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.