CGP-48506 increases contractility of ventricular myocytes and myofilaments by effects on actin-myosin reaction.
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.
Wolska
B M
BM
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago 60612-7342, USA.
Kitada
Y
Y
Palmiter
K A
KA
Westfall
M V
MV
Johnson
M D
MD
Solaro
R J
RJ
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001392:Azocines / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D009994:Osmolar Concentration; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013829:Thiadiazines / Q000494:pharmacology; D016276:Ventricular Function / Q000187:drug effects*
D000199:Actins; D001392:Azocines; D002316:Cardiotonic Agents; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; C095056:BA 41899; C004717:diacetylmonoxime; D009218:Myosins; D003931:Diacetyl; D002118:Calcium