SCH00013, a novel Ca(2+) sensitizer with positive inotropic and no chronotropic action in heart failure.
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.
Tadano
Naoto
N
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Morimoto
Sachio
S
Yoshimura
Akira
A
Miura
Makoto
M
Yoshioka
Kimitomo
K
Sakato
Mitsuo
M
Ohtsuki
Iwao
I
Miwa
Yoshikazu
Y
Takahashi-Yanaga
Fumi
F
Sasaguri
Toshiyuki
T
D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology* / Q000502:physiology; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004095:Dihydropyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004285:Dogs; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000473:pathology; D011724:Pyridazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits; D012518:Sarcomeres / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D002316:Cardiotonic Agents; D004095:Dihydropyridines; D011724:Pyridazines; C115124:Sch 00013; D000676:Amrinone; D002118:Calcium