Bradykinin promotes ischemic norepinephrine release in guinea pig and human hearts

We previously reported that bradykinin (BK; 1-1000 nM) facilitates norepine phrine (NE) release from cardiac sympathetic nerves. Because BK production increases in myocardial ischemia, endogenous BK could foster NE release and associated arrhythmias. We tested this hypothesis in guinea pig and human myocardial ischemia models. BK administration (100 nM) markedly enhanced ex ocytotic and carrier-mediated NE overflow from guinea pig hearts subjected to 10- and 20-min ischemia/reperfusion, respectively. Ventricular fibrillat ion invariably occurred after 20-min global ischemia; BK prolonged its dura tion 3-fold. The BK B-2 receptor antagonist HOE140 (30 nM) blocked the effe cts of BK, whereas the B-2 receptor antagonist des-Arg(9)-Leu(8)-BK (1 mu M ; i.e., 2.5 x pA(2)) did not. When serine proteinase inhibitors (500 KIU/ml aprotinin and 100 mu g/ml soybean trypsin inhibitor) were used to prevent the formation of endogenous BK, NE overflow and reperfusion arrhythmias wer e diminished. in contrast, when kininase I and II inhibitors (DL-2-mercapto methyl-3-guanidinoethylthiopropanoic acid and enalaprilat, each 1 mu M) wer e used to prevent the degradation of endogenous BK, NE overflow and reperfu sion arrhythmias were enhanced. B-2 receptor blockade abolished these effec ts but was ineffective if kininases were not inhibited. B-2 receptor stimul ation, by either exogenous or endogenous BK, also markedly enhanced carrier -mediated NE release in the human myocardial ischemia model; conversely, in hibition of BK biosynthesis diminished ischemic NE release. Because atheros clerotic heart disease impairs endothelial BK production, in myocardial isc hemia BK could accumulate at sympathetic nerve endings, thus augmenting exo cytotic and carrier-mediated NE release and favoring coronary vasoconstrict ion and arrhythmias.