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 (ISOmax) in association with an increase in Ca2+ transients of 7% of ISOmax in the control, while they are 8 and 6% of ISOmax 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.
Footnotes
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This research was supported in part by grants-in-aid for Scientific Research (B) (11557203) from the Ministry of Education, Science, Sports, and Culture, Japan.
- Abbreviations:
- [Ca2+]i
- intracellular Ca2+ concentration
- ISOmax
- maximal response to isoproterenol
- [Ca2+]o
- extracellular Ca2+ concentration
- Received March 12, 2001.
- Accepted May 15, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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