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

1 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. 2 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). 3 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 . 4 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. 5 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. 6 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.British Journal of Pharmacology (2005) 145 , 1143–1152. doi: 10.1038/sj.bjp.0706292