SCH00013, a Novel Ca2+ Sensitizer With Positive Inotropic and No Chronotropic Action in Heart Failure

Abstract

We investigated the effects of the agent SCH00013 on Ca2+-induced force generation in rabbit skinned cardiac muscle fibers and in vivo cardiac function in high-pacing-induced heart failure dogs. The Ca2+-induced force generation in skinned cardiac muscle fibers was determined at pH 6.2 – 7.4, and SCH00013 was found to have a significant Ca2+ sensitizing effect at pH 7.2 to 7.4. There was no significant difference in the Ca2+ sensitizing action between the enantiomers of SCH00013. The Ca2+ sensitizing effect of SCH00013 was dependent on the sarcomere length, being significant only at a long sarcomere length. SCH00013 elicited a positive inotropic effect at more than 0.3 and 1 mg/kg, i.v. in normal and heart failure dogs, respectively, with no chronotropic action. These results strongly suggested that SCH00013 is a novel Ca2+ sensitizer that elicits a positive inotropic and no chronotropic effect in heart failure, probably through enhancing the Frank-Starling mechanism. Keywords:: Ca2+ sensitizer, skinned cardiac muscle fiber, sarcomere length, high-pacing, Frank-Starling mechanism