RT Journal Article
SR Electronic
T1 Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade on β-Adrenoceptor Signaling in Heart Failure Produced by Myocardial Infarction in Rabbits: Reversal of Altered Expression of β-Adrenoceptor Kinase and G<sub>iα</sub>
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 370
OP 379
DO 10.1124/jpet.102.040956
VO 304
IS 1
A1 Takao Makino
A1 Yuichi Hattori
A1 Naoyuki Matsuda
A1 Hisao Onozuka
A1 Ichiro Sakuma
A1 Akira Kitabatake
YR 2003
UL http://jpet.aspetjournals.org/content/304/1/370.abstract
AB 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 β-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. β-Adrenoceptor density, β-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 β-adrenoceptor kinase 1 and Giα were significantly elevated in MI rabbits, suggesting that these molecules are contributing to the defects in myocardial β-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 β-adrenoceptor signaling system in the failing heart. This may be important for the beneficial effects of these agents in HF. The American Society for Pharmacology and Experimental Therapeutics