Antiarrhythmic effects of the angiotensin converting enzyme inhibitor perindoprilat in a pig model of acute regional myocardial ischemia
Muller, C.A.; Opie, L.H.; Peisach, M.; Pineda, C.A.
Journal of Cardiovascular Pharmacology 19(5): 748-754
1992
ISSN/ISBN: 0160-2446 PMID: 1381773 Document Number: 390566
Previous studies on the possible antiarrhythmic effects of angiotensin converting enzyme (ACE) inhibitors during early ischemia in pigs have been conclusive or negative; however, proof of adequate ACE inhibition was not provided. Perindoprilat, 0.06 mg/kg, i.v., was administered 30 min prior to ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Plasma ACE activity was decreased by 95.0 .+-. 1.9% when measured 5 min before CAL. Within 5 min of CAL, the ventricular fibrillation threshold (VFT) in the control group was decreased from 11.8 .+-. 1.9 to 7.2 .+-. 1.2 mA (p < 0.01). Perindoprilat prevented the fall in the VFT and the increase in left ventricular end-diastolic pressure caused by CAL. Perindoprilat decreased arterial pressure. Cardiac output (thermodilution) was decreased by 23 .+-. 3% after CAL in the control group and by only 10 .+-. 5% (p < 0.05) in the perindoprilat group (both versus pre-CAL values). In the control group cyclic AMP was increased from 0.97 .+-. 0.04 (pre-CAL) to 1.16 .+-. 0.04 nmol/g (p < 0.05) in the central ischemic zone 20 min after CAL. Perindolprilat prevented this increase in cyclic AMP. Twenty minutes after CAL blood flow (microsphere method) in the nonischemic zone of the perindoprilat group was increased, whereas blood flow in the central ischemic zone was decreased compared to the control group. However, levels of tissue metabolite (ATP, phosphocreatine, lactate) measured in drill biopsies in the same zones of the two groups were similar. The antiarrhythmic effects of perindoprilat at a dose that adequately inhibits plasma ACE activity in this model are possibly related to an improvement in hemodynamics and/or to prevention of the rise of cyclic AMP in the ischemic zone.