Effects of OR-1896, a metabolite of levosimendan, on force of contraction and Ca²⁺ transients under acidotic condition in aequorin-loaded canine ventricular myocardium

Abstract.

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 Ca²⁺ transients of 2% of ISO_max (P<0.05). The sensitivity of myofilaments to Ca²⁺ ions was increased by OR-1896 in acidotic conditions, whereas the relationship of Ca²⁺ transients and contractile force during an increase in elevation of the extracellular Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ mobilization was markedly attenuated in acidotic conditions.