Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine.
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OBJECTIVES: Our aim was to investigate the potential therapeutic role of endothelial nitric oxide synthase (eNOS) in the modulation of cardiac O(2) consumption induced by the angiotensin converting enzyme (ACE) inhibitor ramiprilat and amlodipine. METHODS: Three different groups of mice were used; wild type, wild type in the presence of N-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/l) or genetically altered mice lacking the eNOS gene (eNOS -/-). Myocardial O(2) consumption was measured using a Clark-type O(2) electrode in an air-tight stirred bath. Concentration-response curves to ramiprilat (RAM), amlodipine (AMLO), diltiazem (DIL), carbachol (CCL), substance P (SP) and S-nitroso-N-acetyl-penicillamine (SNAP) were performed. The rate of decrease in O(2) concentration was expressed as a percentage of the baseline. RESULTS: Baseline O(2) consumption was not different between the three groups of mice. In tissues from wild type mice, RAM (10(-5) mol/l), AMLO (10(-5) mol/l), DIL (10(-4) mol/l), CCL (10(-4) mol/l), SP (10(-7) mol/l) and SNAP (10(-4) mol/l) reduced myocardial O(2) consumption by -32+/-4, -27+/-10, -20+/-6, -25+/-2, -22+/-4 and -42+/-4%, respectively. The responses to RAM, AMLO, CCL and SP were absent in tissues taken from eNOS -/- mice (-7.1+/-4.3, -5.0+/-6.0, -5.2+/-5.1 and -0.4+/-0.2%, respectively). In addition, L-NAME significantly (P<0.05) inhibited the reduction in O(2) consumption induced by RAM (-9.8+/-4.4%), AMLO (-1.0+/-6.0%), CCL (-8.8+/-3.7%) and SP (-6.6+/-4.9%) in cardiac tissues from wild type mice. In contrast, NO-independent responses to the calcium channel antagonist, DIL, and responses to the NO donor, SNAP, were not affected in cardiac tissues taken from eNOS -/- (DIL: -20+/-4%; SNAP: -46+/-6%) or L-NAME-treated (DIL: -17+/-2%; SNAP: -33+/-5%) mice. CONCLUSIONS: These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O(2) consumption. This action may contribute to the therapeutic action of ACE inhibitors and amlodipine. (+info)
Effects of long-term treatment with calcium antagonists on periarterial nerve function in the mesenteric artery of spontaneously hypertensive rats.
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The effect of long-term treatment with dihydropyridine calcium antagonists (amlodipine, pranidipine, nicardipine) on the periarterial nerve function was investigated in the perfused mesenteric vascular bed isolated from spontaneously hypertensive rat (SHR). Male 8-week-old SHR received amlodipine (0.01% and 0.02%) and nicardipine (0.1%) in drinking water and pranidipine (0.0035% and 0.035%) in rat chow for 7 weeks. Mean blood pressure in SHR was significantly lowered by long-term treatment with each calcium antagonist. In mesenteric vascular preparations treated with each calcium antagonist, vasoconstriction induced by periarterial nerve stimulation (PNS; 4, 8 and 12 Hz) was significantly smaller than that in non-treated SHR. The PNS (8 Hz)-evoked norepinephrine (NE) overflow in the perfusate was significantly decreased by amlodipine and pranidipine treatment, whereas nicardipine-treatment significantly enhanced the overflow of NE. In preparations with active tone produced by methoxamine and guanethidine, the PNS-induced vasodilation mediated by calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves was not affected by these drugs. These results suggest that long-term treatment of SHR with long-acting drugs, amlodipine and pranidipine, reduces sympathetic adrenergic nerve function but calcium antagonists have no effect on CGRPergic nerve function. (+info)
Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients.
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Hypertension and hyperfiltration are two important risk factors for the development of chronic allograft nephropathy. Transforming growth factor-beta(1) (TGF-beta(1)) is the main cytokine involved in the fibrotic process that is involved in chronic rejection. Angiotensin II upregulates TGF-beta(1) production. Angiotensin II receptor antagonists therefore could not only control BP but also reduce TGF-beta(1) production in renal transplant patients. The aim of this study was to compare the effects of losartan and amlodipine on renal hemodynamics, as well as TGF-beta(1) and endothelin-1 (ET-1) plasma levels in a group of renal transplant patients who had normal renal function and who were treated with cyclosporine. Seventeen renal transplant patients who were receiving cyclosporine and who had normal graft function were included in a random 2 x 2 crossover trial with amlodipine and losartan (6 wk with each therapy). Three studies were performed (at baseline and at the end of both treatment periods) to determine renal hemodynamics, TGF-beta(1), and ET-1. Both treatments controlled BP to a similar degree, but only amlodipine increased GFR through an increase in the estimated glomerular hydrostatic pressure and filtration fraction. In contrast, losartan maintained GFR and reduced estimated glomerular hydrostatic pressure and filtration fraction significantly. Losartan and amlodipine had opposite effects on TGF-beta(1). Amlodipine did not affect TGF-beta(1) concentrations. In contrast, losartan reduced the plasma levels of TGF-beta(1) by approximately by 50% (from baseline, 5.2 to 2.6 ng/ml; P: = 0.01); the majority of the patients reached normal levels of TGF-beta(1). ET-1 concentrations were significantly higher during amlodipine compared with losartan treatment. The present study documents that with similar control of BP, losartan and amlodipine have opposite effects on renal hemodynamics and on TGF-beta1 concentrations. These differences could be important for the management of chronic allograft nephropathy. (+info)
Antihypertensive efficacy of amlodipine in children with chronic kidney diseases.
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In adults the calcium antagonist amlodipine given once a day has proved to be an attractive addition to the antihypertensive armamentarium. The present report describes our experience in 43 paediatric outpatients (26 boys and 17 girls, aged between 1.1 and 19, median 9.8 years) with chronic kidney diseases. The patients were given amlodipine for 16 weeks as part of their antihypertensive treatment. Before amlodipine arterial pressure was 150 (142-163)/90 (84-95) mm Hg (median and interquartile range). Six patients withdrew from amlodipine because of oedema, flushing or headache. In the remaining patients amlodipine 7.7 (6.9-9.4) mg/m(2) body surface area once a day significantly decreased arterial pressure by 17 (13-22)/10 (7-13) mm Hg. The efficacy of amlodipine was more pronounced in girls than in boys. No changes in heart rate, body weight and circulating haemoglobin, sodium, potassium and creatinine were noted. In none of the patients circulating potassium, sodium or creatinine changed by more than 0.5 mmol/l, 5 mmol/l respectively 20%. In 11 patients concomitantly treated with cyclosporine the dosage and the trough-level of this agent were stable throughout the trial. In conclusion the present experience in paediatric outpatients with chronic kidney diseases supports the view that amlodipine is an effective and rather well tolerated antihypertensive drug when given once a day. (+info)
Usefulness of serum carboxy-terminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients.
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BACKGROUND: We investigated whether serum concentration of carboxy-terminal propeptide of procollagen type I (PIP), a marker of collagen type I synthesis, can be used to assess the ability of antihypertensive treatment to regress myocardial fibrosis in hypertensive patients. METHODS AND RESULTS: The study was performed in 37 patients with essential hypertension and hypertensive heart disease. After randomization, 21 patients were assigned to losartan and 16 patients to amlodipine treatment. At baseline and after 12 months, right septal endomyocardial biopsies were performed to quantify collagen volume fraction (CVF) on picrosirius red-stained sections with an automated image-analysis system. Serum PIP was measured by specific radioimmunoassay. Nineteen patients in the losartan group and 11 in the amlodipine group finished the study. Time-course changes in blood pressure during treatment were similar in the 2 groups of patients. In losartan-treated patients, CVF decreased from 5.65+/-2.03% to 3.96+/-1.46% (P<0.01) and PIP from 127+/-30 to 99+/-26 microgram/L (P<0.01). Neither CVF or PIP changed significantly in amlodipine-treated patients. CVF was directly correlated with PIP (r=0.44, P<0.001) in all hypertensives before and after treatment. CONCLUSIONS: These findings suggest that the ability of antihypertensive treatment to regress fibrosis in hypertensives with biopsy-proven myocardial fibrosis is independent of its antihypertensive efficacy. Our data also suggest that blockade of the angiotensin II type 1 receptor is associated with inhibition of collagen type I synthesis and regression of myocardial fibrosis in hypertensives. Thus, determination of serum PIP may be useful to assess the cardioreparative properties of antihypertensive treatment in hypertensives. (+info)
Right atrial function in hypertensive patients: effects of antihypertensive therapy.
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OBJECTIVES: The effects (16 weeks) of oral antihypertensive drugs on right atrial (RA) function were evaluated by two-dimensional and Doppler echocardiography in 64 patients with mild-to-moderate essential hypertension. Thirty-two age- and sex-matched normal subjects served as controls. BACKGROUND: Hypertension alters the diastolic properties of the left ventricle and disturbs the left atrial contractile activities. RA performance may also alter in essential hypertension. METHODS: From the tricuspid flow velocity curves the E/A ratio, the velocity-time integrals (Ei and Ai, respectively) as well as the sum, TTi = Ei + Ai, were measured. RA active contribution (RAAC) was expressed as the ratio RAAC = Ai/TTi. RESULTS: RA-A/E ratio, RA-Ai and RAAC were increased while RA-TTi were decreased in hypertensives compared to controls, P < 0.0001 for all comparisions. After therapy TTi increased (from 13.2 +/- 1.6 to 16.2 +/- 2.0 cm with ramipril, and from 12.9 +/- 1.1 to 14.4 +/- 1.2 cm with amlodipine, P < 0.001) and RAAC decreased (from 0.19 +/- 0.01 to 0.13 +/- 0.01, with ramipril and from 0.19 +/- 0.01 to 0.16 +/- 0.00, with amlodipine P < 0.001) while RA dimensions did not change. the decrease in RAAC was significantly greater with ramipril (P < 0.001) and was significantly influenced by the decrease in left ventricular mass (P < 0.001) and right ventricular relaxation (P < 0.001). CONCLUSIONS: RA function is deteriorated in patients with essential hypertension. The fall in the arterial blood pressure produced by antihypertensive treatment was associated with improved RA performance and reduced left ventricular mass without changes in RA dimensions. The left ventricular mass and the right ventricular relaxation influenced the changes in RA performance. (+info)
Once-daily treatment of patients with hypertension: a placebo-controlled study of amlodipine and benazepril vs amlodipine or benazepril alone.
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OBJECTIVE: To compare the efficacy, tolerability, and safety of once-daily therapy with amlodipine 5 mg/benazepril 10 mg vs amlodipine 5 mg, benazepril 10 mg, and placebo. DESIGN: Randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. SETTING: Twenty-two clinical centres, including private practice groups and academic research clinics. PATIENTS: A total of 530 patients between 21 and 80 years of age with essential hypertension were screened for the study, and 454 were randomised to treatment with amlodipine 5 mg/benazepril 10 mg, amlodipine 5 mg, benazepril 10 mg, or placebo for 8 weeks. RESULTS: Amlodipine 5 mg/benazepril 10 mg produced greater reductions from baseline in sitting diastolic blood pressure than amlodipine 5 mg (P < 0.03), benazepril 10 mg (P < 0.001), and placebo (P < 0.001). The response rate in the amlodipine 5-mg/benazepril 10-mg treatment group (66.4%) was better than that observed in the amlodipine 5-mg (50.0% P < 0.02), benazepril 10-mg (38.3% P < 0.001), and placebo (24.4% P < 0.001) groups. There was no significant difference in heart rate among the four groups. The incidence of oedema in the amlodipine 5-mg/benazepril 10-mg (1.7%) group was somewhat less than that in the amlodipine 5-mg (4.5%) group. CONCLUSIONS: Therapy with amlodipine 5 mg/benazepril 10 mg was well tolerated and was superior to amlodipine 5 mg, benazepril 10 mg, and placebo in reducing sitting diastolic blood pressure in patients with essential hypertension. (+info)
Efficacy and safety of a therapeutic interchange from high-dose calcium channel blockers to a fixed-dose combination of amlodipine/benazepril in patients with moderate-to-severe hypertension.
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BACKGROUND: Recent hypertension trials have demonstrated the importance of achieving goal blood pressures to reduce the risk of target organ damage. In patients with moderate to severe hypertension, the use of high-dose monotherapy and/or combinations of drugs are necessary to achieve these goals. Fixed-dose combination products may be useful in these patients by reducing the number of daily doses required to control blood pressure. OBJECTIVE: The objective of the present study was to evaluate the efficacy and safety of a therapeutic interchange between high-dose calcium channel blocker therapy and a fixed-dose combination of amlodipine/ benazepril (Lotrel; Novartis Pharmaceuticals, USA) in patients with moderate to severe hypertension. METHODS: A total of 75 patients were switched from amlodipine (n = 25), felodipine (n = 25), and nifedipine-GITS (n = 25) to amlodipine/benazepril. Twenty-eight of the 75 patients (37%) were taking either a beta-blocker or a diuretic in addition to the high-dose calcium channel blocker prior to the switch. Blood pressure control, side effects and the cost of the therapeutic interchange were evaluated in the year following the therapeutic interchange. RESULTS: Sixty-six of the 75 (88%) patients were successfully switched with maintenance of blood pressure control and without the development of new dose-limiting side effects. Reasons for treatment failure after the therapeutic interchange included loss of blood pressure control in five patients and the development of new dose-limiting side effects in four patients. These side effects included cough in three patients and rash in one patient. After accounting for differences in drug acquisition cost and costs related to the switch (clinic and emergency room and laboratory tests), a cost savings of $16030 for all 75 patients was realised in the first year. The per patient-per year cost savings was $214. CONCLUSIONS: Our data indicate that a therapeutic interchange from selected high-dose calcium channel blockers to a fixed-dose combination of amlodipine/ benazepril can be successfully accomplished in the majority of patients. (+info)