Isolated rat hearts exhibited a biphasic contractile response to varying concentrations of
ruthenium red. A negative inotropic effect was observed with concentrations of 0.025-0.5 microM, whereas a reversal of these initial changes toward control or even exceeding the predrug values was obtained as
ruthenium red concentration was increased to 2.5 or 5.0 microM. High concentrations (12.5-25.0 microM) of
ruthenium red caused a sustained
contracture. In contrast, isolated frog hearts exhibited only a sustained negative inotropic effect at 0.25-12.5 microM
ruthenium red. In studies with rat heart, both negative and positive inotropic effects of 2.5 microM
ruthenium red were blocked either by increasing the concentration of Ca2+ (from 1.25 to 5.0 mM) or by decreasing the concentration of Na+ (from 140 to 35 mM) in the perfusion medium. The
contracture induced by 12.5 microM
ruthenium red was markedly inhibited when Ca2+ in the medium was lowered. The positive inotropic effect and
contracture due to
ruthenium red were also blocked by 1 microM of
verapamil and 1.5 mM of
amiloride; however, these interventions did not prevent the initial negative inotropic effect of
ruthenium red. These experiments suggest the role of extracellular Ca2+ in the dose- and time-dependent effects of
ruthenium red on contractile function of the rat heart. Furthermore, the positive inotropic response to
ruthenium red may be related to its actions on the Na+-dependent Ca2+ movements in the cardiac cell.