Halothane impairs the bioenergetic functions of isolated rat liver mitochondria.
The effect of halothane, a potent and popular volatile anesthetic, on isolated rat liver mitochondria was examined. Halothane inhibited state 3 and dinitrophenol-induced uncoupled respiration with NAD(+)-linked substrates, but not with FAD-linked substrates, and did not affect the oxidation-reduction state of mitochondrial cytochromes. Moreover, halothane increased state 4 respiration and ATPase activity and decreased the extra-mitochrondrial pH change coupled to ATP synthesis. These results indicate that halothane impairs mitochondrial ATP production by interfering with both the electron transport from NAD+ to FAD and the coupling of oxidative phosphorylation. Halothane only slightly affected the membrane potential, which is commonly dissipated by typical classical uncouplers. Moreover, halothane inhibited both ATP-driven and respiration-driven Ca2+ accumulation in mitochondria and stimulated Ca2+ release from mitochondrial stores at concentrations higher than those at which it inhibited ATP production. These findings indicate that the uncoupling action of halothane is not classical. During halothane anesthesia, these mitochondrial abnormalities may contribute to hepatocyte dysfunctions.
Tsuchiya
M
M
Department of Anesthesiology, Kochi Medical School, Japan.
Takahashi
M
M
Tomoda
M
M
Ueda
W
W
Hirakawa
M
M
D000251:Adenosine Triphosphatases / Q000032:analysis; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects; D003580:Cytochromes / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006221:Halothane / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007656:Ketoglutaric Acids / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000187:drug effects*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013386:Succinates / Q000494:pharmacology; D019802:Succinic Acid
D015220:Calcium Channels; D003580:Cytochromes; D007656:Ketoglutaric Acids; D013386:Succinates; D019802:Succinic Acid; D000251:Adenosine Triphosphatases; D002118:Calcium; D006221:Halothane