The overall objectives of this research proposal are: (a) the localization of binding sites for norepinephrine on or within the cardiac muscle cell; (b) the development of a model to define the mechanisms by which endogenous norepinephrine regulates cardiac muscle contraction and relaxation. Studies are planned to test several hypotheses: (a) the active site for norepinephrine binding is on the cell membrane rather than intracellular, (b) the uptake of norepinephrine by the sympathetic nerve ending is a major determinant of the concentration of norepinephrine at the receptor site, (c) norepinephrine produces its positive inotropic action by an augmentation of the amount of calcium entering the cytosol during the action potential, and (d) the relaxant action of norepinephrine is independent of its positive inotropic effect. The experimental approach will combine tracer, mechanical and electrophysiological techniques in mammalian ventricular muscle. The proposed studies will be geared toward defining (a) the relationship between radiolabeled catecholamine and calcium kinetics and muscle contraction, and (b) the relationships among membrane potential, calcium transport and muscle mechanics. An alteration in adrenergic tone is one of the fundamental mechanisms of moment-to-moment regulation of cardiac function. An increase in adrenergic tone is common to most cardiac disorders whereas endogenous catecholamine levels are markedly lowered in advanced heart disease. For these reasons an understanding of the mechanism of norepinephrine action is basic to an understanding of how both normal and diseased hearts respond to changing demands on the circulation.