title: MCI-154, a novel cardiotonic agent, reverses the acidic pH-induced decrease in responses of cardiac myofilaments to Ca++: comparison with sulmazole and pimobendan.
abstract: In the present study, we have examined the effects of decreasing pH from 7.0 to 6.6 on the tension developed by direct activation of the myofilaments in chemically skinned fibers from guinea pig papillary muscles. We then compared the effects of the novel inotropic agents MCI-154, pimobendan and sulmazole, which have direct action on cardiac myofilaments, on the acidic pH-induced changes in responses of the contractile system to Ca++. The reduction of pH from 7.0 to 6.8 shifted the pCa (-log[Ca++] M)-tension relation curve to the right with no change in maximum tension. However, the reduction of pH from 7.0 to 6.6 shifted the pCa tension relation curve to the right and also depressed maximum force development. These effects were reversible by returning to neutral pH (pH 7.0), but were not overcome by increasing the free [Ca++] (decreasing pCa from 4.4 to 4.0). The amplitude of pMg-ATP (-log[MgATP]M)-tension curve in the absence of free Ca++ (Ca++ less than 1 nM, bell-shaped curve) was shifted downward by reducing pH from 7.0 to 6.6. MCI-154 (1-100 microM) reversed the acidic pH-induced decrease of tension development which was activated by pCa 5.8 in a concentration-dependent manner. Moreover, the acidosis induced reductions of maximum tension (pCa, 4.4) and pMgATP 6.0-activated tension (Ca++ less than 1 nM) were also reversed by MCI-154 (1-100 microM) in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Pharmaceuticals Laboratory, Mitsubishi Kasei Corporation, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kitada
authors.forename: Y
authors.initials: Y
authors.lastname: Abe
authors.forename: A
authors.initials: A
authors.lastname: Narimatsu
authors.forename: A
authors.initials: A
authors.lastname: Tobe
mesh_terms: D000138:Acidosis / Q000378:metabolism; D008841:Actin Cytoskeleton; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D011724:Pyridazines / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D007093:Imidazoles; D011724:Pyridazines; C041648:pimobendan; C052228:MCI 154; C029758:sulmazole; D002118:Calcium