MECHANISMS OF REGULATION OF CARDIAC AFFERENTS

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DESCRIPTION (provided by the applicant): Reflexes from the heart play an important role in regulation of the cardiovascular system during myocardial ischemia and reperfusion. Responses can include profound alterations in hemodynamic function manifested as either reflex cardiovascular depression during stimulation of vagal afferent endings or excitation with activation of sympathetic (spinal) afferents. Stimulation of sensory nerves in the heart thus can cause hypotension, bradyarrhythmias, nausea and vomiting (vagal afferents) or angina, hypertension and tachyarrhythmias (sympathetic afferents). Limited information is available on mechanisms of activation of sympathetic cardiac afferents that also function as cardiac nociceptors, although our recent data in cats indicate that, in contrast to adenosine, reactive oxygen species (ROS), especially hydroxyl radicals ('OH), kinins, protons (H+) and prostaglandins are important stimuli. Because inhibition of these stimuli and their receptor interactions does not fully eliminate the response of these sensory afferent endings to ischemia, we suspect that other metabolic or mechanical stimuli play a role in their activation and that interactions between stimuli are present. We propose a series of studies to test the hypotheses that platelets are a source of serotonin (5HT) and histamine. Activated platelets release serotonin and histamine that, through 5HT3 and H1 and possibly H2 receptors, respectively, stimulate cardiac sympathetic afferents during ischemia and reperfusion. Interactions between these two putative and other known chemical mediators will be explored. In addition, the role of diacylglycerol/protein kinase C (PKC) and cyclic adenosine monophosphate (cAMP)/protein kinaseA (PKA) signaling systems in histamine's action on ischemically sensitive cardiac sympathetic afferents will be defined. We will employ liquid chromatography to measure the production of mediators in blood and tissue. Single unit afferent electrical activity will be recorded and selective pharmacological receptor blockade or enzymatic pathway inhibition will be used to evaluate the role of each potential chemical mediator. Chemosensitive, mechanosensitive and bimodal endings of unmyelinated and myelinated fibers will be identified through a series of chemical and mechanical challenges, the latter assessed by hemodynamic measurement and regional myocardial deformation. The proposed studies therefore will define mechanisms by which cardiac sympathetic endings are activated during ischemia and reperfusion. Such information will provide physicians with a better understanding of angina and potentially dangerous sympathoexcitatory cardiac reflexes and may suggest therapeutic approaches designed to limit these events that impact patient morbidity and mortality during myocardial ischemia.