The overall goal of this proposal is to test the hypothesis that chronic b-adrenergic receptor desensitization in heart failure contributes to the progressive deterioration of contractile function in this disease. The strategy to achieve this goal will be to combine transgenic technology with the comprehensive physiological analysis of myocardial function before and after the development of hypertrophy and heart failure. Thus, the specific aims are: To determine the in vivo cardiac phenotype of transgenic mice which overexpress bARK-1, an inhibitor of bARK, and GRK-5 with regard to: 1) various G protein-coupled receptor signaling pathways; 2) contractile function of isolated adult myocardial cells in response to various agonists and changes in the force-frequency relation; 3) whether alterations in bARK activity can affect cardiac function in the conscious animal with intact autonomic influences at rest and with dynamic exercise; and 4) whether chronic alterations in cardiac b-adrenergic receptor coupling will modify the progression of cardiac dysfunction by applying models of pressure overload hypertrophy (transverse aortic constriction) and heart failure (aortic insufficiency).
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