The proposed work is concerned with the regulation of carbohydrate metabolism by drugs and hormones. Studies will be made with the perfused, isolated rat heart and rat diaphragm tissue incubated in vitro. The actions of insulin and epinephrine on glucose uptake, glycogen synthesis and lactate formation will be studied in cardiac and skeletal muscle. Special efforts will be made to study the factors that regulate the glucose to glycogen pathway which appears to be associated with enzymes present on cellular membranes. Insulin and lithium ions stimulate this pathway, while agents that increase the cellular content of cyclic AMP inhibit glycogen synthesis. Substances that markedly decrease glycogen synthesis in muscle epinephrine and phosphodiesterase inhibitors. The actions of such compounds on carbohydrate metabolism will be studied in detail and their effects will be correlated with changes in the tissue concentrations of cyclic AMP. Lithium ions exert a marked insulin-like action on muscle by a mechanism different from that of insulin. The metabolic effect of lithium is associated with the entrance of this ion into the muscle cell. In the propose investigation we plan experiments designed to elucidate the mechanism by which lithium has such pronounced effects on cellular metabolism.