POSTISCHEMIC ANTIARRHYTHMIC EFFECTS OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS - ROLE OF SUPPRESSION OF ENDOGENOUS ENDOTHELIN SECRETION

Background ACE inhibitors improve reperfusion function in several anim al models. We tested the hypothesis that ACE inhibitor-induced coronar y protection and inhibition of reperfusion arrhythmias are mediated by suppression of cardiac endothelin-1 (ET-1) secretion and action. Meth ods and Results The effects of two ACE inhibitors on ET-1 secretion an d mechanical function during ischemia and reperfusion were studied in perfused rat hearts. Drugs were infused during the control (60 minutes ), ischemic (60 minutes), and reperfusion (30 minutes) period. ET-1 ap pearing in coronary effluents and the interstitium was analyzed by rad ioimmunoassay. We observed (1) in hearts treated with ramiprilat (100 nmol/L) or captopril (5 mu mol/L), a significant reduction of ET-1 sec retion under all three experimental conditions and fewer ventricular e xtrasystoles during reperfusion; (2) increased ET-1 secretion and nume rous tachyarrhythmic events in the presence of ACE inhibitor and a bra dykinin B-2 receptor antagonist, icatibant (100nmol/L); (3) an almost- complete suppression of reperfusion arrhythmias when an ET receptor an tagonist, ie, SE 209670 (5 mu mol/L) or PD 142893 (200 nmol/L), was in fused together with ACE inhibitor and icatibant; and (4) SE 209670 alo ne to be equally antiarrhythmic as ACE inhibitors. Exogenous ET-1 (40 pmol/L) was proarrhythmic, whereas exogenous bradykinin (100 nmol/L) r educed ET-1 secretion and improved cardiac rhythm. Conclusions ACE inh ibitors suppress endogenous ET-1 secretion, which results in improved coronary function and stabilization of cardiac rhythm after ischemia i n this model. Suppression of ET-1 results from both removal of endogen ous angiotensin II and accumulation of endogenous bradykinin/nitric ox ide. ET receptor antagonists may be prime antiarrhythmic drugs worthy of testing in cardiac patients, either alone or together with ACE inhi bitors.