Effects of halothane on calcium(2+)-activated tension of the contractile proteins and calcium(2+) uptake and release by the sarcoplasmic reticulum in skinned human myocardial fibers.
Based on studies using skinned myocardial fibers from animals, it has been postulated that one of the major mechanisms by which halothane depresses myocardial contractility is by decreasing the Ca2+ content of the sarcoplasmic reticulum (SR). In this study we examined, in skinned human myocardial fibers, the effects of halothane on Ca(2+)-activated tension development of the contractile proteins and Ca2+ uptake and release by the SR. Left ventricular muscle samples obtained from patients undergoing aortocoronary bypass operations were mechanically skinned and immersed in test solutions equilibrated with N2 and halothane preceded and followed by immersion in control solution (no halothane). To study Ca(2+)-activated tension development of the contractile proteins, free Ca2+ concentrations in the bathing solutions were buffered by EGTA. To study Ca2+ uptake and release by the SR, Ca2+ was loaded into the SR and released with caffeine and the resulting tension transients were measured. Halothane (1%-3%) depressed maximum Ca(2+)-activated tensions (pCa = -log[Ca2+](M) = 3.8) by 5% for each 1% increase in concentration. Tensions generated by submaximum Ca2+ concentrations expressed as a percentage of maximum tension were not significantly decreased by halothane except at 3%. Halothane decreased Ca2+ uptake (IC50 = 1.7%), and increased (by approximately 50%) Ca2+ release by the SR. We conclude that decreased activation of the contractile proteins and Ca2+ uptake by the SR can both contribute to the myocardial depression produced by halothane. Of these, decreased Ca2+ uptake by the SR is probably a major mechanism for halothane depression of myocardium.
Sivarajan
M
M
Department of Anesthesiology, University of Washington, Seattle, USA.
Su
J Y
JY
Hofer
B O
BO
D000818:Animals; D002021:Buffers; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics; D003285:Contractile Proteins / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid; D006221:Halothane / Q000008:administration & dosage / Q000494:pharmacology*; D006352:Heart Ventricles; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009584:Nitrogen / Q000494:pharmacology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism
D002021:Buffers; D003285:Contractile Proteins; D002110:Caffeine; D004533:Egtazic Acid; D009584:Nitrogen; D002118:Calcium; D006221:Halothane