Effect of 2,3-butanedione monoxime on myocyte resting force during prolonged metabolic inhibition.
The chemical phosphatase 2,3-butanedione monoxime (BDM) has been reported to inhibit both Ca(2+)-induced myofilament force development and rigor due to ATP depletion. However, during prolonged hypoxia in cultured ventricular myocytes BDM delays but does not prevent a marked increase in resting force. To investigate the mechanisms involved we measured the effects of BDM on intracellular Ca2+ concentration ([Ca2+]i; indo 1), force development (video motion detector), and ATP contents (luciferase assay) in cultured embryonic chick ventricular myocytes and adult rabbit ventricular myocytes subjected to prolonged metabolic inhibition with 1 mM NaCN and 20 mM 2-deoxyglucose. In the absence of metabolic inhibition, 20 mM BDM depressed force development even when [Ca2+]i was markedly elevated by exposure to zero-Na solution or 10 mM caffeine in chick cells, and 30 mM BDM completely inhibited Ca(2+)-induced force development in rabbit myocytes. During metabolic inhibition, 20 mM BDM delayed the onset of an increase in resting force (from 5.44 +/- 0.87 to 13.67 +/- 1.34 min in chick myocytes; from 19.13 +/- 2.23 to 32.43 +/- 3.30 min in rabbit myocytes, means +/- SE, n = 8-9). However, the rates of ATP depletion and rise in [Ca2+]i after metabolic inhibition were not altered by BDM. In the presence of BDM, during prolonged metabolic inhibition in both chick and rabbit myocytes, abrupt spontaneous or evoked alterations in [Ca2+]i were associated with corresponding changes in force. During the initial increase in resting force induced by metabolic inhibition, exposure to BDM caused a partial transient relaxation. We conclude that the delayed increase in resting force during metabolic inhibition in the presence of BDM is due to redevelopment of Ca2+ sensitivity of the myofilaments in the presence of an increased [Ca2+]i as a consequence of severe ATP depletion, whereas in the absence of BDM the more rapidly developing increase in resting force during metabolic inhibition is initially due to a rise in [Ca2+]i followed by development of rigor.
Ikenouchi
H
H
Department of Medicine, University of Utah School of Medicine, Salt Lake City 84132.
Zhao
L
L
Barry
W H
WH
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D003847:Deoxyglucose / Q000494:pharmacology; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009994:Osmolar Concentration; D011817:Rabbits; D012964:Sodium / Q000378:metabolism; D012966:Sodium Cyanide / Q000494:pharmacology; D013997:Time Factors
C004717:diacetylmonoxime; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D012964:Sodium; D003931:Diacetyl; D012966:Sodium Cyanide; D002118:Calcium