Mechanism of action of 2,3-butanedione monoxime on contracture during metabolic inhibition.
The effect of 2,3-butanedione monoxime (BDM) was investigated during metabolic inhibition (MI) in papillary muscles. MI caused a rapid decrease in developed force and an increase in resting force, along with a decrease in ATP and creatine phosphate (CrP). Addition of BDM before MI decreased maximal contracture force, increased the time, and slowed the rates of ATP and CrP depletion. BDM addition at the peak of contracture did not alter the level of developed contracture. To simulate MI in skinned fiber preparations, we decreased the [MgATP] at pCa 8. [MgATP] of 3.2 microM resulted in a large increase in resting force. The force developed was less in BDM-pretreated muscles. Addition of 10 mM BDM at steady state did not affect force development ([MgATP] 3.2 microM, pCa 8.0). Cross-bridge kinetics in intact and skinned muscle fibers with and without BDM in the presence and absence of MI were studied. Intact muscles with MI revealed no frequency dependence at peak contracture and had elevated stiffness values. In skinned fibers, at [MgATP] of 3.2 microM and pCa of 8, no frequency dependence was observed, and the muscles had similarly high stiffness values. BDM pretreatment in both intact and skinned fibers inhibited rigor formation. These results suggest that BDM inhibits cross-bridge formation in the weak-binding state or actively cycling cross bridges.
Hajjar
R J
RJ
Cardiovascular Disease and Muscle Research Laboratories, Charles A. Dana Research Institute, Boston 02115.
Ingwall
J S
JS
Gwathmey
J K
JK
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D004548:Elasticity; D005289:Ferrets; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D009994:Osmolar Concentration; D010210:Papillary Muscles / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D010710:Phosphates / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D013997:Time Factors
D010710:Phosphates; D010725:Phosphocreatine; C004717:diacetylmonoxime; D000255:Adenosine Triphosphate; D003931:Diacetyl; D002118:Calcium