dihydropyridines and Cardiac-Output--Low

The present study was undertaken to examine the effects of a calcium channel blocker, azelnidipine (1 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, temocapril (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker (ARB), olmesartan (5 mg/kg/day), and their combination on Dahl salt-sensitive rats (DS rats) developing heart failure with preserved systolic function. DS rats were fed a high-salt diet (8% NaCl) from 7 weeks of age and progressively developed hypertension. Although monotherapy with azelnidipine lowered the blood pressure of DS rats to a greater extent than monotherapy with temocapril or olmesartan, the three drugs had similar effects on cardiac hypertrophy, cardiac fibrosis, the expressions of brain natriuretic peptide, transforming growth factor-beta1, collagen I, collagen III and monocyte chemoattractant protein-1 mRNA (as estimated by Northern blot analysis), and cardiac diastolic dysfunction (as estimated by echocardiography). These results show that ACE and AT1 receptor, as well as hypertension, are involved in the development of heart failure with preserved systolic function in DS rats. The combination of azelnidipine with olmesartan or temocapril produced no additive hypotensive effect in DS rats and no additive effect on cardiac hypertrophy or gene expressions. However, the combination therapy prolonged the survival rate of DS rats more than azelnidipine (p <0.01) or temocapril alone (p <0.05), and this additive beneficial effect by the combination therapy was associated with a greater reduction of cardiac fibrosis, urinary albumin excretion and serum creatinine. Our results thus showed that the combination of a calcium channel blocker with an ARB or an ACE inhibitor had additive preventive effects on a rat model of hypertensive heart failure with preserved systolic function. Thus, combination therapy with these agents seems to be a useful therapeutic strategy for the prevention of hypertensive heart failure.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cardiac Output, Low; Creatinine; Dihydropyridines; Drug Combinations; Echocardiography; Gene Expression; Hypertension; Imidazoles; Myocardium; Olmesartan Medoxomil; Organ Size; Rats; Rats, Inbred Dahl; Survival Analysis; Tetrazoles; Thiazepines

The goal of this study was to compare responses to a calcium promoter, BAY y 5959, and dobutamine (Dob) in heart failure (HF). Dogs (n = 9) were chronically instrumented and studied in the conscious state before and after pacing-induced HF. In the control state, BAY y 5959 (20 microgram. kg-1. min-1) increased the first derivative of left ventricular (LV) pressure (dP/dt) by 83 +/- 8% and mean arterial pressure (MAP) by 8 +/- 2% and decreased heart rate (HR) by 30 +/- 3%. With Dob (10 microgram. kg-1. min-1) LV dP/dt rose similarly (+80 +/- 6%), but HR also rose (+25 +/- 4%) (P < 0.05 vs. BAY y 5959). After HF developed, BAY y 5959 still increased LV dP/dt by 108 +/- 8% and MAP by 21 +/- 2% and decreased HR by 28 +/- 4%, whereas Dob increased LV dP/dt by only 50 +/- 7% (P < 0.05 vs. BAY y 5959) and MAP by 7 +/- 3%, and HR did not change (+3 +/- 3%) (P < 0.05 vs. BAY y 5959). In HF, cardiac work increased more (P < 0. 05) with BAY y 5959 (+105 +/- 13%) compared with Dob (+47 +/- 11%), yet myocardial oxygen consumption increased similarly with the two drugs. Accordingly, mechanical efficiency increased more (P < 0.05) with BAY y 5959 (+73 +/- 14%) than with Dob (+17 +/- 12%). These data indicate that 1) increases in contractility mediated directly by Ca2+ are relatively resistant to desensitization in HF; and 2) the calcium-channel promoter can produce increases in myocardial contractility and cardiac work similar to those of Dob at a significantly lower oxygen cost, thereby enhancing mechanical efficiency in HF.

Topics: Animals; Calcium Channel Agonists; Calcium Channels; Cardiac Output; Cardiac Output, Low; Cardiotonic Agents; Catecholamines; Dihydropyridines; Dobutamine; Dogs; Drug Resistance; Female; Heart Rate; Hemodynamics; Male; Myocardial Contraction; Oxygen Consumption; Ventricular Function, Left