E-1020, a water soluble imidazopyridine, has direct effects on Ca(2+)-dependent force and ATP hydrolysis of canine and bovine cardiac myofilaments.
E-1020 is a cardiotonic agent that acts as a cyclic-AMP phosphodiesterase inhibitor but also may have actions which alter myofilament response to Ca2+. To identify direct actions of E-1020 on cardiac contractile proteins, effects of E-1020 on myofibrillar Ca2+ dependent MgATPase and force generation in chemically skinned fiber bundles were measured. In bovine cardiac myofibrils, E-1020 (100 microM) significantly increased myofilament Ca2+ sensitivity and Ca(2+)-dependent ATPase activity at submaximal pCa values. At pCa 6.75, E-1020 significantly increased ATPase activity in bovine (10-100 microM) and canine (1-100 microM) cardiac myofibrils but had no effect on rat cardiac myofibrils. Moreover, in one population of canine ventricular fiber bundles, E-1020 (0.01-10 microM) significantly increased isometric tension at pCa 6.5 and 6.0, whereas in another population of bundles E-1020 had no effect on tension. In no case was resting (pCa 8.0) or maximal tension (pCa 4.5) increased by E-1020. Measurements of Ca2+ binding to canine ventricular skinned fiber preparations demonstrated that E-1020 does not alter the affinity of myofilament troponin C for Ca2+. We conclude that part of the mechanism by which E-1020 acts as an inotropic agent may involve alterations in the responsiveness of contractile proteins to Ca2+. The lack of effect of E-1020 on some preparations may be dependent on isoform populations of myofilament proteins.
Powers
F M
FM
Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine 60680, USA.
Palmiter
K A
KA
Solaro
R J
RJ
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002417:Cattle; D004285:Dogs; D006868:Hydrolysis; D007093:Imidazoles / Q000494:pharmacology*; D007537:Isometric Contraction; D009206:Myocardium / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats
D002316:Cardiotonic Agents; D007093:Imidazoles; D011728:Pyridones; C059498:olprinone; D000255:Adenosine Triphosphate; D002118:Calcium