title: Effects of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on beta-adrenoceptor signaling in heart failure produced by myocardial Infarction in rabbits: reversal of altered expression of beta-adrenoceptor kinase and G i alpha.
abstract: 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 beta-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. beta-Adrenoceptor density, beta-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 beta-adrenoceptor kinase 1 and G(i alpha) were significantly elevated in MI rabbits, suggesting that these molecules are contributing to the defects in myocardial beta-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 beta-adrenoceptor signaling system in the failing heart. This may be important for the beneficial effects of these agents in HF.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Makino
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsuda
authors.forename: Hisao
authors.initials: H
authors.lastname: Onozuka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sakuma
authors.forename: Akira
authors.initials: A
authors.lastname: Kitabatake
mesh_terms: D000262:Adenylyl Cyclases / Q000096:biosynthesis; D000318:Adrenergic beta-Agonists / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis*; D015536:Down-Regulation / Q000187:drug effects; D004452:Echocardiography; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000096:biosynthesis*; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D020120:Iodocyanopindolol / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D009638:Norepinephrine / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits; D011869:Radioligand Assay; D044140:Receptor, Angiotensin, Type 1; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013841:Thiazepines / Q000494:pharmacology; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D000318:Adrenergic beta-Agonists; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D011943:Receptors, Adrenergic, beta; D013841:Thiazepines; D020120:Iodocyanopindolol; C055603:temocapril hydrochloride; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; D009638:Norepinephrine