Dual regulation of myofilament Ca2+ sensitivity by levosimendan in normal and acidotic conditions in aequorin‐loaded canine ventricular myocardium

Experiments were carried out in canine ventricular trabeculae loaded with aequorin to investigate the effects of levosimendan (R) - (4- (1, 4, 5, 6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl-hydrazono) -propanedinitrile on contractile force and Ca (2+) transients in normal and acidotic conditions. The concentration-response curve for the positive inotropic effect (PIE) of levosimendan was bell-shaped, that is, it declined markedly at 10 (-4) M after achieving the maximum at 10 (-5) M in normal (pH (o) =7. 4) and acidotic conditions (pH (o) =6. 6). The positive inotropic effect (PIE) of levosimendan up to 10 (-5) M was associated with an increase in Ca (2+) transients and a shift of the relationship of Ca (2+) transients and force to the left of that of elevation of Ca (2+) (o). Levosimendan at 10 (-4) M elicited a negative inotropic effect (NIE) in association with a further increase in Ca (2+) transients, and during washout Ca (2+) transients increased further, while the force was abolished before both signals recovered to the control. In acidotic conditions, the relationship of Ca (2+) transients and force during the application of levosimendan in normal conditions was essentially unaltered, whereas the PIE was suppressed due to attenuation of the increase in Ca (2+) transients. In summary, in intact canine ventricular myocardium, levosimendan elicits a dual inotropic effect: at lower concentrations, it induces a PIE by a combination of increases in Ca (2+) transients and Ca (2+) sensitivity, while at higher concentrations it elicits an NIE due to a decrease in Ca (2+) sensitivity. Acidosis inhibits the PIE of levosimendan due to suppression of the increase in Ca (2+) transients in response to the compound.