Therapeutic effects of angiotensin II type 1 receptor blocker at an advanced stage of hypertensive diastolic heart failure.
OBJECTIVE
Angiotensin II type 1 receptor blocker (ARB) is increasingly prescribed for the treatment of systolic heart failure with a growing body of clinical evidence. The roles of ARB, however, remain to be clarified in the treatment of diastolic heart failure (DHF), particularly at its advanced stage. This experimental study investigated the effects of ARB administered at an advanced stage of hypertensive DHF.


METHODS
Dahl salt-sensitive rats fed an 8% NaCl diet from age 7 weeks represent overt DHF at age 20 weeks, as noted in previous studies (hypertensive DHF model). The DHF model rats were randomly divided into two groups at age 17 weeks when left ventricular diastolic dysfunction, hypertrophy, fibrosis, macrophage infiltration and reactive oxygen species generation were already augmented; six rats treated for 3 weeks with a subdepressor dose of ARB (olmesartan 0.6 mg/kg per day), and six untreated rats.


RESULTS
The 3-week administration of ARB significantly decreased the left ventricular end-diastolic pressure in association with attenuation of left ventricular hypertrophy, fibrosis and diastolic dysfunction. Macrophage infiltration was attenuated with decreased gene expression of transforming growth factor-beta1 and monocyte chemoattractant protein-1 in the left ventricular myocardium of the ARB-treated rats. The production of reactive oxygen species also decreased with NADPH oxidase activity.


CONCLUSIONS
ARB provides beneficial effects in hypertensive DHF independent of its antihypertensive effects even if initiated at an advanced stage. The beneficial effects are at least partly attributed to the attenuation of inflammatory changes and oxidative stress through the suppression of cytokine and chemokine production and of NADPH oxidase activity.
Nishio
Mayu
M
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Sakata
Yasushi
Y
Mano
Toshiaki
T
Yoshida
Junichi
J
Ohtani
Tomohito
T
Takeda
Yasuharu
Y
Miwa
Takeshi
T
Masuyama
Tohru
T
Yamamoto
Kazuhiro
K
Hori
Masatsugu
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy*; D006973:Hypertension / Q000188:drug therapy; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation; D008297:Male; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D018932:Chemokine CCL2; D007093:Imidazoles; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D053773:Transforming Growth Factor beta1; C437965:olmesartan; D019255:NADPH Oxidases