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Valsartan and coronary haemodynamics in early post-myocardial infarction in rats
M Gervais1, C Richer, P Fornes
1Département de Pharmacologie, Faculté de Médecine, Paris-Sud, Le Kremlin-Bicêtre, France.
Insights
Angiotensin II AT1 receptor blockade prolonged survival post-myocardial infarction (MI) in rats. Early blockade did not improve coronary vasodilatation reserve (CVR), suggesting other mechanisms are responsible for survival benefits.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Heart Failure Pathophysiology
Background:
- Angiotensin II AT1 receptor blockade improves survival in post-myocardial infarction (MI) heart failure.
- The role of early coronary vasodilatation reserve (CVR) improvement in this survival benefit is unclear.
Purpose of the Study:
- To investigate if early AT1 receptor blockade-induced improvement in CVR contributes to prolonged survival after MI.
- To assess the effects of valsartan on systemic and coronary hemodynamics and cardiac remodeling in post-MI rats.
Main Methods:
- Wistar rats with MI were treated with valsartan (5 or 50 mg/kg) or placebo for 6 weeks.
- Systemic and coronary hemodynamics, including CVR, were measured.
- Cardiac hypertrophy and fibrosis were assessed.
Main Results:
- Valsartan (5 mg/kg) had no significant effect on hemodynamics or cardiac remodeling, and decreased CVR.
- Valsartan (50 mg/kg) reduced blood pressure, limited cardiac hypertrophy but not fibrosis, and only improved right ventricular CVR.
- Neither dose improved overall CVR significantly.
Conclusions:
- Early AT1 receptor blockade-induced improvement in coronary hemodynamics is not responsible for long-term survival prolongation post-MI.
- Prevention of cardiac hypertrophy, but not fibrosis, suggests fibrosis is a key determinant of CVR.
Abstract:
Angiotensin II AT1 receptor blockade (AT1-) has been shown to prolong survival in post-myocardial infarction (MI) heart failure in rats. In this study, we investigated whether an early AT1-induced improvement in coronary vasodilatation reserve (CVR) might be involved in this beneficial effect. Wistar rats with MI were treated daily and orally for 6 weeks with valsartan, 5 (MI-V5) or 50 mg/kg (MI-V50). MI-controls and sham-operated rats (S-controls) received no treatment. Subsequently, systemic and coronary haemodynamics (at baseline and at maximal vasodilatation, CVR fluospheres) were investigated in the conscious state, and cardiac remodelling (hypertrophy and fibrosis) was assessed. As compared to MI-controls. valsartan (5 mg/kg), had no effect on systemic haemodynamics or myocardial hypertrophy and fibrosis development, gave slightly improved basal left and right ventricular coronary flow and resistance values, but decreased left and right CVR values. Valsartan (50 mg/kg), decreased blood pressure (-11%) and left ventricular end diastolic pressure (-32%), limited the development of cardiac hypertrophy (19%) but not that of fibrosis, slightly improved basal left ventricular flow and resistance values but only the right ventricular CVR value was increased. We conclude that in rats with post-MI. an early AT1-induced improvement in coronary haemodynamics is not responsible for the long-term survival prolongation observed. Furthermore. that cardiac hypertrophy was prevented whereas fibrosis was not, suggests that the latter is a pivotal determinant of CVR.