Circulation, Vol 89, 2204-2211, Copyright © 1994 by American Heart Association
M Kojima, I Shiojima, T Yamazaki, I Komuro, Z Zou, Y Wang, T Mizuno, K Ueki, K Tobe and T Kadowaki
BACKGROUND: Previous studies have demonstrated that angiotensin II (Ang II)
acts as a growth-promoting factor directly on cardiac myocytes and that
angiotensin-converting enzyme inhibitor induces regression of hypertrophied
hearts both in experimental animals and in humans. These results suggest
that the renin-angiotensin system (RAS) is involved in the formation of
left ventricular hypertrophy (LVH). To elucidate the role of RAS in the
progression of cardiac hypertrophy, we evaluated the effect of an Ang II
receptor antagonist on LVH in spontaneously hypertensive rats (SHRs) and
investigated the molecular mechanisms by which antagonizing Ang II
receptors reduces cell hypertrophy of myocytes using the in vitro model of
mechanical stretch. METHODS AND RESULTS: In the in vivo study, we treated
SHRs with the nonpeptide Ang II receptor antagonist TCV-116 (0.1, 1, or 10
mg/kg per day) or hydralazine (10 mg/kg per day). Blood pressure was
measured by the tail- cuff method, and wall thickness of left ventricle was
serially monitored using M-mode echocardiography. Rats were killed at the
age of 13, 17, 21, or 25 weeks, and left ventricular (LV) weight,
transverse diameter of cardiomyocytes, relative amount of V3 myosin heavy
chain (MHC), and degree of interstitial collagen accumulation were
examined. Untreated SHRs progressively developed severe hypertension, but
treatment with TCV-116 or hydralazine inhibited the increase in blood
pressure. Treatment with TCV-116 reduced LV weight, LV wall thickness,
transverse diameter of myocytes, relative amount of V3 MHC, and
interstitial fibrosis, whereas treatment with hydralazine slightly
prevented an increase in LV wall thickness but did not exert significant
reduction in other parameters. In the in vitro study, neonatal rat
cardiomyocytes were cultured on deformable silicone dishes and mechanically
stretched with or without pretreatment of CV-11974 (an active metabolite of
TCV-116), and [3H]phenylalanine incorporation, activity of
mitogen-activated protein (MAP) kinase, and c-fos mRNA expression were
analyzed. Pretreatment of cultured cardiomyocytes with 10(-7) mol/L
CV-11974 inhibited an increase in [3H]phenylalanine incorporation, MAP
kinase activity, and c-fos gene expression induced by stretch of
cardiomyocytes. CONCLUSIONS: The Ang II receptor antagonist TCV-116 induced
regression of cardiac hypertrophy and had cardioprotective effects on
hypertrophied myocardium in vivo, and antagonizing Ang II receptors
inhibited intracellular signaling of stretch-mediated cardiomyocyte
hypertrophy in vitro. These results suggest a crucial role of the cardiac
RAS in the development of LVH produced by pressure overload.
ARTICLES
Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro
Department of Medicine III, Tokyo University School of Medicine, Japan.
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