title: Additive beneficial effects of the combination of a calcium channel blocker and an angiotensin blocker on a hypertensive rat-heart failure model.
abstract: 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.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan. kimmitsu@gpo-u.ac.jp
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Izumi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yoshida
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
mesh_terms: D000419:Albuminuria; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002303:Cardiac Output, Low / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D003404:Creatinine / Q000097:blood; D004095:Dihydropyridines / Q000494:pharmacology; D004338:Drug Combinations; D004452:Echocardiography; D015870:Gene Expression; D006973:Hypertension / Q000150:complications*; D007093:Imidazoles / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D000068557:Olmesartan Medoxomil; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D020303:Rats, Inbred Dahl; D016019:Survival Analysis; D013777:Tetrazoles / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004338:Drug Combinations; D007093:Imidazoles; D013777:Tetrazoles; D013841:Thiazepines; D001383:Azetidinecarboxylic Acid; D000068557:Olmesartan Medoxomil; C055603:temocapril hydrochloride; D003404:Creatinine; C061679:azelnidipine