Cardiac and renal effects of standard versus rigorous blood pressure control in autosomal-dominant polycystic kidney disease: results of a seven-year prospective randomized study.
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This study sought to investigate the cardiac and renal effects of rigorous versus standard BP control on autosomal-dominant polycystic kidney disease (ADPKD). A prospective, randomized, 7-yr study was performed to examine the effect of rigorous (<120/80 mmHg) versus standard (135-140/85-90 mmHg) BP control on left ventricular mass index (LVMI) and kidney function in 75 hypertensive ADPKD patients with left ventricular hypertrophy. LVMI was measured by echocardiogram at baseline and at 1 and 7 yr. Renal function was assessed by measuring serum creatinine and 24-h creatinine clearance every 6 mo for 3 yr, then annually for an additional 4 yr. The baseline characteristics were comparable in the two groups. During the study, average mean arterial pressure was 90 +/- 5 mmHg for the rigorous group and 101 +/- 4 mmHg for the standard group (P < 0.0001). The LVMI decreased by 21% in the standard group and by 35% in the rigorous group. A mixed model longitudinal data analysis revealed that rigorous BP control was significantly more effective in decreasing LVMI (P < 0.01). There was no statistically significant difference in renal function between the two groups. In conclusion, left ventricular hypertrophy, a major cardiovascular risk factor, was decreased to a significantly greater extent by rigorous than standard BP control. This finding has particular clinical importance because cardiovascular complications are the most common cause of death in ADPKD patients. (+info)
Impaired regulation of renal oxygen consumption in spontaneously hypertensive rats.
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Abnormalities of nitric oxide (NO) and oxygen radical synthesis and of oxygen consumption have been described in the spontaneously hypertensive rat (SHR) and may contribute to the pathogenesis of hypertension. NO plays a role in the regulation of renal oxygen consumption in normal kidney, so the response of renal cortical oxygen consumption to stimulators of NO production before and after the addition of the superoxide scavenging agent tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) was studied. Baseline cortical oxygen consumption was similar in SHR and Wistar-Kyoto (WKY) rats (SHR: 600 +/- 55 nmol O(2)/min per g, WKY: 611 +/- 51 nmol O(2)/min per g, P > 0.05). Addition of bradykinin, enalaprilat, and amlodipine decreased oxygen consumption significantly less in SHR than WKY (SHR: bradykinin -13.9 +/- 1.9%, enalaprilat -15.3 +/- 1.6%, amlodipine -11.9 +/- 0.7%; WKY: bradykinin -22.8 +/- 1.0%, enalaprilat -24.1 +/- 2.0%, amlodipine -20.7 +/- 2.3%; P < 0.05), consistent with less NO effect in SHR. Addition of tempol reversed the defects in responsiveness to enalaprilat and amlodipine, suggesting that inactivation of NO by superoxide contributes to decreased NO availability. The response to an NO donor was similar in both groups and was unaffected by the addition of tempol. These results demonstrate that NO availability in the kidney is decreased in SHR, resulting in increased oxygen consumption. This effect is due to enhanced production of superoxide in SHR. By lowering intrarenal oxygen levels, reduced NO may contribute to susceptibility to injury and renal fibrosis. Increasing NO production, decreasing oxidant stress, or both might prevent these changes by improving renal oxygenation. (+info)
Von Willebrand factor, soluble P-selectin, and target organ damage in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).
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To investigate the relationship between soluble markers of platelet, endothelial and rheological function, and target organ damage and their response to intensified management in a population of middle-age hypertensive patients at high risk of cardiovascular complications, we studied 382 consecutive patients (308 men; mean age, 63 years, SD 8) along with 60 normotensive controls free of cardiovascular disease. Patients were divided into those with target organ damage (TOD; n=107) and those free of end-organ damage. Plasma levels of soluble P-selectin (sP-sel), a marker of platelet activation, and von Willebrand factor (vWF), an index of endothelial damage/dysfunction (both enzyme-linked immunosorbent assay), and the rheological indices fibrinogen, plasma viscosity, hematocrit, platelet, and white cell count were measured. In 53 patients, variables were further measured after 6 months of intensified cardiovascular risk management. Patients with TOD had significantly higher vWF, 137 (SD 33) versus 125 (SD 33) IU/dL (P=0.002,) and a greater proportion of smokers, 31% versus 16% (P=0.002). There were no statistically significant differences in plasma viscosity, fibrinogen, hematocrit, white blood cell count, platelet count, or sP-sel between the 2 subgroups. In multivariate analysis, vWF was a significant independent predictor for TOD. After 6 months of intensified management in 53 patients who entered the trial, there were significant reductions in systolic blood pressure, total cholesterol, hematocrit, plasma viscosity, sP-sel, and vWF (all P<0.01) but no significant change in fibrinogen. In conclusion, there is a relationship between TOD and endothelial damage/dysfunction in hypertension. Intensified management results in improvements in hemorheology, endothelial and platelet function. (+info)
Amlodipine inhibits pro-inflammatory cytokines and free radical production and inducible nitric oxide synthase expression in lipopolysaccharide/interferon-gamma-stimulated cultured vascular smooth muscle cells.
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Overproduction of nitric oxide (NO) from inducible nitric oxide synthase (iNOS) is importantly involved in the pathogenesis of endotoxemia and atherosclerosis. Calcium antagonists are commonly used as cardiovascular drugs and have a beneficial effect on prolonging survival in various models of endotoxin shock. The present study was to investigate the effect of a calcium antagonist amlodipine on nitrite, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) formation and iNOS induction both in lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma)-treated rat aortic smooth muscle cells (RASMC) and in a rat model of endotoxemia. Incubation with amlodipine (0.1 - 10 microM) for 24 h resulted in a significant and dose-dependent attenuation in medium nitrite, TNF-alpha and IL-1beta formation as well as iNOS protein expression in LPS/IFN-gamma-treated RASMC. In addition, amlodipine inhibited leucigenin-induced superoxide formation in RASMC. In the rat endotoxic model, the serum nitrite/nitrate, TNF-alpha and IL-1beta levels as well as iNOS protein expression of lungs were also suppressed by administration of amlodipine (50 microg/kg, i.v.). These results suggest that amlodipine may exert vascular beneficial effects by suppressing pro-inflammatory cytokines and free radical generation as well as iNOS induction in smooth muscle cells during activation of inflammatory mechanism. (+info)
The effects of amlodipine on cerebral circulatory values in patients with essential hypertension.
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OBJECTIVE: This study assessed the effects of calcium channel blocker Amlodipine on the cerebral circulation in patients with essential hypertension. METHODS: Cerebral circulation in 37 patients with essential hypertension and 10 healthy subjects was assessed using rheoplethysmography. In patients with essential hypertension cerebral circulation values were also re-estimated after treatment with Amlodipine (5-10 mg daily). RESULTS: The cerebral circulatory parameters in hypertensive patients before treatment with Amlodipine were different from those in healthy persons. Amlodipine along with the reduction in systemic blood pressure caused attenuation of cerebrovascular abnormalities: decrease in spastic signs and increase in cerebral blood supply in patients with essential hypertension. CONCLUSION: Amlodipine causes reduction of cerebral vascular resistance and promotes improvement in arterial blood filling in patients with essential hypertension. These changes in cerebral circulation may be secondary to the increase of cardiac output--known effect of Amlodipine. (+info)
Differential effects of a long-acting angiotensin converting enzyme inhibitor (temocapril) and a long-acting calcium antagonist (amlodipine) on ventricular ectopic beats in older hypertensive patients.
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We studied differences in the effects of a long-acting angiotensin-converting enzyme (ACE) inhibitor (temocapril) and a long-acting calcium channel blocker (amlodipine) on ventricular ectopic beats (VEB) in relation to sympathetic nerve activity in 46 patients with essential hypertension. We performed 24-h Holter electrocardiography and ambulatory blood pressure (BP) monitoring simultaneously, and examined blood samples during the baseline, temocapril and amlodipine treatment periods. The ambulatory BP was lower in the amlodipine period than in the temocapril period. However, the number of VEB was significantly increased in the amlodipine period compared to that in the baseline period (11.9 vs. 7.4/day, p<0.05). In the temocapril period, the number of VEB was not significantly increased compared to that in the baseline period (8.6 vs. 7.4/day, p=0.30). Ambulatory heart rate (HR) was significantly increased in the amlodipine period compared to that in the baseline period (24-h HR: 70 vs. 66 bpm, p<0.001; daytime HR: 75 vs. 71 bpm, p<0.001; nocturnal HR: 60 vs. 58 bpm, p<0.05). Plasma norepinephrine (NE) also was significantly increased in the amlodipine period compared to that in the baseline period (457 vs. 369 pg/ml, p<0.001). However, when patients receiving amlodipine were divided into a high dose group (8.6 +/- 1.2 mg/day) and a low dose group (4.6 +/- 1.2 mg/day), increases in HR and plasma NE levels were found only in the high dose group. These results indicate that amlodipine is effective at lowering BP in older hypertensives, although it may increase VEB, especially when given at a high dose. (+info)
Effects of angiotensin converting enzyme inhibitor and calcium antagonist on endothelial function in patients with essential hypertension.
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The endothelium plays an important role in maintaining vascular tone and function. Essential hypertension is associated with alterations in endothelial function. The effects of antihypertensive agents on endothelial function have not been fully evaluated in human hypertension and data on the forearm circulation of humans are controversial. The aim of this study was to determine whether treatment with an angiotensin converting enzyme (ACE) inhibitor or a calcium antagonist improves endothelial dysfunction in hypertensive patients and whether the mechanism involved could be related to antioxidant activity. Endothelial function was estimated using venous occlusion plethysmography in 18 hypertensive patients and 11 healthy volunteers. The patients in the hypertension group were treated with enalapril or amlodipine. The change of forearm blood flow (FBF) was measured during acetylcholine infusion through the brachial artery and also during intra-arterial vitamin C infusion to explore the effects of vitamin C on responses to acetylcholine. FBF response to acetylcholine was significantly enhanced by intra-arterial infusion of vitamin C in the hypertensive group before antihypertensive treatment. Co-infusion of L-NMMA(N(G)-monomethyl-L-arginine), an inhibitor of nitric oxide synthase, blunted forearm blood flow response to acetylcholine. After antihypertensive treatment with enalapril or amlodipine for 2 months in the hypertensive group, endothelium-dependent vasorelaxation (vasodilatory response to acetylcholine) was significantly improved. Even though the mechanisms leading to depressed endothelial function in essential hypertension remain to be elucidated, our study shows that treatment with an ACE inhibitor or a calcium antagonist resulted in demonstrable improvement by a mechanism that is probably related to antioxidant activity. (+info)
Endothelin receptor antagonist combined with a calcium channel blocker attenuates renal injury in spontaneous hypertensive rats with diabetes.
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OBJECTIVE: To investigate the effects of the mixed endothelin receptor antagonist, bosentan, combined with the long-acting calcium channel blocker, amlodipine, compared to the angiotensin-converting enzyme inhibitor, cilazapril, on the progressive renal injury in spontaneous hypertensive rats (SHR) with diabetes. METHODS: Diabetic hypertensive rats (SHR-DM) were induced by streptozotozin injected in male SHR (7-week-old),and divided into an untreated and three treated groups: 1) cilazapril treated group; 2) bosentan+amlodipine treated group; and 3) amlodipine treated group. Wistar Kyoto rats (WKY) and SHR rats served as normotensive and hypertensive control, respectively. The mean arterial blood pressure, renal function, endothelin and angiotensin II levels as well as the protein expression of renal extracellular matrix components and transforming growth factor (TGF)-beta1 were determined at the end of the 4th week. RESULTS: Mean arterial blood pressure significantly increased in SHR and SHR-DM rats compared to WKY rats. All the therapies reduced the blood pressure to normal levels. However, the enhanced urinary protein excretion, the decreased creatinine clearance as well as the increased plasma and intrarenal endothelin and angiotens in II levels were found in the untreated SHR-DM and prevented by treatment with bosentan+amlodipine and cilazapril. Similarly, these two kinds of therapies in SHR-DM abolished the overexpression of renal TGF-beta1 by Western blot analysis and reduced the accumulation of collagen type IV, laminin and fibronectin proteins by an immunochemical approach. Amlodipine monotherapy had no detectable effects on the above parameters. CONCLUSION: Bosentan combined with amlodipine can offer similar renoprotective effects on that of cilazapril and may be a potent therapy to attenuate renal injury by reducing renal protein levels of TGF-beta1 in diabetes with a hypertensive state. (+info)