MYOCARDIAL RELEASE OF ENDOTHELIN (ET) AND ENHANCED ET(A) RECEPTOR-MEDIATED CORONARY VASOCONSTRICTION AFTER CORONARY-THROMBOSIS AND THROMBOLYSIS IN PIGS

We investigated changes in vascular reactivity to endothelin (ET) and local release of ET-like immunoreactivity (ET-LI) induced by myocardial ischemia and reperfusion in a pig model of coronary thrombosis and thrombolysis and studied the possible mechanisms producing the changed vascular reactivity to ET-I, We induced coronary thrombosis by inserting a copper coil into the left anterior descending coronary artery (LAD) and achieved thrombolysis with tissue plasminogen activator (t-PA). Vascular reactivity to ET-1 in the nonischemic and ischemic/reperfused LAD diagonal branches was evaluated in vitro. ET-LI was analyzed in plasma from the great cardiac vein and aorta for estimation of local release. The vasoconstrictor response to ET-I was enhanced twofold (p < 0.01) in the ischemic/reperfused arteries as compared with the nonischemic arteries, The vasoconstriction induced by the ET(B) receptor agonist [Ala(1,3,11,15)]ET-1 Or serotonin was not significantly affected by ischemia/reperfusion. The ET(A) receptor antagonist BQ-123 reversed the ET-l-induced vascular contraction to a similar degree in ischemic/reperfused and control arteries. The ET-l-induced vasoconstriction of control arteries was not affected by inhibition of nitric oxide (NO) synthase with N-G-nitro-L-arginine (L-NNA) or cyclooxygenase with indomethacin, During reperfusion, the myocardial venoarterial plasma concentration difference of ET-LI and blood flow increased, resulting in an increased overflow of ET-LI, Our results demonstrate that coronary thrombosis and thrombolysis evokes enhanced local release of ET-LI during the reperfusion period and increases the vasoconstrictor effects of ET-1 through a mechanism related to ET(A) receptor activation but unrelated to altered endothelial function. These changes may play a role in the development of ischemic/reperfusion injury and no-reflow phenomenon.