Behavioral stress has been increasingly implicated in the genesis of cardiac arrhythmias. It is well established that the arrhythmogenic effect of stress is a consequence of enhanced release of catecholamines and altered autonomic tone. The possibility that neuroactive peptides constitute a critical link in the response to stress has not been adequately explored. The opioid system is of particular interest, because opioid receptor subtypes are known to be differentially activated in response to various forms of stress and because available evidence indicates an influence of these substances on both ventricular electrical stability and myocardial perfusion. Opioid peptide secretion into the blood is mediated in large part by central and peripheral catecholamines, and the releasing factor for pituitary endorphin secretion (corticotropin-releasing factor or CRF) profoundly influences catecholamine secretion. Our proposed studies will: 1. Characterize the pattern of endogenous opioid release in response to passive-aversive stress and induction of an anger-like state. 2. Relate the observed changes in plasma opioid levels to the corresponding stress-induced alterations in hemodynamic and cardiac electrophysiologic function. 3. Explore the potential use of selective opiod ad CRF agonists and antagonists in modulating the deleterious effects of these well-characterized forms of behavioral stress on myocardial perfusion and ventricular electrical stability. The methods to be employed will be those of coronary arterial flow measurement, radiolabeled microspheres, coronary angiography, biochemical assessment of cardiac metabolism, radioimmunoassay for peptides, and cardiac electrical testing. These studies will serve to define the role of neuropeptides in mediating the effects of stress on coronary hemodynamic function and cardiac rhythm. Important clinial insights can be anticipated from an improved understanding of these relationships.
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