title: MCI-154, a cardiac Ca2+ sensitizer, reverses the depression in maximal Ca2+-activated force by inorganic phosphate and acidic pH in skinned fiber of guinea pig heart.
abstract: Intracellular accumulation of inorganic phosphate (Pi) and intracellular acidosis, which occur in ischemic and hypoxic hearts, reduce the force of contraction by decreasing the responsiveness of contractile system to Ca2+. In the present study we investigated the effects of MCI-154, 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-dependently 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 concentration (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 inhibited the rightward shift of the pCa-tension relationships, with a marked decrease of maximal force produced by 20 mM Pi or acidic pH (decrease in pH from 7.0 to 6.6). MCI-154 also improved the decline in maximal Ca2+-activated force by 20 mM Pi under acidic pH, but the acidosis did not further decrease the effect of 20 mM Pi. Milrinone, a cyclic AMP-dependent phosphodiesterase inhibitor, and pimobendan, another Ca2+ sensitizer, did not improve the Pi-induced contractile failure. These 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 myosin. MCI-154 may be a promising agent for myocardial contractile failure, in which Pi and H+ progressively increase.
authors.affiliation: Pharmaceutical Laboratory I, Yokohama Research Center, Mitsubishi Chemical Corporation, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kitada
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010710:Phosphates / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology; D016276:Ventricular Function
chemical_list: D002316:Cardiotonic Agents; D010710:Phosphates; D011724:Pyridazines; D011728:Pyridones; C041648:pimobendan; C052228:MCI 154; D020105:Milrinone; D002118:Calcium