Increase in myofibrillar Ca2+ sensitivity induced by UD-CG 212 Cl, an active metabolite of pimobendan, in canine ventricular myocardium.
We performed experiments in canine ventricular trabeculae loaded with aequorin to elucidate the mechanism of 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. The maximum response to UD-CG 212 Cl achieved at 10(-5) M was 18% of ISOmax and it was associated with an increase in Ca2+ transients of 7% of ISOmax. For a given increase in force, the increase in Ca2+ transients induced by UD-CG 212 Cl was less than that induced by elevation of [Ca2+]o. The positive inotropic effect of UD-CG 212 Cl was not associated with an impairment of relaxation and it was abolished by carbachol. In conclusion, UD-CG 212 Cl has a positive inotropic effect partly due to an increase in myofibrillar Ca2+ sensitivity that is exerted via cross talk with a signal transduction pathway that involves cAMP.
Takahashi
R
R
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Endoh
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009210:Myofibrils / Q000378:metabolism*; D011724:Pyridazines / Q000378:metabolism* / Q000494:pharmacology*; D015398:Signal Transduction
D002316:Cardiotonic Agents; D011724:Pyridazines; C041648:pimobendan; C047936:UD CG 212 Cl; D002217:Carbachol; D002118:Calcium