Responses of contractile function to ruthenium red in rat heart
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.