Electrical and mechanical activities of the isolated guinea pig papillary muscle were measured simultaneously, and the effects of various degrees of hypoxia and metabolic inhibitors were examined. Hypoxia selectively diminished the action potential duration (APD) dependently upon the degree of hypoxia with little affecting the other parameters of the action potential. Hypoxia concomitantly depressed the contractile force (CF), but the decrease in CF always preceded the decrease in APD ; thus, the complete excitation-contraction uncoupling was sometimes observed. Metabolic inhibitors (dinitrophenol, DNP and monoiodoacetic acid, IAA) produced qualitatively the same changes in the electrical and mechanical activities. However, DNP mimicked hypoxia better than IAA which produced rather parallel decreases in CF and APD. The slow response action potential (elicited after inactivation of the excitatory fast Na system of the membrane) was completely blocked by hypoxia and metabolic inhibitors, which was partially restored by isoproterenol, histamine and tetraethylammonium. When isoproterenol was present in the bathing solution, the decreases in CF and APD produced by hypoxia were accelerated, but ATP and propranolol did not significantly modify the hypoxically induced changes.