The theme of the proposal focuses on the delineation of the cerebral mechanisms that mediate the effects of specific environmental events (i.e., psychosocial stressors) on the vulnerability of the ischemic heart to arrhythmogenesis. Previous investigations have implicated a noradrenergic process in the cerebral cortex to be a crucial part of the mechanism. Project 1 will investigate the effects of both cerebral and pharmacologic interventions on the stress-related increase in cardiac vulnerability that occurs in an established conscious-pig model for sudden cardiac death. Project 2 will explore what the stress-related biochemical responses of the heart are and then, once identified, study their reverals by specific cerebral and pharmacologic interventions. Project 3 is an interconnecting study that will relate the pharmacology studied in the whole brain of the conscious animal to that studied in model brain-systems in Projects 4 and 5. In Project 3 the classification will be made of subtypes of the muscarinic receptors in relevant neural and cardiac tissues, and characterization of ligands studied in Projects 1 and 2 will also be performed. Projects 3 and 4 together will study the role of the regulatory proteins and the interactions of the beta- and muscarinic-receptors in the cellular mechanism of long-term potentiation of synaptic efficacy. Project 4 will study the effects of beta-adrenergic and muscarinic interactions on the alterations of synaptic efficacy in the hippocampal slice preparation, a simple model of the cerebral cortex. Project 5 will characerize the pharmacology of noradrenergic mechanisms in another simple model of the cerebral cortex, the olfactory bulb. Project 6 will study the joint effects of pharmacologic interventions on the cerebral event-related slow potential and cardiac ectopy; the slow potential has been previously identified in animal studies as a cerebral representation of environmental stressors. Project 7 will study various environmental events and their consequent cerebral and cardiac responses to determine those paradigms most effective in identifying the patient-at-risk for sudden cardiac death. This last project will also attempt to explain why smoking behavior is associated with increased risk for sudden cardiac death. Both an Administrative Core and an Animal Surgery and Instrumentation Core will support the six projects.
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