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Effects of angiotensin II AT1-receptor blockade on coronary dynamics, function, and structure in postischemic heart
M Gervais1, P Fornes, C Richer
1Département de Pharmacologie, Faculté de Medecine Paris-Sud (UPRES 392), Le Kremlin-Bicêtre, France.
Insights
Long-term treatment with Angiotensin II AT1-receptor blockers (AT1-s) improved coronary function and structure in rats with heart failure. Short-term treatment showed limited benefits, highlighting the importance of prolonged AT1-s therapy for cardiovascular health.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Heart Failure Pathophysiology
Background:
- Postischemic heart failure (CHF) in rats is characterized by impaired coronary dynamics and function.
- Angiotensin II AT1-receptor blockers (AT1-s) are known to prolong survival in this model.
- The specific effects of AT1-s on coronary function and structure over time remain to be fully elucidated.
Purpose of the Study:
- To investigate the impact of short- and long-term AT1-receptor blockade on coronary dynamics, endothelial function, and cardiac structure in experimental CHF.
- To determine if beneficial effects on coronary circulation correlate with survival prolongation.
Main Methods:
- Experimental heart failure induced by coronary artery ligation in rats.
- Treatment with irbesartan (an AT1-s) for 6 weeks or 6 months.
- Assessment of coronary blood flow and coronary dilatation reserve (CDR) using fluorescent microspheres and dipyridamole.
- In vitro assessment of coronary endothelial function via acetylcholine-induced relaxation.
- Histological analysis of cardiac hypertrophy and pericoronary fibrosis.
Main Results:
- CHF rats exhibited depressed CDR at 7 weeks and 6 months post-ligation; endothelial function was impaired only at 6 months.
- Short-term irbesartan treatment did not improve CDR or prevent cardiac remodeling.
- Long-term irbesartan treatment preserved right ventricular CDR, prevented endothelial dysfunction, limited cardiac hypertrophy and fibrosis, and improved hemodynamics.
Conclusions:
- In postischemic CHF, coronary dilatation reserve alterations precede endothelial dysfunction.
- Prolonged AT1-receptor blockade is crucial for maintaining coronary function, preventing endothelial degradation, and reducing adverse cardiac remodeling.
- These improvements in myocardial perfusion likely contribute to the survival benefits observed with long-term AT1-s therapy.
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.