Abstract

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 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.