SCH00013, a novel Ca(2+) sensitizer with positive inotropic and no chronotropic action in heart failure

J Pharmacol Sci. 2005 Jan;97(1):53-60. doi: 10.1254/jphs.fp0040654. Epub 2005 Jan 8.

Abstract

We investigated the effects of the agent SCH00013 on Ca(2+)-induced force generation in rabbit skinned cardiac muscle fibers and in vivo cardiac function in high-pacing-induced heart failure dogs. The Ca(2+)-induced force generation in skinned cardiac muscle fibers was determined at pH 6.2 - 7.4, and SCH00013 was found to have a significant Ca(2+) sensitizing effect at pH 7.2 to 7.4. There was no significant difference in the Ca(2+) sensitizing action between the enantiomers of SCH00013. The Ca(2+) 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 Ca(2+) sensitizer that elicits a positive inotropic and no chronotropic effect in heart failure, probably through enhancing the Frank-Starling mechanism.

Publication types

  • Comparative Study

MeSH terms

  • Amrinone / pharmacology
  • Animals
  • Calcium / pharmacology*
  • Calcium / physiology
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / chemistry
  • Cardiotonic Agents / pharmacokinetics
  • Dihydropyridines / administration & dosage
  • Dihydropyridines / pharmacokinetics*
  • Disease Models, Animal
  • Dogs
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Heart Rate / physiology*
  • Hydrogen-Ion Concentration
  • Injections, Intravenous
  • Male
  • Myocardial Contraction / drug effects*
  • Myocardial Contraction / physiology
  • Myocytes, Cardiac / pathology
  • Pyridazines / administration & dosage
  • Pyridazines / pharmacokinetics*
  • Rabbits
  • Sarcomeres / drug effects
  • Sarcomeres / physiology
  • Stereoisomerism
  • Ventricular Function, Left / drug effects
  • Ventricular Function, Left / physiology

Substances

  • Cardiotonic Agents
  • Dihydropyridines
  • Pyridazines
  • Sch 00013
  • Amrinone
  • Calcium