Cgp 48506, a novel benzodiazocine derivative, increases
contractility of rat ventricular myocytes and myofilaments by direct
effects on the actin-myosin reaction.
Wolska, Beata M., Yoshimi Kitada, Kimberly A. Palmiter, Margaret V.
Westfall, Mary D. Johnson, and R. John Solaro.
Department of Physiology and Biophysics, University of Illinois at
Chicago, College of Medicine, Chicago, IL 60612-7342
APStracts 2:0282H, 1995.
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 permeablized fibers
of rat ventricular muscle. CGP 48506 is unique in that it is able to
sensitize cardiac myofialments to Ca2+, but unlike all other agents
in this class, it is not an inhibitor of phosphodiesterase (PDE III).
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 to 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 pCa-force relation to the left. However, compared to 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, as EMD 57033, is
a positive inotropic agent working through a direct effect downstream
from TnC. CGP 48506, however, appears to have a unique mechanism
resulting in less effect on diastolic function.
Received 27 April 1995; accepted in final form 27 June 1995.
APS Manuscript Number H393-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 11 July 1995.