Neural mechanisms have been implicated in the generation of cardiac arrhythmias and also have the potential for triggering coronary vasospasm. The heart contains an elaborate neural network that includes sympathetic nerves, intrinsic cardiac ganglia and sensory nerves. This proposal is based on the recent discovery that sensory neurons can have efferent functions mediated by tachykinins (TKs) and calcitonin gene-related peptide (CGRP) that are released from their peripheral processes. The PI will evaluate the hypothesis that TKs have direct effects on coronary flow and affect the function of cardiac ganglia by stimulating postjunctional TK receptors on cholinergic neurons. The problem will be addressed at cellular, isolated organ and whole animal levels using the guinea pig. The PI will also test the hypothesis that local effects of the TKs and/or CGRP contribute to cardiac and coronary responses evoked by ischemia and reperfusion.
Six specific aims have been defined to address the hypotheses.
Aim 1. Use isolated hearts to identify the responses mediated by specific types of TK receptor and autoradiographic methods to localize and quantify these receptors.
Aim 2. Determine the importance of TK receptor types, nitric oxide, cholinergic neurons and noncholinergic mechanisms to responses evoked by SP and NKA in isolated hearts.
Aim 3. Identify and characterize responses to endogenous TKs in the isolated heart model.
Aim 4. Determine effects of exogenous and endogenous TKs on intracardiac neurons and intraganglionic transmission in vitro using microelectrode recording techniques.
Aim 5. Determine effects of exogenous and endogenous TKs on cholinergic neurons in cardiac ganglia in vivo.
Aim 6. Use selective TK and CGRP antagonists to identify cardiac and coronary effects of endogenous sensory neuropeptides in isolated hearts and anesthetized guinea pigs during ischemia and reperfusion. This line of investigation could ultimately establish sensory neuron peptide receptors as targets for therapy of specific cardiac arrhythmias and coronary vasospasm.
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