Lusitropic effects of a Ca2+ sensitization with a new cardiotonic agent, MCI-154, on diseased human hearts

Recognition of the problems of conventional cardiotonic agents has led to an interest in drugs that produce a positive inotropic action by altering the responsiveness of myofilament to Ca2+ (i.e., Ca2+ sensitizing agents). The importance of the effects of these compounds on left ventricular (LV) systolic function has been emphasized, whereas the effect of them on LV diastolic function is still problematic. To investigate the lusitropic action of a novel Ca2+ sensitizing agent, MCI-154, we compared the effects of MCI-154 on LV relaxation and filling dynamics with those of dobutamine in diseased human hearts.

We assessed the slope of the end-systolic pressure-volume relation (Emax), the time constant of LV pressure decay (Tw) and the maximum rate of LV early filling (dV/dtmax) before and after the infusion of dobutamine (n = 10) or MCI-154 (n = 9). LV volume and pressure were measured by a conductance catheter and a micro-tip catheter pressure transducer.

When both agents increased Emax comparably, dobutamine decreased Tw from 51 to 37 ms and MCI-154 decreased Tw from 54 to 44 ms. The decrease of Tw with MCI-154 was less than that with dobutamine (17 vs. 29%, P < 0.05). At the same time, dobutamine increased dV/dtmax per end-diastolic volume (dV/dtmax/V) from 2.84 to 3.88 s-1, whereas MCI-154 did not.

Diastolic properties were not compromised by MCI-154, though the alteration in them with MCI-154 was less than that with dobutamine when MCI-154 increased LV contractile state to the same extent as dobutamine. The present results suggest that MCI-154 would be an ideal Ca2+ sensitizing agent that enhances force during systole without impairing diastolic function.