THE EFFECTS OF ORAL PRETREATMENT WITH ZOFENOPRIL, AN ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR, ON EARLY REPERFUSION AND SUBSEQUENT ELECTROPHYSIOLOGIC STABILITY IN THE PIG

The effects of oral zofenopril pretreatment were investigated in a chronic closed-chest pig model of ischemia and reperfusion. Pigs (25-35 kg) were pretreated orally with zofenopril (15 mg/day) on the 2 days prior to ischemia, which was evoked by the inflation of a catheter balloon in the left anterior descending coronary artery over 45 minutes. The catheter was then removed and the myocardium was reperfused. After 2 weeks, infarct properties were assessed by signal averaging of the body surface electrocardiogram and the inducibility of malignant ventricular tachyarrhythmias was tested with a programmed electrical stimulation protocol. A significant increase in the pressure-rate product (43±11%, mean±SEM), indicating the oxygen demand of the heart, was prevented by zofenopril (19±8%, p<0.05). Zofenopril reduced the peak efflux of adrenaline (1302±213 vs. 3201±760 pg/ml; p<0.05), noradrenaline (402±54 vs. 902±282 pg/ml; p<0.05), and of the adenosine catabolites inosine and hypoxanthine (56±4 vs. 78±9, pg/ml; p<0.05) in the coronary venous effluent. The efflux of the cytoplasmatic enzyme creatine phosphokinase was not significantly reduced after zofenopril (p=0.08). No difference in plasma renin levels between the groups were found. After 2 weeks, late potentials were found only in the surviving animals from the untreated group, i.e., the voltage vector magnitude was more reduced, and a prolongation of the QRS duration and of the terminal low-amplitude part of the high-frequency QRS were found. Moreover, zofenopril had caused a significant reduction of the inducibility of sustained ventricular tachyarrhythmias. These findings support the view that catecholamine and purine efflux, and an adverse increase in the oxygen demand during early reperfusion are reduced by zofenopril pretreatment, leading to a higher electrophysiologic stability of the subsequently developed infarct after 2 weeks. © 1990 Kluwer Academic Publishers.