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  • Title: Bradykinin promotes ischemic norepinephrine release in guinea pig and human hearts.
    Author: Hatta E, Maruyama R, Marshall SJ, Imamura M, Levi R.
    Journal: J Pharmacol Exp Ther; 1999 Mar; 288(3):919-27. PubMed ID: 10027827.
    Abstract:
    We previously reported that bradykinin (BK; 1-1000 nM) facilitates norepinephrine (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 exocytotic and carrier-mediated NE overflow from guinea pig hearts subjected to 10- and 20-min ischemia/reperfusion, respectively. Ventricular fibrillation invariably occurred after 20-min global ischemia; BK prolonged its duration 3-fold. The BK B2 receptor antagonist HOE140 (30 nM) blocked the effects of BK, whereas the B1 receptor antagonist des-Arg9-Leu8-BK (1 microM; i.e., 2.5 x pA2) did not. When serine proteinase inhibitors (500 KIU/ml aprotinin and 100 microg/ml soybean trypsin inhibitor) were used to prevent the formation of endogenous BK, NE overflow and reperfusion arrhythmias were diminished. In contrast, when kininase I and II inhibitors (DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid and enalaprilat, each 1 microM) were used to prevent the degradation of endogenous BK, NE overflow and reperfusion arrhythmias were enhanced. B2 receptor blockade abolished these effects but was ineffective if kininases were not inhibited. B2 receptor stimulation, by either exogenous or endogenous BK, also markedly enhanced carrier-mediated NE release in the human myocardial ischemia model; conversely, inhibition of BK biosynthesis diminished ischemic NE release. Because atherosclerotic heart disease impairs endothelial BK production, in myocardial ischemia BK could accumulate at sympathetic nerve endings, thus augmenting exocytotic and carrier-mediated NE release and favoring coronary vasoconstriction and arrhythmias.
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