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Vol. 288, Issue 3, 919-927, March 1999
Department of Pharmacology, Cornell University Medical College, New
York, New York
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 µM; i.e.,
2.5 × pA2) did not. When serine proteinase inhibitors (500 KIU/ml aprotinin and 100 µg/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 µM) 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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