To investigate the influence of local cardiac converting
enzyme (CE) inhibition on the effects of
angiotensin I (ANG I), ANG II, and
bradykinin (BK), experiments were performed in ischemic isolated perfused working rat hearts. Acute regional
myocardial ischemia was induced by 15 min occlusion of the left coronary artery followed by reperfusion. In ischemic isolated rat hearts, perfusion with
ramiprilat (100 ng/ml, 2.58 x 10(-7) mol/l), the active moiety of the CE inhibitor
ramipril, after
coronary occlusion protected against
ventricular fibrillation that invariably occurred in untreated control hearts in the reperfusion period. Addition of ANG I and ANG II to the perfusate enhanced, whereas BK reduced postischemic reperfusion arrhythmias, which were almost abolished in the hearts from
ramipril (1 mg/kg p.o.) pretreated rats. Perfusion with ANG I and ANG II reduced cardiac function and coronary flow, increased the activities of
lactate dehydrogenase and
creatine kinase in the perfusate, and decreased high-energy-rich
phosphates and
glycogen in the myocardium. In contrast, BK reduced the enzymatic activities in the perfusate and improved the metabolic parameters in the myocardium. In hearts from
ramipril pretreated animals, the ANG I effects were abolished, whereas the ANG II actions remained unchanged. The results of these experiments are consistent with the hypothesis that the beneficial effects of CE inhibitors on ventricular
arrhythmias, cardiac function, and metabolism are due to local interference with CE in the coronary vascular wall or heart tissue and subsequent reduction of local ANG II generation and BK degradation.