Phenol appears in high concentrations in renal failure with uremia. The effects of this material on contractile activity of isolated cardiac muscle were studied in right ventricular moderator band (MB) of piglets and papillary muscle (PM) of cats and kittens. The muscles were bathed in modified Krebs solution containing 5.6 mM glucose at 30 C and gassed with 95% O2 and 5% CO2. They were paced at 24 contractions per minute, isometrically at Lmax. Over the range 2.5-119.0 mg%, phenol produced dose-related decreases in both developed tension (DT) and maximal rate of tension development (max dT/dt) in MB of piglets. In contrast, the dose-dependent negative inotropic effect of phenol was not detected in feline PM until concentrations in excess of 12.5 mg% were used. Increasing extracellular Ca2+ from 2.5 to 5.0 mM as well as the addition of norepinephrine (3.94 x 10(-7) M) attenuated the phenol-induced cardiac depression in porcine MB. There were no further changes in either DT or max dT/dt when the extracellular Ca2+ was increased to 10 mM. These findings demonstrate that phenol elicits a direct negative inotropic effect on mammalian cardiac muscle that is modified by calcium and norepinephrine. Phenol may participate in the biochemical alterations leading to cardiac failure and death in uremia.