Different effect of the Ca(2+) sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium.
Ca(2+) sensitizers may be advantageous for treatment in human heart failure by increasing cardiac force without increasing the Ca(2+) transient or energy consumption. To study the mode of action of the Ca(2+) sensitizers EMD 57033 (EMD) and CGP 48506 (CGP), their influence on butanedione monoxime (BDM)-mediated depression of cross-bridge cycling was analyzed in human myocardium (explanted hearts, dilated cardiomyopathy, n = 19). In Triton X (1%)-skinned fiber preparations of left ventricular myocardium from patients suffering from dilated cardiomyopathy, troponin I was extracted by vanadate (10 mM) treatment, resulting in a Ca(2+)-independent contraction. In troponin I-depleted fibers BDM (5-50 mM) was applied in the absence and presence of EMD (10 microM) or CGP (10 microM). To analyze the influence on cross-bridge kinetics, tension cost (ratio of ATPase activity and tension development) was studied. BDM exerted a dose-dependent force inhibition in troponin I-depleted fibers (IC(50) = 7.22 mM), which was antagonized by EMD (IC(50) of BDM + EMD = 19.97 mM) and CGP (IC(50) of BDM + CGP = 15.30 mM). EMD increased Ca(2+) sensitivity of force and maximal force in Triton X-skinned fibers. The Ca(2+)-sensitizing effect of CGP was accompanied by an increased Ca(2+) sensitivity of myosin-ATPase activity, an increased slope of the Ca(2+) force and Ca(2+) ATPase curve, as well as a reduced maximal myosin ATPase activity. CGP and EMD reduced tension cost. In conclusion, EMD and CGP antagonize the BDM-mediated relaxation in troponin I-depleted cardiac muscle fibers. The Ca(2+)-sensitizing effect of CGP seems to be dependent on an improvement of the myofilament cooperativity, whereas EMD seems to operate by increasing the force per cross-bridge.
Brixius
K
K
Laboratory of Muscle Research and Molecular Cardiology, Clinic III of Internal Medicine, University of Cologne, Köln, Germany.
Mehlhorn
U
U
Bloch
W
W
Schwinger
R H
RH
D000328:Adult; D001392:Azocines / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D013829:Thiadiazines / Q000494:pharmacology*; D019210:Troponin I / Q000502:physiology
D001392:Azocines; D002316:Cardiotonic Agents; D011804:Quinolines; D013829:Thiadiazines; D019210:Troponin I; C070609:EMD 53998; C095056:BA 41899; C004717:diacetylmonoxime; D003931:Diacetyl; D002118:Calcium