AJP - Heart and Circulatory Physiology, Vol 270, Issue 1 24-H32, Copyright © 1996 by American Physiological Society

ARTICLES

CGP-48506 increases contractility of ventricular myocytes and myofilaments by effects on actin-myosin reaction

B. M. Wolska, Y. Kitada, K. A. Palmiter, M. V. Westfall, M. D. Johnson and R. J. Solaro
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago 60612-7342, USA.

We measured the effects of the benzodiazocine derivative, CGP-48506 (5-methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1, 5-benzodiazocine-2,4-dione), on contraction of intact myocytes and permeabilized fibers of rat ventricular muscle. CGP-48506 is unique in that it is able to sensitize cardiac myofilaments to Ca2+, but unlike all other agents in this class, it is not an inhibitor of type III phosphodiesterase. When added to isolated intact myocytes, CGP-48506 significantly increased the amplitude of cell shortening with little or no change in the Ca2+ transient, as determined by the fluorescence ratio of fura 2. The late phase of the relation between fura 2 ratio and cell length was shifted to the left in the presence of CGP-48506. CGP-48506 also induced a relatively small decrease in diastolic length. However, compared with the thiadiazinone EMD-57033, CGP-48506 had a much smaller effect on diastolic length at concentrations in which there was a bigger inotropic effect. When added to solutions bathing detergent-extracted (skinned) fiber bundles, CGP-48506 increased maximum force. CGP-48506 also increased submaximal force and shifted the pGa-force relation to the left. However, compared with EMD-57033, there was less of an effect of CGP-48506 on force at relatively high pCa values. CGP-48506 did not alter Ca2+ binding to myofilament troponin C. CGP-48506 was able to reverse inhibition of contraction induced by butanedione monoxime both in intact cells and in skinned fiber bundles. Our results indicate that CGP-48506, like EMD-57033, is a positive inotropic agent working through a direct effect downstream from troponin C. CGP-48506, however, appears to have a unique mechanism resulting in less effect on diastolic function.

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