Inotropic effects of MCI-154 on rat cardiac myocytes.

Calcium sensitizers exert positive inotropic effects without increasing intracellular Ca~(2+). Thus, they avoid the undesired effects of Ca~(2+) overload such as arrhythmias and cell injury, but most of them may impair myocyte relaxation. However, MCI-154, also a calcium sensitizer, has no impairment to cardiomyocyte relaxation. To clarify the underlying mechanisms, we examined the effects of MCL-154 on Ca~(2+) transient and cell contraction using ion imaging system, and its influence on L-type Ca~(2+) current and Na~+/Ca~(2+) exchange current with patch clamp technique in rat ventricular myocytes as well. The results showed that: (1) MCI-154 (1～100μmol/L) had no effect on L-type Ca~(2+) current; (2) MCI-154 concentration-dependently increased cell shortening from 5.00±1.6μm of control to 6.2±1.6μm at lμmol/L, 8.7±1.6μm at 10μmol/L and 14.0±1.4μm at 100μmol/L, respectively, with a slight increase in Ca~(2+) transient amplitude and an abbreviation of Ca~(2+) transient restore kinetics assessed by time to 50% restore (TR_(50)) and time to 90% restore (TR_(90)); (3) MCI-154 dose- dependently increased the electrogenic Na~+/Ca~(2+) exchange current both in the inward and the outward directions in rat ventricular myocytes. These results indicate that MCI-154 exerted a positive inotropic action without impairing myocyte relaxation. The stimulation of inward Na~+/Ca~(2+) exchange current may accelerate the Ca~(2+) efflux, leading to abbreviations of TR_(50). and TR_(90) in rat myocytes. The findings suggest that the improvement by MCI-154 of myocyte relaxation is attributed to the forward mode of Na~+/Ca~(2+) exchange.