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.

Abstract

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.

Angiotensin AT1 receptor antagonism and protection against cardiovascular end-organ damage

“…These results indicated that candesartan was superior to hydralazine as far as renal protection was concerned. 15 It has been reported that losartan 16,17 and candesartan cilexetil [18][19][20][21][22] also protected the development of cardiac hypertrophy in spontaneously hypertensive rats (SHR), but hydralazine did not, 19,21,22 although it reduced BP, supporting the assumption that AT 1 receptor antagonists have protective action against cardiac hypertrophy independent of BP-lowering action. In DOCA/salt hypertensive rats losartan also inhibited cardiac hypertrophy despite not having a significant anti-hypertensive action.…”

Continuous Blockade of L-Type Ca2+ Channels Suppresses Activation of Calcineurin and Development of Cardiac Hypertrophy in Spontaneously Hypertensive Rats

“…injection of nifedipine (Bayer Yakuhin, Ltd., Tokyo, Japan) (10 mg/kg/day) three times a day through the right jugular vein; 3) continuous infusion of nifedipine (10 mg/kg/day, 0.5 µl/h) by a subcutaneously implanted osmotic minipump (Alzet ® , model 2002; Muromachi Kikai Co., Ltd., Tokyo, Japan). All treatments were started from the age of 12 weeks, when cardiac hypertrophy had already developed (17), and continued to 24 weeks (Fig. 1).…”

“…1). Systolic blood pressure (BP) and heart rate (HR) were measured before treatment and every week after administration of vehicle or nifedipine using the tail-cuff plethysmography method in conscious rats (17). After 4, 8 and 12 weeks of treatment, 6 rats of each group were subjected to the following analyses.…”

Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress

“…13 We further investigated the relation between hypertensive cardiac hypertrophy and the cardiac reninangiotensin system. 14 In an in vivo study, spontaneously hypertensive rats (SHR) were assigned to the treatment with a nonpeptide Ang II type 1 receptor antagonist of candesartan or a vasodilating agent of hydralazine. Blood pressure was measured by a tail cuff method, and the wall thickness of the left ventricle was serially monitored using M-mode echocardiography.…”