Bradykinin activates a cross-signaling pathway between sensory and adrenergic nerve endings in the heart: A novel mechanism of ischemic norepinephrine release?

We had shown that bradykinin (BK) generated by cardiac sympathetic nerve en dings (i.e., synaptosomes) promotes exocytotic norepinephrine (NE) release in an autocrine mode. Because the synaptosomal preparation may include sens ory C-fiber endings, which BK is known to stimulate, sensory nerves could c ontribute to the proadrenergic effects of BK in the heart. We report that B K is a potent releaser of NE from guinea pig heart synaptosomes (EC50 simil ar to 20 nM), an effect mediated by B-2 receptors, and almost completely ab olished by prior C-fiber destruction or blockade of calcitonin gene-related peptide and neurokinin-1 receptors. C-fiber destruction also greatly decre ased 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 receptor s initiated NE release from cardiac synaptosomes, indicating that stimulati on of sensory neurons in turn activates sympathetic nerve terminals. Thus, BK is likely to release NE in the heart in part by first liberating calcito nin gene-related peptide and Substance P from sensory nerve endings; these neuropeptides then stimulate specific receptors on sympathetic terminals. T his action of BK is positively modulated by cyclooxygenase products, attenu ated by activation of histamine H-3 receptors, and potentiated at a lower p H. The NE-releasing action of BK is likely to be enhanced in myocardial isc hemia, when protons accumulate, C fibers become activated, and the producti on of prostaglandins and BK increases. Because NE is a major arrhythmogenic agent, the activation of this interneuronal signaling system between senso ry and adrenergic neurons may contribute to ischemic dysrhythmias and sudde n cardiac death.