CARDIOPROTECTIVE EFFECTS BY RAMIPRIL AFTER ISCHEMIA AND REPERFUSION IN EXPERIMENTAL STUDIES

ACE inhibitors induce an increase in kinin levels with subsequent rele ase of nitric oxide (NO) and prostacyclin, as shown in cultured endoth elium cells and isolated rat hearts. Isolated perfused working rat hea rts continuously release kinins and prostacyclin. During ischemia afte r ligation of the left coronary artery kinin and prostacyclin concentr ations in the venous effluent of the hearts are increased. ACE inhibit ion with ramiprilat increases kinin concentrations during normoxia, is chemia and reperfusion, whereas deendothelialization markedly reduces kinin and prostacyclin outflow in controls as well as in ACE inhibitor -treated hearts. Rat hearts with postischemic reperfusion arrhythmias are protected by ramiprilat- and bradykinin perfusion, cardiodynamics and metabolism of treated hearts are improved. These effects are obser ved in concentrations too low to increase coronary flow. The cardiopro tective effects of ramiprilat and bradykinin are abolished by the spec ific B-2-kinin receptor antagonist icatibant and by an inhibitor of NO -synthase. Long-term treatment (20 weeks) with ramipril in a blood-pre ssure-lowering dose (1 mg/kg/day) and a sub-antihypertensive dose (10 mu mg/kg/day) protects spontaneously hypertensive rats (stroke prone) against hypertension and left ventricular hypertrophy in the high dose . In addition, both treatment regimens induce myocardial capillary gro wth. isolated hearts of these animals show increased myocardial contra ctility and coronary flow, reduced release of cytosolic enzymes into t he coronary effluent, and improved myocardial metabolism. These change s are observed even at a dose of ramipril which does not affect blood pressure and left ventricular hypertrophy. They are abolished by chron ic blockade of kinin receptors with icatibant. Conclusion: Perfusion o f isolated rat hearts with ramiprilat and bradykinin (in vitro), and l ong-term treatment with ramipril (ex vivo) has been shown to be cardio protective. These beneficial effects are abolished by B-2-kinin recept or blockade. Accumulation of endothelial derived kinins with subsequen t release of NO and prostacyclin most likely contributes to the benefi cial effects of the ACE inhibitor ramipril.