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

Am J Physiol. 1996 Jan;270(1 Pt 2):H24-32. doi: 10.1152/ajpheart.1996.270.1.H24.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actin Cytoskeleton / drug effects*
  • Actin Cytoskeleton / metabolism
  • Actins / metabolism*
  • Animals
  • Azocines / pharmacology*
  • Calcium / physiology
  • Cardiotonic Agents / pharmacology*
  • Diacetyl / analogs & derivatives
  • Diacetyl / pharmacology
  • Dogs
  • Dose-Response Relationship, Drug
  • Male
  • Myocardial Contraction / drug effects*
  • Myocardium / cytology
  • Myocardium / metabolism
  • Myosins / metabolism*
  • Osmolar Concentration
  • Quinolines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Thiadiazines / pharmacology
  • Ventricular Function / drug effects*

Substances

  • Actins
  • Azocines
  • Cardiotonic Agents
  • Quinolines
  • Thiadiazines
  • EMD 53998
  • BA 41899
  • diacetylmonoxime
  • Myosins
  • Diacetyl
  • Calcium