Abstract
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.
Footnotes
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Send reprint requests to: Roberto Levi, M.D., Dept. of Pharmacology, Cornell University Weill Medical College, 1300 York Ave., New York, NY. E-mail: rlevi{at}med.cornell.edu
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↵1 This work was supported by National Institutes of Health Grants HL-34215, HL-46403, and CA-62948 and in part by a Fellowship of the American Heart Association, New York City Affiliate, to R. M.. A preliminary version of these findings was presented at Experimental Biology ’98, April, 1998 (San Francisco, CA) and was published in abstract form in FASEB J 1998;12:A398.
- Abbreviations:
- BK
- bradykinin
- CGRP
- calcitonin gene-related peptide
- NE
- norepinephrine
- Received February 11, 1999.
- Accepted April 15, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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