A New Cardiotonic Drug Reduces the Energy Cost of Active Tension in Cardiac Muscle

Abstract

The novel thiadiazinone EMD 57033 (EMD) increases the calcium responsiveness of the contractile proteins in cardiac muscle. In skinned ventricular trabeculate isolated from guinea-pig heart, application of 10 μM EMD shifted the curve relating isometric tension to the applied calcium concentration to the left and increased maximal tension by 15%. In intact trabeculae, the rate of heat production, an indicator of the rate of ATP hydrolysis in the steady state, and isometric tension were measured at 37°C. Both the thiadiazinone (EMD; 2.5, 5, and 10 μM) and the cardiac glycoside dihydro-ouabain (DHO; 5, 10, and 20 μM) produced a concentration-dependent increase in contraction-related heart production (Hc) and in the tension time integral of isometric contractions (Td). In the presence of EMD the energy cost of active tension (Hc/Td) was substantially decreased as compared to control conditions. The energy cost of the positive inotropic effect of EMD (43.8 mW N-1 cm-1) was only about half as large as the energy cost of the positive inotropic effect of DHO (88.4 mW N-1 cm-1). It is concluded that EMD causes a change in cross-bridge kinetics that increases the contractility of cardiac muscle and improves the economy of chemo-mechanical energy transduction. Our results suggest that EMD 57033 represents a prototype of a new class of cardiotonic agents that might be potentially useful in the therapy of congestive heart failure.