Decrease in Ca(2+)-sensitizing effect of UD-CG 212 Cl, a metabolite of pimobendan, under acidotic condition in canine ventricular myocardium

• Published in: The Journal of pharmacology and experimental therapeutics 2001-09, Vol.298 (3), p.1060-1066
• Main Authors: Takahashi, R, Shimazaki, Y, Endoh, M
• Format: Article
• Language: English
• Subjects: Acidosis - metabolism; Actin Cytoskeleton - metabolism; Aequorin - pharmacology; Animals; Calcium - metabolism; Cardiotonic Agents - pharmacology; Dogs; Female; Heart - drug effects; Heart Ventricles - drug effects; Heart Ventricles - metabolism; In Vitro Techniques; Male; Myocardial Contraction - drug effects; Myocardium - metabolism; Pyridazines - pharmacokinetics; Pyridazines - pharmacology
• ISSN: 0022-3565

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.