in nephritic rats. Our results indicate that renal autoregulation is impaired in Thy-1 nephritis. Furthermore, the present data provide evidence that prostanoids contribute to maintain renal circulation in nephritic rats. Finally, our findings suggest that mesangial cells and/or 5'-nucleotidase plays an important role in mediating renal autoregulation.

Abstract: The benefit of the add-on angiotensin II receptor blocker candesartan to angiotensin-converting enzyme (ACE) inhibitors in inhibition of progression of nephropathy in hypertensive patient with nondiabetic renal disease compared with monotherapy with ACE inhibitors remains controversial. All patients were previously treated with ACE inhibitors. Urinary protein excretion of patients exceeded 1.0 g/d despite treatment with ACE inhibitors. Ninety hypertensive patients with chronic renal insufficiency were randomly assigned to one of two groups. One group received ACE inhibitor plus candesartan (2 to 12 mg/d), and a control group received only ACE inhibitor. The target BP was < or = 130/80 mmHg. The primary outcome was the changes in serum creatinine and the reduction of proteinuria. The mean duration of follow-up was 3.1 +/- 0.4 yr. At years 2 and 3, systolic and diastolic BP were reduced from 140 +/- 3/84 +/- 2 to 129 +/- 1/78 +/- 2 mmHg (candesartan group) and from 135 +/- 2/85 +/- 2 to 130 +/- 2/80 +/- 2 mmHg (ACE inhibitors group). In both groups, both systolic and diastolic BP decreased significantly from the beginning to the end of the study (P < 0.01). The serum creatinine concentration increased from 3.02 +/- 0.27 to 3.38 +/- 0.49 mg/dl (candesartan plus ACE inhibitor group) versus 3.00 +/- 0.37 to 4.48 +/- 0.57 mg/dl (ACE inhibitor group; P < 0.01) at year 3. Although the level of proteinuria significantly declined in each group (P < 0.05), the degree of reductions in proteinuria was greater in the candesartan group than in the ACE inhibitors group (P < 0.01). In the patients who were treated with candesartan and ACE inhibitor or ACE inhibitor alone, pretreatment proteinuria correlated significantly with decline of renal function, whereas reduction of proteinuria negatively correlated with decline in renal function in the patients who were treated with candesartan. Candesartan with an ACE inhibitor is effective in slowing the progression of renal insufficiency in hypertensive patients with nondiabetic renal disease through reduction of proteinuria.

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Abstract: We recently experienced a case of a female hemodialysis patient with multiple intestinal angiodysplasias. In 2001, she complained of melena, and angiographic embolization halted bleeding from ileum angiodysplasia. In 2002, she again complained of black stool. Abdominal angiography found jejunum angiodysplasia, and pharmacological therapy with estrogen/progesterone was required to stop the bleeding. Ethical demands to develop new hemodialyzers that do not release estrogen-like substances are discussed.

Abstract: BACKGROUND: Pulse wave velocity (PWV) is commonly elevated in haemodialysis (HD) patients having cardiovascular diseases. Disturbances in calcium-phosphate metabolism are among the established cardiovascular risk factors in HD patients. The present study was performed to assess the effect of sevelamer on PWV in HD patients. METHODS: Fifteen patients, who had been treated with calcium carbonate as a phosphate binder, were entered into the study. Changes in PWV during the 6 months before sevelamer administration were compared with PWV changes during 6 months of receiving sevelamer. Serum biochemistry parameters were also assessed. RESULTS: Compared with the preceding control period, the sevelamer period resulted in decreased serum calcium (9.9+/-0.1 to 9.6+/-0.1 mg/dl, n = 15; P<0.01) in association with reductions in oral calcium load (4.3+/-0.4 to 2.3+/-0.6 g/day; P<0.001). Serum phosphorus and whole parathyroid hormone remained unchanged. Sevelamer reduced serum total cholesterol (167+/-7 to 148+/-6 mg/dl; P<0.001) and LDL-cholesterol (85+/-8 to 65+/-7 mg/dl; P<0.001), without modifying HDL-cholesterol or triglycerides. Finally, sevelamer reversed the increase in PWV observed during the control period (from 46+/-16 to -20+/-9 cm/s/month; P<0.01). CONCLUSIONS: In chronic HD patients, sevelamer decreased serum total- and LDL-cholesterol as well as calcium. Moreover, our findings suggest that treatment with sevelamer attenuates the progressive increase in PWV observed during calcium carbonate treatment.

Abstract: OBJECTIVE: Homocysteine is one of the cardiovascular risk factors in hemodialysis (HD) patients. Studies were performed to assess the effects of folic acid on pulse wave velocity (PWV) in HD patients. METHODS: In a cross-sectional study, plasma total homocysteine (tHcy) was measured in 49 patients on maintenance HD. Ten HD patients younger than 45 years old entered the prospective study. Monthly changes in PWV were compared before and during folic acid treatment. RESULTS: Younger HD patients had higher tHcy (r = -0.53, n = 49, P < .001). Patients who manifested myocardial ischemia (37 +/- 3 nmol/mL) possessed higher tHcy than those who did not (30 +/- 3 nmol/mL, P < .05). In prospective study, folic acid treatment (10 to 20 mg/d) failed to alter blood pressure and biochemical parameters, including lipids, calcium, phosphate, and parathormone. However, in association with a decrease in tHcy (46 +/- 5 to 27 +/- 3 nmol/mL, n = 10, P < .005), progressive increases in PWV (33 +/- 8 to 3 +/- 6 cm/sec/month, P < .01) were stopped. CONCLUSIONS: The present findings indicate that young HD patients are exposed to severe hyperhomocysteinemia, and suggest that relatively large doses of folic acid attenuate progressive increases in PWV of young or middle-age HD patients.

Abstract: BACKGROUND: Reflection pressure may influence the clinical course of chronic kidney diseases (CKDs). The relationship between the augmentation index (AI) and progression of non-diabetic CKDs was characterized. METHODS: Ninety-nine patients were enrolled into the study. Pulse wave form analysis was performed to determine AI that assesses arterial stiffness. RESULTS: In a cross-sectional study, a multiple regression analysis found that AI correlated positively to age and weight, and negatively to height and heart rate (R(2) = 0.50). Furthermore, echocardiography was performed in 51 patients who gave their consent. In male patients under angiotensin inhibition, left ventricular mass index increased as AI was elevated (r = 0.33, slope = 0.85 +/- 0.30 g/m(2)/%, p < 0.05, n = 23). A prospective study was performed in 41 patients who consented to having their creatinine clearance measured repeatedly. In the patients with angiotensin inhibition a higher basal AI resulted in a greater annual decrease in creatinine clearance (r = -0.52, slope = -0.43 +/- 0.14 ml/min/year/%, p < 0.01, n = 27). CONCLUSION: The present data indicate that AI as well as angiotensin contribute to the development of left ventricular hypertrophy. Furthermore, our results suggest that in addition to angiotensin, AI is a risk factor of progression of non-diabetic CKDs.

Abstract: We examined the efficacy of candesartan in reducing cardiovascular events in hypertensive patients with coexisting chronic kidney disease and cardiovascular diseases. This open-label, prospective study was conducted from 1999 to 2002, and 141 hypertensive subjects 60 to 75 years old with non-diabetic chronic renal insufficiency were enrolled. Before randomization of the patients, we examined their past medical history and found that 69 patients had been hospitalized due to myocardial infarction (MI) or stroke. Therefore, the patients were divided into 2 groups, one with previous histories of MI or stroke and the other with no previous history of Ml or stroke. The patients were randomized to receive either the angiotensin receptor blocker candesartan or conventional treatment. The mean duration of follow-up was 3.1 +/- 0.4 years. The primary outcome was a primary cardiovascular event (MI, stroke, or heart failure) verified by hospitalization. At the end of the study, in the patients with past history of cardiovascular diseases, blood pressure was reduced from 146.4 +/- 7.2/79.2 +/- 5.1 to 34.4 +/- 6.1/72.3 +/- 4.0 mmHg in the candesartan group and from 145.3 +/- 5.1/80.1 +/- 3.8 to 133.4 +/- 5.8/73.8 +/- 4.2 mmHg in the conventional treatment group. In the patients without past history of cardiovascular diseases, blood pressure was reduced from 143.2 +/- 4.3/78.3 +/- 4.8 to 133.8 +/- 5.3/ 73.1 +/- 3.8 mmHg in the candesartan group and from 143.9 +/- 6.8/78.1 +/- 4.2 to 132.6 +/- 5.4/74.5 +/- 4.4 mmHg in the conventional treatment group at the end of the study. There were no significant differences between the candesartan group and the conventional treatment group in the reduction of blood pressures. Among patients with a past history of cardiovascular disease, the serum creatinine concentration increased from 1.49 +/- 0.38 to 1.58 +/- 0.42 by candesartan treatment and from 1.50 +/- 0.32 to 1.89 +/- 0.37 by conventional treatment. On the other hand, in patients with no past history of cardiovascular disease, the serum creatinine concentration increased from 1.44 +/- 0.42 to 1.46 +/- 0.40 by candesartan treatment and from 1.46 +/- 0.44 to 1.51 +/- 0.38 by conventional treatment. Although, there was no significant difference in the incidence of cardiovascular events between the 2 groups with the candesartan-based and conventional-based antihypertensive treatment, in patients without cardiovascular events (12/36 vs. 7/34: these figures indicate events per total participated persons per 3 years; following figures are the same as this), treatment with candesartan reduced the incidence of cardiovascular events in the patients with past history of cardiovascular diseases (20/33 vs. 32/ 38). In particular, candesartan-based treatment reduced the incidence of congestive heart failure by 66.4% in these patients. In conclusion, this prospective, open-labeled randomized study suggests that 1) previous history of cardiovascular diseases is a major risk factor for cardiovascular events; and 2) candesartan is effective for reduction of cardiovascular events in hypertensive patients with coexisting chronic kidney disease and cardiovascular diseases, especially for prevention of congestive heart failure.

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Abstract: BACKGROUND: To identify differences between the effects of calcitriol and the calcitriol analogue, maxacalcitol, on parathyroid hormone (PTH) and bone metabolisms, we conducted a randomized prospective multicentre study on patients on chronic haemodialysis. METHODS: We randomly assigned 91 patients with secondary hyperparathyroidism [intact PTH (iPTH) > or =150 pg/ml] to have either calcitriol (47 patients) or maxacalcitol (44 patients) therapy, for 12 months after a 1 month control period. Serum electrolytes, bone alkaline phosphatase (bAP), iPTH, total PTH and PTH(1-84) (whole PTH) levels were measured periodically. The first end point was a serum iPTH of <150 pg/ml, the second was the iPTH levels obtained. RESULTS: Treatment was discontinued for various reasons in nine patients in each group, but no serious side effects were observed in either group. The numbers of cases reaching the first end point were not significantly different between the two groups. Serum calcium concentration was significantly higher in the maxacalcitol than the calcitriol group during early treatment, but not at the end of treatment. Throughout the treatment period there were no significant differences between the two groups in serum iPTH, inorganic phosphate, the product of the serum calcium and inorganic phosphorus concentrations, bAP, or the ratio of whole PTH to total PTH minus whole PTH. Nor were the changes in these parameters significantly different between the two groups comparing the patients with moderate to severe hyperparathyroidism (basal iPTH > or =500 pg/ml). CONCLUSION: Calcitriol and maxacalcitol are equally effective on PTH and bone metabolism.

Abstract: Studies were performed to examine whether pulse wave velocity (PWV) is a useful indicator of arteriosclerosis in hemodialysis (HD) patients. In total, 72 patients were enrolled. Annual changes in PWV were compared to clinical parameters and therapeutic maneuvers. PWV increased in diabetic patients faster than non-diabetics (35 +/- 10 cm/s/month versus 10 +/- 4 cm/s/month, P < 0.05). Changes in PWV showed strong correlations to triglyceride level exposed during observation period (r = 0.50, P < 0.05) and HD duration (r = 0.46, P < 0.05). In addition, we found that PWV of some patients decreased (regressors), while the others increased (non-regressors). Regressors more frequently received combined treatment with angiotensin blockade and lipid-lowering drugs or vitamin E-coated dialyzers than non-regressors (P < 0.05). Our data demonstrate that PWV is useful as a marker of arteriosclerosis in HD patients. Furthermore, the present results suggest that combined treatment with both angiotensin inhibition and lipid-lowering drugs or vitamin E-coated membrane would slow the progression of arteriosclerosis in HD patients.

Abstract: The authors report, for the first time, potentially fatal adverse effects of combined treatment using beta lactam and low-density lipoprotein (LDL) apheresis with dextran sulfate adsorption. A 62-year-old man was receiving LDL apheresis because of peripheral artery disease. Cefmetazole was administered to treat infection of a leg ulcer. Although antibiotics alone did not cause any allergic reactions, he manifested circulatory collapse during LDL apheresis. Possible mechanisms for shock were discussed.

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Abstract: To investigate the role of ryanodine receptors in glomerular arterioles, experiments were performed using an isolated perfused hydronephrotic kidney model. In the first series of studies, BAYK-8644 (300 nM), a calcium agonist, constricted afferent (19.6 +/- 0.6 to 17.6 +/- 0.5 microm, n = 6, P < 0.01) but not efferent arterioles. Furthermore, BAYK-8644 elicited afferent arteriolar oscillatory movements. Subsequent administration of nifedipine (1 microM) inhibited both afferent arteriolar oscillation and constriction by BAYK-8644 (to 19.4 +/- 0.5 microm). In the second group, although BAYK-8644 constricted afferent arterioles treated with 1 microM of thapsigargin (19.7 +/- 0.6 to 16.8 +/- 0.6 microm, n = 5, P < 0.05), it failed to induce rhythmic contraction. Removal of extracellular calcium with EGTA (2 mM) reversed BAYK-8644-induced afferent arteriolar constriction (to 20.0 +/- 0.5 microm). In the third series of investigations, ryanodine (10 microM) but not 2-aminoethoxyphenyl borate (100 microM) abolished afferent arteriolar vasomotion by BAYK-8644. In the fourth series of experiments, in the presence of caffeine (1 mM), the stronger activation of voltage-dependent calcium channels by higher potassium media resulted in greater afferent arteriolar constriction and faster oscillation. Our results indicate that L-type calcium channels are rich in preglomerular but not postglomerular microvessels. Furthermore, the present findings suggest that either prolonged calcium influx through voltage-dependent calcium channels (BAYK-8644) or sensitized ryanodine receptors (caffeine) is required to trigger periodic calcium release through ryanodine receptors in afferent arterioles.

Abstract: AIMS: To assess the effects of erythropoietin (EPO) on bone metabolism in patients receiving chronic hemodialysis (HD). METHODS: Forty one patients were divided into two groups whether they required the administration of EPO to treat renal anemia or not. Serial measurements of predialysis blood samples and bone mineral density were performed prospectively over a year. RESULTS: The administration of EPO was associated with an increased serum creatinine (11.9 +/- 0.4 to 12.5 +/- 0.4 mg/dl, p < 0.05), insulin-like growth factor binding protein (3.0 +/- 0.2 to 3.4 +/- 0.2 micrograms/ml, p < 0.05) as well as decreased iron level (112 +/- 7 to 88 +/- 7 micrograms/dl, p < 0.005). Furthermore, in EPO-treated group, exogenous EPO doses correlated with the increments in 1,25-dihydroxy-vitamin D (r = 0.38, p < 0.05), intact osteocalcin (r = 0.42, p < 0.05) and bone alkali-phosphatase (r = 0.53, p < 0.005), but not intact parathyroid hormone (r = 0.09). Both metacarpal index (0.47 +/- 0.02 to 0.47 +/- 0.02) and the summation of gray scale/diameter (2.68 +/- 0.06 to 2.61 +/- 0.07 mmAl), bone mineral density parameters, remained unchanged. CONCLUSION: The present data provide evidence that EPO may modulate the production of 1,25-dihydroxy-vitamin D in HD patients. Furthermore, our findings suggest that EPO therapy activates insulin-like growth factor system in HD patients, possibly through its actions on metabolism.

Abstract: BACKGROUND: This study assessed the calcium-activating mechanisms mediating glomerular arteriolar constriction by angiotensin II (Ang II). METHODS: Immunohistochemical and physiological studies were carried out, using antibody against transient receptor potential (TRP)-1 and an isolated perfused kidney model. RESULTS: Immunohistochemical experiments demonstrated that TRP-1 proteins were transcribed on both afferent and efferent arteriolar myocytes. In the first series of physiological experiments, Ang II (0.3 nmol/L) considerably constricted afferent (20.2 +/- 0.9 to 14.9 +/- 0.7 microm) and efferent arterioles (18.4 +/- 0.7 to 14.0 +/- 0.7 microm). The addition of nifedipine (1 micromol/L) restored decrements in afferent (to 20.0 +/- 0.8 microm) but not efferent arteriolar diameters. Further administration of SKF-96365 (100 micromol/L), a TRP channel blocker, reversed efferent arteriolar constriction (to 16.2 +/- 0.8 micromol/L). In the second group, although 2-aminoethoxydiphenyl borate (100 micromol/L), an inhibitor of inositol trisphosphate-induced calcium release (IP3CR), did not alter glomerular arteriolar diameters, it prevented Ang II-induced afferent arteriolar constriction and attenuated efferent arteriolar constriction (18.8 +/- 0.8 to 16.9 +/- microm). Subsequent removal of extracellular calcium abolished residual efferent arteriolar constriction (to 19.1 +/- 0.8 microm). CONCLUSIONS: Our data provide evidence that Ang II elicits IP3CR, possibly inducing a cellular response that activates voltage-dependent calcium channels on afferent arterioles. The present results suggest that Ang II-induced efferent arteriolar constriction involves IP3CR and calcium influx sensitive to SKF-96365.

Abstract: AIM: To characterize the relationship between oxidative stress and atherosclerosis in HD patients. METHODS: Seventy-five HD patients were entered into the study. Ox-LDL was measured as a probe for peroxidation and compared to clinical atherosclerotic parameters. Prospective studies were also performed to assess the effects of vitamin E-bonded membrane on oxidative stress. RESULTS: Elderly patients tended to show elevated Ox-LDL (alpha = 0.060+/-0.021 ng/microg LDL protein/year, r = 0.35, p < 0.05). Levels of Ox-LDL in the patients with positive history for atherosclerotic diseases (3.1+/-0.4 ng/microg LDL protein, n = 36) were higher than those with a negative history (1.6+/-0.2, n = 39, p < 0.01). Further-more, ankle/brachial pressure index was negatively correlated to Ox-LDL (alpha = -0.052+/-0.012/ng/microg LDL protein, r = 0.42, p < 0.01). Application of vitamin E-bonded membrane for 10 months (-38+/-11%, n = 14, p < 0.05), but not synthetic membrane, ameliorated Ox-LDL. CONCLUSIONS: Our results indicate that Ox-LDL is elevated in aged HD patients. In addition, the present data provide evidence that vitamin E-bonded dialyzers attenuate oxidative stress. Finally, our findings suggest that Ox-LDL correlates to the magnitude of peripheral arterial diseases in HD patients.

Abstract: AIMS: In order to assess the long-term influence of high-flux hemodiafiltration (HDF) on hemodynamic stability in patients with dialysis-related amyloidosis. METHODS: HDF with high-flux dialyzers was performed for a year in 11 patients who had undergone the surgery for carpal tunnel syndrome. Patients were divided into two groups, and for each group synthetic or cellulose membrane dialyzers were applied. RESULTS: A year after the exchange from standard hemodialysis to HDF with cellulose high-flux dialyzers, beta(2)-microglobulin was decreased (45+/-3 to 28+/-2 mg/l, n = 5, p< 0.05), but plasma non-refilling ratio was not altered. However, the continuance of synthetic high-flux HDF for a year decreased plasma non-refilling ratio (17+/-5 to 7+/-4%, p<0.05), hypotensive episodes (4.3+/-0.6 to 2.5+/-0.4 sessions/month, p<0.05) and muscle cramps (3.8+/-0.5 to 1.8+/-0.5 sessions/month, p<0.01) in addition to the decrements in serum beta(2)-microglobulin (45+/-5 to 33+/-2 mg/l, n = 6, p<0.01). CONCLUSIONS: Although the study on a large number of patients may be required to draw a final conclusion, our present data suggest that biocompatible high-flux HDF is uniquely suited for dialysis-related amyloidosis.

Abstract: In order to estimate the influence of flux on plasma refilling during hemodialysis (HD), prospective crossover studies were performed in 10 HD patients with low-flux and high-flux dialyzers. Hematocrit was continuously monitored to assess changes in blood volume. In addition, plasma osmolarity and total protein concentration were measured. Intradialytic reductions in body weight (-5 +/- 1 vs -5 +/- 1%) and plasma osmolarity (-5 +/- 1 vs -5 +/- 1%) were similar in both conditions. Although mean blood pressure remained unchanged in either state, the decrease in blood volume was larger in high-flux HD (-13 +/- 2 vs -10 +/- 2%, p<0.05). In spite of greater contraction in blood volume during high-flux HD, total proteins were increased equally between low-flux and high-flux HD (11 +/- 4 vs 11 +/- 4%). Our data that although high-flux HD failed to induce significant drops in blood pressure, it elicited greater magnitude of decreases in blood volume, implicate the judicious application of high-flux HD.

Abstract: Role of protein kinase C in angiotensin II-induced constriction of renal microvessels. BACKGROUND: Although angiotensin II (Ang II) exerts its action through multiple vasomotor mechanisms, the contribution of phosphoinositol hydrolysis products to Ang II-induced renal vasoconstriction remains undetermined. METHODS: The role of protein kinase C (PKC) in Ang II-induced afferent (AFF) and efferent (EFF) arteriolar constriction was examined using the isolated perfused hydronephrotic rat kidney. RESULTS: Ang II (0.3 nmol/L)-induced EFF constriction was refractory to inhibition of voltage-dependent calcium channels by pranidipine (1 micromol/L, 19 +/- 2% reversal) but was completely reversed by a PKC inhibitor, chelerythrine (1 micromol/L, 96 +/- 2% reversal). Furthermore, direct PKC activation by phorbol myristate acetate (PMA; 1 micromol/L) caused prominent EFF constriction, and this constriction was inhibited by manganese and free calcium medium. In contrast, Ang II-induced AFF constriction was completely abolished by pranidipine (98 +/- 4% reversal) and was partially inhibited by chelerythrine (55 +/- 3% reversal). Although PMA elicited marked AFF constriction, this constriction was insensitive to the calcium antagonist, but was totally inhibited by manganese or free calcium medium. CONCLUSIONS: PKC plays an obligatory role in Ang II-induced EFF constriction that requires extracellular calcium entry through nonselective cation channels. In contrast, in concert with our recent findings demonstrating a complete dilation by thapsigargin, Ang II-induced AFF constriction is mainly mediated by inositol trisphosphate (IP3) and voltage-dependent calcium channel pathways, but could not be attributed to the PKC-activated calcium entry pathway (for example, nonselective cation channels). Rather, Ang II-stimulated PKC may cross-talk to the IP3/voltage-dependent calcium channel pathway and could modulate the vasoconstrictor mechanism of the AFF. Thus, the role of PKC during Ang II stimulation differs in AFF and EFF, which may constitute segmental heterogeneity in the renal microvasculature.

Abstract: In this study, we have shown that intravenously administered antisense oligodeoxynucleotide (ODN) was demonstrated to be taken up by tubular epithelium, after which it blocked mRNA expression of target genes in normal and nephritic rats. Therefore, we injected osteopontin (OPN) antisense ODN to Goodpasture syndrome (GPS) rats every second day between days 27 and 35, the time when renal OPN expression increased and interstitial monocyte infiltration was aggravated. In parallel to blockade of tubular OPN expression, this treatment significantly attenuated monocyte infiltration and preserved renal plasma flow in GPS rats at day 37, compared with sense ODN-treated and untreated GPS rats. No significant changes were observed in OPN mRNA level by RT-PCR and histopathology of the glomeruli after ODN treatment, which was compatible with an absence of differences in the urinary protein excretion rate. In conclusion, OPN expressed by tubular epithelium played a pivotal role in mediating peritubular monocyte infiltration consequent to glomerular disease.

Abstract: The important contribution of hypertension to the progression of renal failure is well realized. However, it have been less discussed which drugs are suitable for the different stages of progressive renal failure. The present study examined the effects of timing of antihypertensive therapy using calcium channel blocker and angiotensin converting enzyme inhibitor in 5/6 nephrectomized spontaneously hypertensive rats (SHRs). Forty male 6 week old SHRs were divided into 5 groups (n=8 in each group), and they were placed on a high salt diet after 5/6 nephrectomy. Group 1, high salt diet without any drug. Group 2 received 0.2 mg/kg/day of amlodipine and group 3 received 0.2 mg/kg/day of enalapril mixed in the high salt diet from week 6 respectively. Similarly group 4 received the same doses of amlodipine, and group 5 received the same doses of enalapril from week 10. Each drug protected from increasing blood pressure in 4 groups, and no significant difference was observed between the effects of amlodipine and enalapril. Proteinuria was reduced with both drugs. In histopathological evaluation, glomerulosclerosis was controlled only in group 2, and arterio/olosclerosis was significantly suppressed in all treated groups except group 5. From these results, both amlodipine and enalapril are renal protective in early stage of renal failure with hypertension. However, in advanced stage of renal failure, amlodipine is superior in its renal protective effect.

Abstract: 1. In order to assess ionic mechanisms mediating renal afferent arteriolar myogenic constriction, experiments were performed using isolated perfused hydronephrotic rat kidneys. 2. Increasing pressure progressively constricted the afferent arteriole (-0.26 +/- 0.02% mmHg-1, n = 21, r = 0.97). Gadolinium (10 microM), a mechanosensitive cation channel blocker, abolished this myogenic constriction. However, high potassium media (30 mM) constricted the afferent arteriole in the presence of gadolinium. 3. Lowering extracellular sodium concentration gradually attenuated afferent arteriolar myogenic constriction. In the perfusate containing 50 mM sodium, the myogenic response was arrested. 4. Afferent arteriolar myogenic constriction was prevented in calcium-free perfusate or by the L-type calcium channel blocker diltiazem (10 microM). 5. Our present findings provide evidence that increasing pressure gates mechanosensitive cation channels on the afferent arteriole, thereby eliciting membrane depolarization and activating voltage-dependent calcium channels.

Abstract: We investigated the effects of a calcium antagonist, efonidipine, which was reported to dilate not only afferent arterioles but also efferent alterioles, on progression of renal failure in salt-loaded partially nephrectomized spontaneously hypertensive rats (SHR). Forty-four SHR's with 5 of 6 nephrectomy were divided into four groups: group 1 as control (n=20); group 2, efonidipine-treated (n=8); group 3, enalapril-treated (n=8); and group 4, nifedipine-treated (n=8). The rats were given these drugs and a high-salt diet (5% NaCl) for 8 weeks. During the experiment, systolic blood pressure (SBP) and daily urinary protein excretion were measured every 2 weeks. At the end of the study, serum creatinine was determined, and renal tissues were obtained for light microscopic examination. SBP was markedly reduced by 8-week antihypertensive treatment. (control, 267+/-7 mmHg; efonidipine, 181+/-7 mmHg; enalapril, 200+/-12 mmHg; nifedipine, 184+/-6 mmHg). Glomerular sclerosis developed markedly in the control group, but was partially prevented in all treated groups. Similarly, urinary protein excretion (UPE) was suppressed by efonidipine (180+/-16 mg/day) and enalapril (186+/-16 mg/day vs. 301+/-28 mg/day for control). In contrast, nifedipine failed to prevent the increase in urinary protein excretion (258+/-22 mg/day). In conclusion, efonidipine attenuates SBP increase and ameliorates glomerular injury as well as nifedipine and enalapril. Furthermore, beneficial effects of efonidipine, but not nifedipine, on proteinuria suggest that different mechanisms mediate the improvement of proteinuria; one possible mechanism could be efferent arteriolar dilation, not reported in nifedipine.

Abstract: -To assess cellular mechanisms mediating myogenic responses of interlobular artery (ILA), experiments were performed with the use of isolated perfused hydronephrotic kidneys. ILAs were divided into 3 groups according to their basal diameters: proximal (>60 microm), intermediate (40 to 60 microm), and distal (<40 microm) ILAs. Myogenic responses were obtained by stepwise increase in perfusion pressure. Greater myogenic responsiveness was observed in ILAs with smaller diameters. Diltiazem (10 micromol/L) inhibited myogenic responses of all segments of ILAs. Furthermore, gadolinium (10 micromol/L), a mechanosensitive cation channel blocker, abolished myogenic responses of distal but not proximal ILA. In contrast, 2-nitro-4-carboxyphenyl-N, N-diphenyl-carbamate (200 micromol/L), an inhibitor of phospholipase C, prevented myogenic responses of proximal but not distal ILA. Finally, basal proximal ILA diameters were increased by treatment with 50 nmol/L of staurosporine (P<0.05), and subsequent addition of thapsigargin (1 micromol/L) blocked myogenic contraction of proximal ILAs. Myogenic responses of intermediate ILAs exhibited characteristics between those of distal and proximal ILAs. Our data indicate that underlying mechanisms for myogenic responses differ in distinct segments of ILAs. The present results suggest that mechanosensitive cation channels are involved in myogenic constriction of distal ILAs. Finally, our findings provide evidence that the stimulation of phospholipase C mediates myogenic contraction of proximal ILAs.

Abstract: In the present study, we have estimated plasma nonrefilling rate and assessed its relationship to blood pressure stability during hemodialysis (HD) with normal or high sodium dialysate and during high flux hemodiafiltration (HDF). In standard HD, the greater plasma nonrefilling rate resulted in the larger decrease in blood pressure (alpha = -6.7 +/- 0.2 mm Hg/%, p < 0.01, n = 75). When compared to standard HD, high flux HDF (n = 6) altered neither plasma refilling nor blood pressure stability. Finally, the restrictive usage of high sodium dialysate reduced plasma nonrefilling rate (21 +/- 3 vs. 16 +/- 2%, p < 0.05, n = 10) and the magnitude of decrease in blood pressure (16 +/- 6 vs. 9 +/- 4 mm Hg, p < 0.05) without increase in interdialytic weight gain. Our data indicate relative safety of high performance HDF, and warrant judicious use of high sodium dialysate for the HD patients with hypotensive episodes.

Abstract: The influence of hydronephrosis (6-10 wk) on the renal vascular response to arginine vasopressin (AVP) was assessed, using isolated perfused normal and hydronephrotic rat kidneys. In normal kidneys, AVP (0.3 nM) reduced renal perfusate flow (RPF) by 55 +/- 7% (P < 0.01). AVP-induced decrements in RPF were reversed partially by diltiazem (10 microM) and completely by 10 nM of an AVP (V1)-receptor antagonist (AVPX). In hydronephrotic kidneys, AVP reduced RPF by 81 +/- 2% (P < 0.01) and constricted afferent (AA) and efferent arterioles (EA) by 33 +/- 3 (P < 0.01) and 33 +/- 5% (P < 0.01), respectively. The addition of diltiazem altered neither RPF nor vessel diameters. Administration of AVPX recovered RPF, AA, and EA diameters. When hydronephrotic kidneys were pretreated with thromboxane (Tx) inhibitors, AVP reduced RPF by 62 +/- 5% (P < 0.01) and constricted AAs and EAs by 26 +/- 2 (P < 0.01) and 17 +/- 3% (P < 0.05), respectively. Under Tx blockade, diltiazem partially reversed the AVP-induced reduction in RPF and restored the decrements in AA diameter. Subsequent addition of AVPX returned RPF and EA diameter. Our data indicate that AVP elicits substantial renal microvascular constriction and suggest that AVP stimulates Tx production in hydronephrotic kidneys, thereby altering renal vascular responsiveness to this peptide.

Abstract: This study was conducted to examine whether the renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy without involving the sympathetic nervous system. Sprague-Dawley rats were divided into control-innervated, control-denervated, hyperthyroid-innervated, and hyperthyroid-denervated groups using intraperitoneal injections of thyroxine and 6-hydroxydopamine. After 8 wk, the heart-to-body weight ratio increased in hyperthyroid groups (63%), and this increase was only partially inhibited by sympathetic denervation. Radioimmunoassays and reverse transcription-polymerase chain reaction revealed increased cardiac levels of renin (33%) and angiotensin II (53%) and enhanced cardiac expression of renin mRNA (225%) in the hyperthyroid groups. These increases were unaffected by sympathetic denervation or 24-h bilateral nephrectomy. In addition, losartan and nicardipine decreased systolic blood pressure to the same extent, but only losartan caused regression of thyroxine-induced cardiac hypertrophy. These results suggest that thyroid hormone activates the cardiac renin-angiotensin system without involving the sympathetic nervous system or the circulating renin-angiotensin system; the activated renin-angiotensin system contributes to cardiac hypertrophy in hyperthyroidism.

Abstract: To assess cellular mechanisms mediating afferent (AA) and efferent arteriolar (EA) constriction by angiotensin II (AngII), experiments were performed using isolated perfused hydronephrotic kidneys. In the first series of studies, AngII (0.3 nM) constricted AAs and EAs by 29+/-3 (n = 8, P < 0.01) and 27+/-3% (n = 8, P < 0.01), respectively. Subsequent addition of nifedipine restored AA but not EA diameter. Manganese (8 mM) reversed EA constriction by 65+/-9% (P < 0.01). In the second group, the addition of N-ethylmaleimide (10 microM), a Gi/Go protein antagonist, abolished AngII- induced EA (n = 6) but not AA constriction (n = 6). In the third series of experiments, treatment with 2-nitro-4-carboxyphenyl-N, N-diphenyl-carbamate (200 microM), a phospholipase C inhibitor, blocked both AA and EA constriction by AngII (n = 6 for each). In the fourth group, thapsigargin (1 microM) prevented AngII-induced AA constriction (n = 8) and attenuated EA constriction (8+/-2% decrease in EA diameter at 0.3 nM AngII, n = 8, P < 0.05). Subsequent addition of manganese (8 mM) reversed EA constriction. Our data provide evidence that in AAs, AngII stimulates phospholipase C with subsequent calcium mobilization that is required to activate voltage-dependent calcium channels. Our results suggest that AngII constricts EAs by activating phospholipase C via the Gi protein family, thereby eliciting both calcium mobilization and calcium entry.

Abstract: The effects of calcium channel blockers (CCBs) and angiotensin converting enzyme (ACE) inhibitors on blood pressure and the progression of renal dysfunction were compared in hypertensive patients with polycystic kidney disease (PKD). Twenty-six patients with PKD and hypertension who had been treated with other antihypertensive agents, such as diuretics, beta-blockers, or alpha-methyldopa, were followed up for two years, during which their blood pressure and renal function were monitored. Patients were divided into two groups classified according to the type of antihypertensive agents given. Group 1 (n = 14) received CCBs, while group 2 (n = 12) received ACE inhibitors. No significant differences were found in their blood pressure control and serum creatinine levels throughout the study. The creatinine clearances were decreased in both groups. However, the decreases in creatinine clearance were smaller (p < 0.05) in the group treated with CCBs. In addition, two patients in group 2 showed rapid increases in serum creatinine. Our data suggest that CCBs reduced blood pressure effectively and preserved renal function in PKD patients at least as well as ACE inhibitors.

Abstract: The effects of IAA-94, a chloride channel blocker and/or low chloride perfusate on afferent arteriolar (AA) constriction by angiotensin II (Ang II), norepinephrine (NE) and increasing pressure (80 to 160 mm Hg) were assessed using isolated perfused hydronephrotic kidneys. In the first series of experiments, Ang II (0.3 nM) constricted AAs by 33 +/- 3% (N = 5, P < 0.01). Subsequent addition of diltiazem (10 microM) restored the decrements in the AA diameters. In the presence of diltiazem (10 microM), increasing pressure did not constrict AAs. In the second series of experiments. elevation of pressure constricted AAs by 20 +/- 2% (N = 7. P < 0.01). Subsequent addition of IAA-94 (30 microM) failed to alter the basal AA diameter and myogenic responsiveness. However, Ang II-induced AA constriction was abolished by IAA-94. In the third series of experiments, decreasing extracellular chloride exaggerated AA constriction by 0.1 nM of Ang II (from 13 +/- 2 to 20 +/- 3%, N = 6, P < 0.05). Similarly, low chloride perfusate enhanced NE (0.1 microM)-induced AA constriction (from 14 +/- 2 to 19 +/- 2%, N = 6, P < 0.05). In contrast, myogenic responsiveness was not influenced by reducing chloride concentrations. The present data provide evidence that both Ang II and NE induce AA constriction by opening chloride channels and subsequent activation of voltage-dependent calcium channels, and suggest that the myogenic response is mediated by activating voltage-dependent calcium channels independently of chloride channels.

Abstract: The effects of a calcium channel blocker, nicardipine, on pressure-natriuresis responses were studied in Dahl salt sensitive (DS) and resistant (DR) rats. Differences in the neural and endocrine background were minimized by renal denervation and by holding plasma vasopressin, aldosterone, corticosterone, and norepinephrine levels constant by intravenous infusion. The renal plasma flow (RPF) and glomerular filtration rate (GFR) of DS rats were disautoregulated in the low renal perfusion pressure range, while those of DR rats were autoregulated. Administration of nicardipine (0.3 microgram/kg/min) into the renal artery significantly increased RPF and GFR and abolished the autoregulation in both strains of rats. Nicardipine also sharpened the pressure-natriuresis responses in both strains without changes in fractional excretion of sodium. These findings suggest that nicardipine increased GFR and thereby improved the pressure-natriuresis responses of DS rats.

Abstract:

Abstract: Previous studies from our laboratory have demonstrated impaired afferent arteriolar responsiveness to pressure in rats 4-6 weeks after the induction of diabetes mellitus. Although the responsible mechanisms mediating this renal autoregulatory defect have not been fully defined, increased polyol metabolism has been implicated as a possible factor involved in the pathogenesis of diabetic complications. We therefore investigated the possible role of this metabolic disturbance in renal autoregulation using the galactose-fed rat, a model characterized by increased polyol pathway activity independent of hyperglycemia or insulin deficiency. Hydronephrosis was induced to permit direct visualization of renal microvessels. Pressure-induced vasoconstriction of afferent arterioles was assessed by quantitating vessel diameter following stepwise increments of renal perfusion pressure (RAP; from 80 to 180 mm Hg) in the hydronephrotic kidneys from control rats and rats fed a 50% galactose diet for 2 or 4 weeks. Vessel diameters were measured from video images by computer-assisted image processing. Control rats exhibited progressive afferent arteriolar vasoconstriction when RAP was increased from 80 to 180 mm Hg (-17.3% +/- 1.0%; P < 0.001). In contrast, myogenic responses to increases in pressure were absent in the afferent arterioles of rats fed a 50% galactose diet for either 2 (-4.1% +/- 1.9%; not significant) or 4 weeks (-2.9 +/- 3.4%; not significant). Our demonstration that the impairment of afferent arteriolar responsiveness to increasing RAP in the normoglycemic galactose-fed rat was identical to that observed in the STZ-diabetic rat suggests that increased polyol accumulation may contribute to the impairment of renal autoregulation in the diabetic rat.

Abstract: Utilizing the in vitro blood-perfused juxtamedullary nephron preparation, we examined the effects of alterations in renal arterial pressure on afferent arteriolar blood flow. With video microscopy and cross-correlation techniques, arteriolar inside diameters and centerline erythrocyte velocity were measured to estimate single afferent arteriolar blood flow. In response to random changes in perfusion pressure, afferent arteriolar diameter (n = 8) varied inversely (-0.53 +/- 0.02%/mmHg), and erythrocyte velocity was directly related (1.4 +/- 0.1%/mmHg). Above 95 mmHg, the slope of the relationship between perfusion pressure and afferent arteriolar blood flow did not differ from zero (0.081 +/- 0.053%/mmHg), suggesting efficient autoregulation. When the tubuloglomerular feedback pathway was interrupted by the addition of furosemide (n = 9) or papillectomy (n = 7), there was attenuation of pressure-induced afferent arteriolar constriction, with impairment in blood flow autoregulation (0.60 +/- 0.05%/mmHg). Superfusion with diltiazem abolished autoregulatory responses in afferent arteriolar diameter and blood flow (1.5 +/- 0.2%/mmHg). These data demonstrate the autoregulation of blood flow of individual afferent arterioles in juxtamedullary nephrons and suggest that both tubuloglomerular feedback-dependent and -independent mechanisms are required for autoregulatory responses.

Abstract: This study was performed to evaluate the contribution of angiotensin II to the effects of nitric oxide (NO) synthesis inhibition on renal hemodynamics and excretory function in rats. Intravenous infusion of N omega-nitro-L-arginine (NLA; 20 micrograms/100 g.min) increased renal arterial pressure (RAP) from 128 +/- 2 to 143 +/- 3 mm Hg (P < 0.05; N = 6) and decreased RBF by 64 +/- 3% (P < 0.01) and GFR by 41 +/- 5% (P < 0.05). In response to reduction of RAP to control levels (127 +/- 2 mm Hg) by means of an adjustable clamp (CL) placed on the suprarenal aorta, RBF and GFR exhibited efficient autoregulation and were not altered. In rats (N = 6) pretreated with the AT1 angiotensin II receptor antagonist losartan (10 mg/kg iv), the infusion of NLA increased RAP (from 114 +/- 1 to 135 +/- 2 mm Hg; P < 0.05) and decreased RBF by 42 +/- 3% (P < 0.05). However, NLA did not decrease GFR in the losartan-treated rats. As in the control rats, the reduction of RAP to 113 +/- 1 mm Hg elicited autoregulatory responses that maintained RBF and GFR. In the untreated rats, at similar RAP (128 +/- 2 (control) versus 127 +/- 2 mm Hg (NLA+CL)). NO synthesis inhibition decreased urine flow and sodium excretion (P < 0.05, in both cases). However, during blockade of AT1 receptors, NLA infusion failed to decrease urine flow and sodium excretion, even when RAP was controlled (114 +/- 1 (control) versus 113 +/- 1 mm Hg (NLA+CL)).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: The renal vasculature is known to possess receptors for dopamine. The effects of dopamine and its mimetics on renal hemodynamics, however, have not been fully determined. In the present study, we have characterized the actions of the dopaminergic (DA1) agonist, YM435, on renal microvascular constriction induced by two dissimilar peptide vasoconstrictors, angiotensin II (AII) and endothelin (ET), in the isolated perfused hydronephrotic rat kidney. AII (0.3 nM) constricted afferent (AA) and efferent arterioles (EA) by 30 +/- 2% and 28 +/- 4%, respectively. ET (0.3 nM) preferentially constricted AA (37 +/- 2%) more than EA (18 +/- 2%). The subsequent administration of YM435 reversed the constrictor effects of AII or ET on both AA and EA in a dose-dependent manner. Although YM435 reversed AA and EA vasoconstriction induced by each peptide, the half-maximal inhibitory concentration for YM435 of ET-induced constriction exceeded that of AII (P < .001). Our findings constitute the first demonstration that YM435 is a potent vasodilator in the setting of either AII- or ET-induced AA and EA constriction. These results indicate that DA1 agonists reverse renal microvascular constriction mediated by AII and/or ET, and suggest that both AA and EA constitute the renal microvascular sites of action for DA1 agonists.

Abstract: The mechanisms mediating renal microvascular constriction induced by angiotensin II (Ang II) and endothelin (ET) have not been fully established. In the present study, we have determined the effects of isradipine, a dihydropyridine calcium antagonist, on Ang II- or ET-induced constriction of afferent arterioles (AAs) and efferent arterioles (EAs) using the isolated perfused hydronephrotic kidney. Ang II (0.3 nmol/L) and ET (0.3 nmol/L) constricted AAs by 36 +/- 2% and 29 +/- 3%, respectively. Isradipine reversed AA constriction induced by both peptides. However, Ang II-induced AA constriction was more sensitive to isradipine than ET-induced constriction (half-maximal inhibitory concentration [IC50], 1.2 +/- 0.2 nmol/L [n = 12] versus 170 +/- 65 nmol/L [n = 19]; P < .01). The sensitivity of Ang II-induced AA constriction to isradipine was identical to that of KCI-induced AA constriction (IC50, 4.2 +/- 0.9 nmol/L; n = 12). Pretreatment with staurosporine (50 nmol/L), a protein kinase C inhibitor, enhanced the sensitivity of ET-induced AA constriction to isradipine (4.3 +/- 1.7 nmol/L, n = 14), rendering it identical to that of KCl-induced AA constriction. Ang II and ET decreased EA diameter by 26 +/- 2% (n = 12) and 12 +/- 2% (n = 8), respectively. In contrast to AA constriction, EA constriction induced by both peptides was relatively refractory to isradipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: We have recently proposed that the actions of endothelin (ET) are in part mediated by opening of chloride channels (K. Iijima, L. Lin, A. Nasjletti, and M. S. Goligorsky. Am. J. Physiol. 260 (Cell Physiol. 29: C982-C992, 1991). In the present study the ability of a chloride channel inhibitor, an indanyloxyacetic acid (IAA-94), to block ET-induced effects was examined in cultured vascular smooth muscle cells (VSMC) by spectrofluorometry and direct videomicroscopic visualization of the renal microcirculation in isolated perfused hydronephrotic kidneys (IPHK). A fluorescein isothiocyanate (FITC)-labeled IAA-94 analogue showed specific binding to VSMC. IAA-94 (30 microM) neither affected basal cytosolic calcium concentration ([Ca2+]i) in VSMC nor peak response to ET, but it significantly curtailed sustained elevation of [Ca2+]i (half-time recovery was 147 +/- 23 vs. 248 +/- 33 s in control, P less than 0.05). IAA-94 blunted ET-induced membrane depolarization from 24.5 +/- 3.3 to 8.0 +/- 1.8 mV. In IPHK, ET constricted afferent arterioles (AA) by 29 +/- 2% (18.7 +/- 0.8 to 13.2 +/- 0.6 microns, P less than 0.001). Isradipine reversed this ET-induced vasoconstriction. Pretreatment with IAA-94 did not alter AA diameter, but markedly attenuated ET-induced AA constriction (reduction of AA diameters by only 9 +/- 2%, P less than 0.001). The subsequent addition of isradipine (0.1-1 microM) did not further dilate AA. Our data indicate that IAA-94 markedly attenuates AA vasoconstriction elicited by ET and suggest that ET-induced opening of chloride channels, membrane depolarization, and subsequent activation of voltage-dependent calcium channels contribute to the vasoconstrictor mechanisms of this peptide.

Abstract: The mechanisms mediating cyclosporin A (CsA)-induced nephrotoxicity have not been established, but damage to endothelial cells by CsA has been proposed as an important factor. In the study presented here, whether endothelial cell function is impaired in the renal vasculature of CsA-treated rats is investigated. The vasodilatory effects of acetylcholine (ACH) on norepinephrine (NE)-induced microvascular constriction in isolated perfused hydronephrotic rat kidneys pretreated with CsA were therefore examined. Hydronephrosis was established to permit direct visualization of renal microvessels. Nephrotoxicity was induced by s.c. injection of CsA (60 mg/kg/day for 5 days). NE (0.3 microM)-induced afferent arteriolar (AA) constriction was exaggerated in CsA rats as compared with that in vehicle (olive oil)-treated control rats. (reduction in diameter of -34 +/- 3 (SE) versus -26 +/- 2%; P less than 0.05). Similarly, efferent arteriolar (EA) constriction by NE in CsA rats exceeded that of controls (-34 +/- 2 versus -22 +/- 3%; P less than 0.01). The vasodilatory responses evoked by ACH were blunted in CsA rats. The AA response to ACH in CsA rats was significantly decreased (P less than 0.005) at ACH concentrations from 1 nM to 1 microM. Similarly, ACH (1 nM to 100 nM) induced less EA vasodilation in CsA rats (P less than 0.025). In control and CsA rats, the addition of nitro-L-arginine abolished AA and EA vasodilation induced by ACH, suggesting that the sustained vasodilatory responses of AA and EA to ACH are mainly dependent on nitric oxide synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: The mechanisms mediating abnormal renal autoregulation in Dahl salt-sensitive (DS) rats have not been fully defined. In the present study, we assessed myogenic responsiveness of interlobular arteries (ILAs), afferent arterioles (AAs), and efferent arterioles in isolated perfused hydronephrotic Dahl rat kidneys. Dahl rats were divided into four groups according to strain (Dahl salt-resistant [DR] or DS rats) and dietary sodium manipulation (rats fed low or high salt diets). Systolic blood pressure was elevated only in DS rats fed the high salt diet (202 +/- 4 mm Hg, p less than 0.05). Myogenic responses were obtained by stepwise elevation of renal arterial pressure. Vessel diameters were determined by computer-assisted videomicroscopy. Preglomerular microvessels of DS and DR rats responded differently to changes in renal arterial pressure. AAs and ILAs manifested diminished myogenic responsiveness to increasing renal arterial pressure in DS rats compared with DR rats (p less than 0.05). Both AAs and ILAs in DS rats manifested a higher threshold pressure for eliciting myogenic responses and a decrease in maximal pressure-induced vasoconstriction. The sensitivity of the AA myogenic response to nifedipine was enhanced in DS rats compared with DR rats (p less than 0.05). For rats fed the high salt diet, preglomerular vessels exhibited reduced myogenic responsiveness in both strains. In contrast to preglomerular microvessels, efferent arterioles from all four groups of rats failed to exhibit pressure-induced vasoconstriction. Our data suggest that diminished myogenic responsiveness of AAs and ILAs in DS rats contributes to impaired renal autoregulation in this strain.

Abstract: To elucidate the effect of natriuretic and antinatriuretic factors on the excretion of an intravenous sodium load, we observed the natriuretic responses of 12 patients with essential hypertension (EHT) and 7 age- and sex-matched normotensive (NT) subjects following the intravenous administration of 1500 mL of normal saline over a 3 h period. After saline infusion, both groups showed increases in urinary sodium excretion (UNaV). The increases in glomerular filtration rate (GFR), atrial natriuretic peptide (ANP) and urinary dopamine excretion (UDAV) and the suppression of plasma renin activity (PRA) were similar in both groups. However, no significant change in blood pressure (BP) was seen in either group. Since significant negative linear correlations between the basal level of PRA and percent change in UNaV or GFR were seen only in EHT, we observed the influence of suppressing the renin-angiotensin system with a converting enzyme inhibitor. After a 7 day treatment with enalapril, GFR and UNaV in EHT after saline infusion were comparable to data obtained in the absence of enalapril, despite a reduction in preexpansion BP. Furthermore, a significant positive correlation between the basal BP and the percent increase in UNaV was seen among EHT after enalapril treatment. These results suggest that the state of the renin-angiotensin system is important in renal sodium excretion in EHT.

Abstract: To examine the role of prostaglandins on pressure natriuresis in Dahl salt-sensitive (DS) rat, the pressure-natriuresis relationships in DS and Dahl salt-resistant (DR) rats were characterized with or without indomethacin (2 mg/kg/h) by utilizing an in vivo renal perfusion study. When untreated, in the DS rat the pressure-natriuresis curve was blunted (P less than .05) and excretion of prostaglandin E2 (38 +/- 11 to 109 +/- 43 pg/min) was decreased in comparison to the DR rat. With indomethacin, the pressure-natriuresis curve in the DR rat was blunted, while no significant changes were observed in the DS rat. Plasma renin activity and concentration of atrial natriuretic peptide were not changed by the treatment of indomethacin in both strains. These results suggest that the decrease in renal prostaglandins, at least in prostaglandin E2, plays some role in blunting pressure natriuresis in DS rat.

Abstract: The renal microvascular effects of DuP 753, an orally active imidazole angiotensin II (ANG II) receptor antagonist were assessed directly in isolated perfused hydronephrotic rat kidneys. Unilateral hydronephrosis was induced to facilitate direct visualization of renal microvessels. Hydronephrotic kidneys were perfused in vitro and microvessel diameters were measured by automated computer-assisted image processing. The administration of 0.3 nmol/L ANG II decreased afferent arteriolar (AA) and efferent arteriolar (EA) diameters by 34 +/- 3% (from 17.9 +/- 0.6 to 11.9 +/- 0.6 microns, P less than .001, n = 11) and 28 +/- 3% (from 17.1 +/- 1.3 to 12.3 +/- 1.3 microns, P less than .001, n = 11), respectively. The subsequent administration of 0.1, 1.0, and 10 mumols/L DuP 753 reversed ANG II-induced vasoconstriction of the AA by 39 +/- 10%, 81 +/- 8%, and 103 +/- 9%, and of the EA by 22 +/- 7%, 51 +/- 6%, and 87 +/- 13%, respectively. These observations indicate that DuP 753 completely blocks both the renal afferent and efferent arteriolar actions of ANG II. In light of the pathogenetic role of ANG II in mediating the deranged renal hemodynamics associated with hypertension, congestive heart failure, and some forms of renal insufficiency, our findings provide a theoretical framework for future studies assessing the potential therapeutic applicability of DuP 753 in reversing ANG II-mediated renal vasoconstriction.

Abstract: Plasma and urine norepinephrine, epinephrine and home blood pressure were measured in 48 young hypertensive men (mean age, 21 years) and 25 matched normotensive controls. Plasma samples were drawn following 30 min rest in the clinic and 24 h urine samples were collected at home. Twenty-one hypertensive patients were given a single dose of clonidine (150 micrograms orally). Changes in blood pressure, heart rate and plasma norepinephrine were assessed. Twenty-five of the hypertensive patients were found to have a normal home blood pressure (defined from records of the normotensive subjects). The other group of patients maintained a high home blood pressure. In comparison to normal subjects, patients with a high home blood pressure were characterized by higher urinary norepinephrine and epinephrine excretion and higher plasma epinephrine. Patients with a normal home blood pressure had normal heart rate at home, normal plasma and urinary catecholamines. However, the two groups of hypertensives could not be distinguished on the basis of clinic blood pressure, plasma or urinary catecholamines due to considerable overlap. At 90 min after oral clonidine administration, the plasma norepinephrine and blood pressure levels were decreased in both groups of hypertensives to a similar extent. The changes in heart rate were significantly smaller in patients with a high home blood pressure than in those with a normal home blood pressure. These results suggest that the patients with a high home blood pressure tended to have a high sympathetic nerve activity. However, the two groups of hypertensives could not be separated on the basis of plasma or urinary catecholamine measurements.

Abstract: The pressure-natriuresis relationships in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were characterized with or without intrarenal renin-angiotensin system (RAS) blockade. The pressure-natriuresis relationship in SHR was shifted toward higher pressure in comparison to WKY. The inhibition of intrarenal RAS by MK-422 (0.3 ug/kg/min) in SHR enabled to excrete more sodium at the same pressure (P less than 0.05), whereas no significant changes were observed in WKY. In SHR, during administration of Thi5,8, D-Phe7-bradykinin (50 micrograms/kg/min), the natriuretic responses to MK-422 were maintained. Intrarenal infusion of Sar1, Ile8-angiotensin (70 ng/kg/min) into SHR increased sodium excretion accompanied by an increase in renal plasma flow. Intrarenally administered angiotensin I (10 ng/kg/min) into WKY showed antinatriuretic effects with minimal changes in renal hemodynamics. These results indicate that alteration of intrarenal RAS in SHR might contribute to reset the pressure-natriuresis relationship.

Abstract: An autopsy case of an elderly man with Takayasu's arteritis and atherosclerosis is presented. Ischemic signs and symptoms including anginal attack were aggravated with activity of arteritis despite administration of prednisolone throughout the entire course. The autopsy revealed severe atherosclerosis over the aorta and its branches, and arteritis in the fibrotic stage in localized area. Vessels of vital organs including heart and kidneys, did not show Takayasu's arteritis but were atherosclerotic. This case highlights the numerous problems encountered in the treatment of elderly patients with vasculitis such as Takayasu's arteritis.

Abstract: The effects of the angiotensin-converting enzyme inhibitor captopril on blood pressure, heart rate, plasma prolactin, and renin activity were examined in a single-blind, placebo-controlled trial on 30 patients with essential hypertension (15 given drug, 15 placebo). Captopril, 25 mg administered orally, reduced the blood pressure and increased the plasma renin activity. Captopril decreased mean plasma prolactin from 17.5 +/- 1.4 ng/mL to 9.1 +/- 1.0 ng/mL (p less than 0.001). Significant correlation was found between captopril-induced change from control values of plasma prolactin (delta plasma prolactin) vs delta plasma renin activity (r = -0.688, p less than 0.001). These results suggest that acute administration of captopril was accompanied by a reduction in plasma prolactin and that this reduction may be of clinical significance during therapy of hypertension.

Abstract: A case of primary aldosteronism associated with renovascular hypertension is reported. The patient, a 46-year-old woman, developed hypertension to the level of 210/110 mmHg. Laboratory data included serum potassium 3.4mEq/l, plasma renin activity 25ng/ml/h and plasma concentration of aldosterone 330 pg/ml. Occlusion of the left renal artery and left adrenal aldosteronoma was diagnosed by radiographic and hormone analysis findings. Left adrenalectomy and nephrectomy corrected the hypertension. The possibility of tertiary aldosteronism is discussed.

Abstract: Plasma and urine norepinephrine, epinephrine, plasma renin activity and aldosterone were measured in 11 young men (mean age, 21 years) with a high blood pressure in the clinic who maintained a high home blood pressure and 12 men with an elevated clinic blood pressure who had a normal home blood pressure. Plasma samples were drawn following 30 min rest in the clinic, and 24-hour urine samples were collected at home. The two groups of hypertensives could not be distinguished on the basis of clinic blood pressure, plasma norepinephrine, epinephrine, renin activity or aldosterone. Patients with a high home blood pressure were characterized by a high urinary norepinephrine excretion. These results suggest that the patients whose blood pressure remained elevated at home had an increased sympathetic nerve activity at home.