Halothane, isoflurane, and sevoflurane increase the kinetics of Ca2+-induced conformational change of recombinant human cardiac troponin C.
BACKGROUND
Halothane, isoflurane, and sevoflurane exert negative inotropic side effects, generally mediated via a reduced availability of intracellular calcium. Other possible mechanisms include modified intracellular calcium handling, impaired actomyosin cross-bridge cycling, and/or alteration of calcium-induced conformational changes of the regulatory troponin complex.


METHODS
We investigated the effect of halothane, isoflurane, and sevoflurane on calcium-dependent kinetics of isolated human recombinant cardiac troponin C labeled with IAANS (HrcTnC(IAANS)) using stopped-flow and calcium titration techniques.


RESULTS
Calcium concentration at half-maximal fluorescence intensity (K(d)) in the control group was 2.1 +/- 0.1 mM. Volatile anesthetics increased calcium sensitivity in a concentration-dependent fashion sevoflurane (K(d) 1.5-1.7 mM, P = 0.001) > halothane (K(d) 1.7-1.9 mM, P < 0.01) > isoflurane (K(d) 1.8-1.9 mM, P < 0.05). The rate constant of conformational changes after rapid dissociation of calcium from HrcTnC(IAANS) (k(off(c))) was moderately prolonged at 4 degrees C by halothane and isoflurane > sevoflurane.


CONCLUSIONS
These mechanisms may counteract the effects of lower calcium availability, and can be responsible for abbreviated, and possibly incomplete, relaxation of cardiac muscle fibers in the presence of volatile anesthetics.
Breukelmann
Dirk
D
Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany. breukel@uni-muenster.de
Housmans
Philippe R
PR
D018685:Anesthetics, Inhalation / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000737:chemistry / Q000502:physiology*; D006221:Halothane / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007530:Isoflurane / Q000737:chemistry / Q000494:pharmacology*; D008738:Methyl Ethers / Q000737:chemistry / Q000494:pharmacology*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics*; D000077149:Sevoflurane; D019209:Troponin C / Q000737:chemistry / Q000493:pharmacokinetics*; D014835:Volatilization
D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D011994:Recombinant Proteins; D019209:Troponin C; D000077149:Sevoflurane; D007530:Isoflurane; D002118:Calcium; D006221:Halothane