Inotropic effects of OR-1896, an active metabolite of levosimendan, on canine ventricular myocardium.
We performed experiments in dog ventricular trabeculae loaded with aequorin to elucidate the mechanism of positive inotropic effect of (R)-N-[4-(4-methyl-6-oxo-1,4,5, 6-tetrahydro-pyridazin-3-yl)-phenyl]-acetamide (OR-1896), an active metabolite of (R)-([4-(1,4,5, 6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono)-pr opaned initrile (levosimendan). Concentration-response curve for OR-1896 was biphasic: positive inotropic effect of OR-1896 reached a plateau at 10(-5) M (1st phase) and the concentration-response curve became steeper at 10(-3) M and higher (2nd phase). Maximum response of the 1st phase was 29% of maximal response to isoproterenol and associated with an increase in Ca(2+) transients of 13% of the maximal response to isoproterenol. For a given increase in force, the increase in Ca(2+) transients by OR-1896 was lower than that induced by elevation of [Ca(2+)](o). The positive inotropic effect of OR-1896 was not associated with impairment of relaxation and it was abolished by carbachol. In conclusion, OR-1896 has a positive inotropic effect partly due to an increase in myofibrillar Ca(2+) sensitivity that is exerted via cross-talk with signal transduction mediated by cAMP.
Takahashi
R
R
Department of Pharmacology, Yamagata University School of Medicine, 990-9585, Yamagata, Japan.
Talukder
M A
MA
Endoh
M
M
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D002046:Bupranolol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006835:Hydrazones / Q000378:metabolism*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011724:Pyridazines / Q000378:metabolism* / Q000494:pharmacology*; D000077464:Simendan
D000081:Acetamides; D002316:Cardiotonic Agents; D006835:Hydrazones; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D011724:Pyridazines; D000077464:Simendan; D002046:Bupranolol; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium