Vol. 304, Issue 1, 370-379, January 2003

Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade on -Adrenoceptor Signaling in Heart Failure Produced by Myocardial Infarction in Rabbits: Reversal of Altered Expression of -Adrenoceptor Kinase and G_i

Takao Makino, Yuichi Hattori, Naoyuki Matsuda, Hisao Onozuka, Ichiro Sakuma and Akira Kitabatake

Departments of Pharmacology (Y.H., N.M.) and Cardiovascular Medicine (T.M., H.O., I.S., A.K.), Hokkaido University School of Medicine, Sapporo, Japan

Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT₁) receptor blockers have been demonstrated to improve symptoms and prognosis in heart failure (HF). We compared the effects of ACE inhibition and AT₁ receptor blockade on myocardial -adrenoceptor desensitization in rabbits with HF established 3 weeks after myocardial infarction (MI) with left circumflex coronary artery ligation. Rabbits with MI were randomized to no treatment, the ACE inhibitor temocapril (0.5 mg/kg/day) or AT₁ receptor blocker valsartan (3 mg/kg/day). Echocardiographic examinations showed that, relative to rabbits with untreated MI, rabbits receiving temocapril or valsartan had a limitation of cardiac remodeling and prevention of the development of systolic dysfunction. Circulating plasma norepinephrine levels that were markedly elevated in MI animals were strongly inhibited by temocapril or valsartan therapy. -Adrenoceptor density, -adrenoceptor proportion showing high-affinity agonist binding, and basal and isoproterenol-stimulated adenylate cyclase activities were significantly reduced in MI rabbits. These defects were similarly reversed by temocapril or valsartan. Importantly, as found in human HF, myocardial protein levels of -adrenoceptor kinase 1 and G_i were significantly elevated in MI rabbits, suggesting that these molecules are contributing to the defects in myocardial -adrenoceptor signaling. The expression levels of these molecules were normalized equally by both treatments. The results suggest that pharmacologically different interventions in the renin-angiotensin system can equivalently improve the derangements in the -adrenoceptor signaling system in the failing heart. This may be important for the beneficial effects of these agents in HF.