title: Effects of angiotensin II AT1-receptor blockade on coronary dynamics, function, and structure in postischemic heart failure in rats.
abstract: Angiotensin II AT1-receptor blockers (AT1-s) prolong survival in experimental postischemic (coronary artery ligation) heart failure (CHF) in rats. The goal of this study was to investigate whether potential beneficial effects of short- and/or long-term treatment with AT1-s on coronary dynamics, function, and structure develop along with the drug-induced survival prolongation in this model. Coronary blood flow was measured (fluorescent microspheres) in conscious sham, untreated, and irbesartan-treated (50 mg/kg daily for 6 weeks or 6 months, starting 8 days after surgery) CHF rats at baseline and at maximal vasodilatation induced by dipyridamole, and coronary dilatation reserve (CDR) was calculated as the ratio of maximal to baseline coronary flow. Coronary endothelial function was assessed in vitro by measuring the coronary relaxant responses to acetylcholine in the three groups of animals. Finally, cardiac hypertrophy and pericoronary fibrosis also were investigated. In CHF rats, left (LV) and right (RV) ventricular CDR were markedly depressed at both 7 weeks and 6 months after ligation, whereas coronary endothelial function was significantly impaired only after 6 months. Short-term AT1-receptor blockade with irbesartan did not prevent CDR deterioration at 7 weeks, nor did it significantly oppose cardiac hypertrophy and pericoronary fibrosis development. Prolonged AT1-receptor blockade prevented both RV CDR deterioration and coronary endothelial function impairment. It also limited significantly the increase in LV end diastolic pressure and the development of cardiac hypertrophy and pericoronary fibrosis. In conclusion, in postischemic CHF in rats, alterations of CDR precede those of coronary endothelial function. Long-, but not short-term AT1-receptor blockade prevents endothelial function degradation, opposes RV CDR impairment, prevents pericoronary fibrosis development, and improves systemic hemodynamics. These effects of AT1-s on coronary dynamics, function, and structure (i.e., on myocardial perfusion) may contribute to the drug-induced survival prolongation in this model.
authors.affiliation: Département de Pharmacologie, Faculté de Medecine Paris-Sud (UPRES 392), Le Kremlin-Bicêtre, France.
authors.forename: M
authors.initials: M
authors.lastname: Gervais
authors.forename: P
authors.initials: P
authors.lastname: Fornes
authors.forename: C
authors.initials: C
authors.lastname: Richer
authors.forename: D
authors.initials: D
authors.lastname: Nisato
authors.forename: J F
authors.initials: JF
authors.lastname: Giudicelli
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000077405:Irbesartan; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles / Q000494:pharmacology*; D014664:Vasodilation
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000077405:Irbesartan