In isolated feline right ventricular papillary muscles, with intact or damaged (exposure to dry air for 30 s) endocardium, the effects of cholic acid were studied. At 35 degrees C and a [Ca2+] of 1.25 mM, isometric twitches and the maximal unloaded velocity of shortening (Vmax) were registered. Endocardial endothelium (EE) and myocardial ultrastructure were evaluated on scanning and transmission electron microscopy. In muscles with intact EE, low concentrations of cholic acid (3 x 10(-9) to 3 x 10(-7) M) or short incubation (30 min) with 3 x 10(-8) M induced a mild positive inotropic response, manifested as an increased peak isometric twitch tension (TT) and shortened twitch duration, without changes in Vmax. This inotropic response was abolished by damaging the EE. It was also absent after the addition of propranolol to muscles with intact EE. Higher concentrations (3 x 10(-6) to 3 x 10(-4) M) or prolonged incubation at 3 x 10(-8) M caused extensive morphologic damage of the EE, without detectable impairment of subjacent myocardium. This was accompanied by a progressive decrease in the TT and further twitch abbreviation, without changes in Vmax, resembling twitches obtained from muscles with experimentally damaged EE. These observations suggest that cholic acid induces an EE-dependent and beta-receptor-mediated positive inotropic effect, while simultaneously causing damage to EE cells.