n-(4-(4-methyl-6-oxo-1-4-5-6-tetrahydropyridazin-3-yl)phenyl)acetamide and Acidosis

We performed experiments in canine ventricular trabeculae loaded with aequorin to elucidate the influence of acidosis on the positive inotropic effect (PIE) of OR-1896 (R)- N-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-acetamide, an active metabolite of levosimendan. The concentration-response curve (CRC) for OR-1896 was biphasic in acidotic conditions (pH(o) 6.6) that was essentially the same as that in control conditions (pH(o) 7.4). The CRC for PIE of OR-1896 reached a plateau at 10(-6) M (first phase) and it became steeper again at 10(-3) M (second phase). Under acidotic conditions the efficacy of the first phase was 10% of the maximal response to isoproterenol (ISO(max)) and the PIE was associated with an increase in Ca(2+) transients of 2% of ISO(max) (P<0.05). The sensitivity of myofilaments to Ca(2+) ions was increased by OR-1896 in acidotic conditions, whereas the relationship of Ca(2+) transients and contractile force during an increase in elevation of the extracellular Ca(2+) concentration and during application of dihydroouabain was shifted prominently to the right in acidotic conditions. In conclusion, OR-1896 elicited a PIE due to an increase in the sensitivity of myofilaments to Ca(2+) ions even in acidotic conditions. The PIE of OR-1896 in acidotic conditions was much less than that in control conditions because the effect of the compound to induce an increase in intracellular Ca(2+) mobilization was markedly attenuated in acidotic conditions.

Topics: Acetamides; Acidosis; Aequorin; Animals; Calcium; Dogs; Dose-Response Relationship, Drug; Female; Heart Ventricles; Hydrazones; Male; Myocardial Contraction; Pyridazines; Simendan