Direct cardiodepressant potency of nadolol was determined by comparing its effect with those of alprenolol, propranolol and pindolol, in both heart-lung preparation and blood-perfused papillary muscle preparation of the dog. In the heart-lung preparation, mean 50% beta-blocking doses of the beta-blockers to inhibit the positive chronotropic action of isoproterenol were 3.75 micrograms for nadolol, 12.5 micrograms for alprenolol, 9.6 micrograms for propranolol and 1.6 micrograms for pindolol. Alprenolol and propranolol in a dose of 10 mg shifted the cardiac function curves rightward and downward, while nadolol and pindolol in the dose of 10 mg did not shift the cardiac function curves. In the blood-perfused papillary muscle preparation, mean 50% beta-blocking doses of the beta-blockers, administered i.v. to the donor dog, to inhibit the positive inotropic action of isoproterenol were 9.1 micrograms/kg for nadolol, 56.6 micrograms/kg for alprenolol, 68.3 micrograms/kg for propranolol and 8.1 micrograms/kg for pindolol. Nadolol did not depress the contractile force in doses up to 1 mg/kg given i.v. or doses up to 10 mg given intra-arterially (i.a.) close to the preparation. Alprenolol and propranolol exerted the dose-related negative inotropic effects, when larger doses (30-300 micrograms) were injected i.a. Thus, it is confirmed that nadolol virtually possesses no direct cardiodepressant activity and also that the depressant activity is exerted only by large doses of the other beta-blockers.