Norepinephrine release and ventricular fibrillation in myocardial ischemia/reperfusion: Roles of angiotensin and bradykinin

Exogenous bradykinin (BK), acting at B-2-receptors, enhances norepinephrine (NE) release and exacerbates arrhythmias (VF) in myocardial ischemia/reper fusion. Inhibition of BK formation (with serine proteinase inhibitors) alle viates NE release and VF, whereas prevention of BK deg radation (with kinin ase inhibitors) potentiates them. Yet serine proteinase and kininase inhibi tors also prevent the formation of angiotensin (AII), a potent NE-release e nhancer. Thus we assessed the respective contribution of AII and BK to NE r elease and VF by using selective B-2- and AT(1)-receptor antagonists. Isola ted guinea pig hearts were subjected to 10- and 20-min global ischemia and 45-min reperfusion. NE overflow (pmol/g:) was similar to 8 (exocytotic) and similar to 750 (carrier mediated). VF, associated with carrier-mediated NE release, lasted similar to 2 min. The B-2-receptor antagonist Hoe 140 (30 nM) affected neither NE overflow nor VF. In contrast, the AT(1)-receptor an tagonist EXP3174 (100 mM) markedly reduced exocytotic and carrier-mediated NE release and shortened VF. When EXP3174 was combined with Hoe 140, NE ove rflow and VF were decreased even further. Thus in myocardial ischemia, loca l AII production contributes to NE release and VF via AT(1)-receptors. Alth ough BK production increases in myocardial ischemia, the effects of BK on a drenergic nerve terminals are uncovered only when BK half-life is prolonged and/or when AII effects are suppressed.