Vol. 298, Issue 3, 1060-1066, September 2001

Decrease in Ca²⁺-Sensitizing Effect of UD-CG 212 Cl, a Metabolite of Pimobendan, under Acidotic Condition in Canine Ventricular Myocardium

Reiko Takahashi, Yasuhisa Shimazaki and Masao Endoh

Department of Pharmacology (R.T., M.E.) and The Second Department of Surgery (Y.S.), Yamagata University School of Medicine, Yamagata, Japan

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 10⁵ M in the control condition at pH 7.4, but was not achieved even at 10⁴ 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 Ca²⁺ 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 Ca²⁺ sensitivity induced by UD-CG 212 Cl, whereas the increase in Ca²⁺ 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 Ca²⁺-sensitizing effect under acidotic condition.