ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS COUNTERACT HYPOXIA-INDUCED CORONARY CONSTRICTION IN THE ISOLATED RAT-HEART

The aim of this study was to evaluate the effects of three angiotensin-converting enzyme (ACE) inhibitors, one with a sulfhydryl group, captopril, and two without, enalapril and ramipril, on coronary flow during prolonged hypoxia in the isolated rat heart. Hypoxia, after a short-lasting vasodilation (20 minutes) induced a sustained coronary vasoconstriction. All the ACE inhibitors significantly increased the magnitude of early vasodilation and were highly effective in counteracting the hypoxia-induced vasoconstriction, but enalapril and ramipril were less potent than captopril. When captopril was compared with N-acetylcysteine no significant difference was found between the two groups. These data support the hypothesis that captopril may act in part through a sulfhydryl group-related mechanism. Combined administration of indomethacin excluded that the ACE inhibitors act through a prostacyclin-mediated mechanism. As it has been recently suggested that the ACE inhibitors have calcium blocking properties, the vasodilating effect of these drugs was also tested in the presence of a high calcium level in the hypoxic perfusate (from 2.5 to 3.75 mmol/L). In the presence of high calcium the early vasodilatory phase was significantly reduced and the rate and magnitude of the vasoconstriction were significantly increased. All the ACE inhibitors significantly affected the rate and entity of vasoconstriction, but captopril and N-acetylcysteine results were more effective than the ACE inhibitors without the sulfhydryl group. The additive vasodilating effect of captopril could be mediated by a decrease in myoplasmic calcium concentration due to the activation of cyclic guanasine monophosphate system related to the sulfhydryl group.