Effects of the Ca2+ sensitizers EMD 57033 and CGP 48506 on myocardial contractility and Ca2+ transients in human ventricular and atrial myocardium

Ca2+ sensitizers like EMD 57033 (EMD) and CGP 48506 (CGP) may be advantageous for the treatment of human heart failure, as they increase force of contraction without increasing the intracellular Ca2+ transients or energy consumption. However, whether or not Ca2+ sensitizers differ in their mode of action in human myocardium is not fully understood. The present study investigates the influence of EMD and CGP on force of contraction (FOC) and the intracellular Ca2+ transient (fura-2 ratio method) in left ventricular papillary muscle strips from left ventricular failing human myocardium (DCM, n=28) as well as in right atrial trabeculae (RA, n=21) obtained from patients undergoing cardiac bypass surgery.    In isolated trabeculae of DCM, FOC was more efficacious and potently increased after application of EMD (EC50 EMD: 4.7±1.0 μmol/l, max. PIE EMD: +12.0±2.0 mN/mm2) than CGP (EC50: 16.9±7.6 μmol/l, max. PIE: +6.4±2.8 mN/mm2). Similar results were obtained in RA. Application of carbachol (100 μmol/l) had no effect on the positive inotropic effect of EMD or CGP. Both Ca2+ sensitizers significantly increased time to half peak relaxation as well as diastolic tension in DCM. EMD (10 μmol/l) and CGP (30 μmol/l) did not affect the Ca2+ transients in RA.    The Ca2+ sensitizers EMD and CGP increase cAMP and Ca2+ independently from the force of contraction in the human myocardium. However, their therapeutic use in human heart failure may be limited as they impair relaxation.