Dual regulation of myofilament Ca 2+ sensitivity by levosimendan in normal and acidotic conditions in aequorin-loaded canine ventricular myocardium

Abstract

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 bellshaped, that is, it declined markedly at 10 -4M after achieving the maximum at 10 -5M 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 -4M 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. © 2005 Nature Publishing Group All rights reserved.