MCI-154, A CARDIAC CA2-ACTIVATED FORCE BY INORGANIC-PHOSPHATE AND ACIDIC PH IN SKINNED FIBER OF GUINEA-PIG HEART( SENSITIZER, REVERSES THE DEPRESSION IN MAXIMAL CA2+)

Intracellular accumulation of inorganic phosphate (Pi) and intracellul ar acidosis, which occur in ischemic and hypoxic hearts, reduce the fo rce of contraction by decreasing the responsiveness of contractile sys tem to Ca2+. In the present study we investigated the effects of MCI-1 54, a Ca2+ sensitizer that can enhance crossbridge interaction, on the decline in maximal Ca2+-activated force by Pi or acidic pH in skinned fiber bundles of guinea pig hearts. MCI-154 can concentration-depende ntly reverse the depression in maximal Ca2+-activated force (pCa 4.4) by 20 mM Pi, which was not recovered by a higher concentration of Ca2 ion (pCa 4.0). The effects of MCI-154 were observed even at a concent ration (0.01 M) at which the drug has no effect on the pCa 4.4-induced maximal force in the absence of 20 mM Pi when given alone. MCI-154 in hibited the rightward shift of the pCa-tension relationships, with a m arked decrease of maximal force produced by 20 mM Pi or acidic pH (dec rease in pH from 7.0 to 6.6). MCI-154 also improved the decline in max imal Ca2+-activated force by 20 mM Pi under acidic pH, but the acidosi s did not further decrease the effect of 20 mM Pi. Milrinone, a cyclic AMP-dependent phosphodiesterase inhibitor, and pimobendan, another Ca 2+ sensitizer, did not improve the Pi-induced contractile failure. The se results indicate that the Ca2+ sensitizer MCI-154 could reverse the contractile failure induced by Pi and/or acidic pH in a skinned fiber preparation via modulation of the strong crossbridge reaction with my osin. MCI-154 may be a promising agent for myocardial contractile fail ure, in which Pi and H+ progressively increase.