Decrease in Ca(2+)-sensitizing effect of UD-CG 212 Cl, a metabolite of pimobendan, under acidotic condition in canine ventricular myocardium.
We studied the influence of acidosis on the positive inotropic effect of UD-CG 212 Cl (4,5-dihydro-6-[2-(4-hydroxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3(2H)-pyridazinone), an active metabolite of pimobendan, in canine ventricular trabeculae loaded with aequorin. The positive inotropic effect of UD-CG 212 Cl was markedly suppressed under acidotic conditions. The maximal contractile response to UD-CG 212 Cl was attained at 10(-5) M in the control condition at pH 7.4, but was not achieved even at 10(-4) M during acidosis. The maximal inotropic effect of UD-CG 212 Cl was 18% of the maximal response to isoproterenol (ISO(max)) in association with an increase in Ca(2+) transients of 7% of ISO(max) in the control, while they are 8 and 6% of ISO(max) under acidosis, respectively. Acidosis abolished the increase in myofilament Ca(2+) sensitivity induced by UD-CG 212 Cl, whereas the increase in Ca(2+) transients induced by the compound was not affected by acidosis. In conclusion, UD-CG 212 Cl elicited a positive inotropic effect even under acidosis, however, UD-CG 212 Cl was much less effective as a cardiotonic agent under acidosis mainly due to a decrease in the Ca(2+)-sensitizing effect under acidotic condition.
Takahashi
R
R
Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japan.
Shimazaki
Y
Y
Endoh
M
M
D000138:Acidosis / Q000378:metabolism*; D008841:Actin Cytoskeleton / Q000378:metabolism; D000331:Aequorin / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000494:pharmacology*
D002316:Cardiotonic Agents; D011724:Pyridazines; C041648:pimobendan; D000331:Aequorin; C047936:UD CG 212 Cl; D002118:Calcium