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

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 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.

• Authors: R Takahashi, Y Shimazaki, M Endoh
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 298 Issue 3 Pg. 1060-6 (Sep 2001) ISSN: 0022-3565 [Print] United States
• PMID: 11504803 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Pyridazines
• pimobendan
• Aequorin
• UD CG 212 Cl
• Calcium

Topics

• Acidosis (metabolism)
• Actin Cytoskeleton (metabolism)
• Aequorin (pharmacology)
• Animals
• Calcium (metabolism)
• Cardiotonic Agents (pharmacology)
• Dogs
• Female
• Heart (drug effects)
• Heart Ventricles (drug effects, metabolism)
• In Vitro Techniques
• Male
• Myocardial Contraction (drug effects)
• Myocardium (metabolism)
• Pyridazines (pharmacokinetics, pharmacology)