Survival of metabolically inhibited ventricular myocytes is enhanced by inhibition of rigor and SR Ca2+ cycling.
During severe ATP depletion, sarcolemmal rupture resulting from rigor- and/or Ca(2+)-induced myofilament force development is considered to be an important cause of irreversible cell injury. Recent experiments in our laboratory demonstrated that during prolonged metabolic inhibition (MI) in adult rabbit ventricular myocytes, in which rigor was prevented by exposure to 30 mM 2,3-butanedione monoxime (BDM), cyclic uptake and release of cystolic Ca2+ occurred and was associated with strong phasic contractions. To investigate the relative contribution of this sarcoplasmic reticulum Ca2+ cycling and associated force development to energy depletion injury, the effects of BDM together with 7 mM caffeine were examined in isolated rabbit ventricular myocytes subjected to MI with 2 mM NaCN and 20 mM 2-deoxyglucose (2-DG). During 90 min of MI with CN and 2-DG, no cells retained a rod shape in the absence of BDM or caffeine. In the presence of both 30 mM BDM and 7 mM caffeine during MI, preservation of rod morphology was enhanced, and 52 +/- 6.2% of cells retained a rod shape 48 h after metabolic inhibition and had normal ATP content and resting membrane potential. Both systolic and diastolic functions of cells that survived MI, however, were impaired. We conclude that exposure to caffeine together with BDM markedly enhances survival of myocytes during severe prolonged ATP depletion. After recovery, these isolated myocytes show some characteristics of stunning.
Koyama
T
T
Cardiology Division, University of Utah Medical Center, Salt Lake City 84132, USA.
Boston
D
D
Ikenouchi
H
H
Barry
W H
WH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival; D003847:Deoxyglucose / Q000494:pharmacology*; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D006352:Heart Ventricles; D007425:Intracellular Membranes / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D012966:Sodium Cyanide / Q000494:pharmacology*
C004717:diacetylmonoxime; D002110:Caffeine; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D003931:Diacetyl; D012966:Sodium Cyanide; D002118:Calcium