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Vol. 290, Issue 2, 656-663, August 1999
Department of Pharmacology, Cornell University Weill
Medical College, New York, New York
We had shown that bradykinin (BK) generated by cardiac sympathetic
nerve endings (i.e., synaptosomes) promotes exocytotic norepinephrine
(NE) release in an autocrine mode. Because the synaptosomal preparation
may include sensory C-fiber endings, which BK is known to stimulate,
sensory nerves could contribute to the proadrenergic effects of BK in
the heart. We report that BK is a potent releaser of NE from guinea pig
heart synaptosomes (EC50 ~20 nM), an effect mediated by
B2 receptors, and almost completely abolished by prior
C-fiber destruction or blockade of calcitonin gene-related peptide and
neurokinin-1 receptors. C-fiber destruction also greatly
decreased BK-induced NE release from the intact heart, whereas
tyramine-induced NE release was unaffected. Furthermore, C-fiber
stimulation with capsaicin and activation of calcitonin gene-related
peptide and neurokinin-1 receptors initiated NE release from cardiac
synaptosomes, indicating that stimulation of sensory neurons in turn
activates sympathetic nerve terminals. Thus, BK is likely to release NE
in the heart in part by first liberating calcitonin gene-related
peptide and Substance P from sensory nerve endings; these neuropeptides
then stimulate specific receptors on sympathetic terminals. This action of BK is positively modulated by cyclooxygenase products, attenuated by
activation of histamine H3 receptors, and potentiated at a lower pH. The NE-releasing action of BK is likely to be enhanced in
myocardial ischemia, when protons accumulate, C fibers become activated, and the production of prostaglandins and BK increases. Because NE is a major arrhythmogenic agent, the activation of this
interneuronal signaling system between sensory and adrenergic neurons
may contribute to ischemic dysrhythmias and sudden cardiac death.
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