The goals of this proposal are to characterize pathogenetic factors which contribute to catecholamine-induced cardiomyopathy and assess their relationship to insulin deficient diabetes mellitus. The methods are designed to define etiologic mechanisms in terms of metabolism, tissue chemical analysis and morphology, and to relate these changes to alterations in functional properties of myocardium. We have shown that alpha adrenergic pathways are involved in the development of myofiber injury. Presently unclear is whether this relates to increased coronary resistance (ischemia?) or primary injury to myofiber membrane systems. A newly developed isolated working rabbit heart system using red cell enhanced buffer perfusate will be employed. Preliminary studies indicate levels of coronary flow, MVO2, and mechanical performance comparable to in vivo preparations. Measurements will include 02 and substrate utilization, high energy phosphates, and marker enzymes of glucose and palmitate utilization. Determinants of coronary regulation will be examined in each model. Experiments are designed to identify these potential mechanisms as primary or cofactors in the genesis of myocyte damage and their relationship to the insulinopenic diabetic state. Immediate effects of acute catecholamine exposure in concentrations known to produce myofiber injury will be determined. Studies will also be done to explore the hypothesis that repeated episodes of myofiber injury by adrenergic agonist will lead to progressive myofiber loss, reduced cardiac performance and the appearance of heart failure. It is anticipated that diabetic animals will exhibit enhanced sensitivity to catecholamine damage, with earlier and more severe functional deterioration. We have shown that endogenous release of catecholamines evoked by tyramine produces identical cardiac lesions. Studies are proposed to determine catecholamine distribution and concentrations, effects of catecholamine depletion with reserpine, morphologic and functional consequences of repeated release episodes, and the relationship of each of these to the diabetic state. The reversibility (or progression) of functional metabolic and biochemical changes will be examined, and the effects of insulin replacement in the diabetic animals subjected to catecholamine challenges will be determined.
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