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E-1020, a water soluble imidazopyridine,has direct effects on Ca2+-dependent force and ATP hydrolysis of canine and bovine cardiac myofilaments
Authors:Powers  Frances M  Palmiter  Kimberly A  Solaro  R John
Institution:(1) Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, 60680 Chicago, Illinois, USA;(2) Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott Avenue, (M/C 901) Rm E202, 60612 Chicago, IL, USA
Abstract: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 mgrM) significantly increased myofilament Ca2+ sensitivity and Ca2+-dependent ATPase activity at submaximal pCa values. At pCa 6.75, E-1020 significantly increased ATPase activity in bovine (10–100 pM) and canine (1–100 pM) cardiac myofibrils but had no effect on rat cardiac myofibrils. Moreover, in one population of canine ventricular fiber bundles, E-1020 (0.0–10 mgrM) 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.
Keywords:E-1020  calcium sensitivity  myofibrillar ATPase activity  skinned fiber bundles  isometric tension
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