Halothane, isoflurane and sevoflurane inhibit NADH: ubiquinone oxidoreductase (complex I) of cardiac mitochondria

Abstract

We have investigated the effects of volatile anaesthetics on electron transport chain activity in the mammalian heart. Halothane, isoflurane and sevoflurane reversibly increased NADH fluorescence (autofluorescence) in intact ventricular myocytes of guinea‐pig, suggesting that NADH oxidation was impaired. Using pig heart submitochondrial particles we found that the anaesthetics dose‐dependently inhibited NADH oxidation in the order: halothane > isoflurane = sevoflurane. Succinate oxidation was unaffected by either isoflurane or sevoflurane, indicating that these agents selectively inhibit complex I (NADH:ubiquinone oxidoreductase). In addition to inhibiting NADH oxidation, halothane also inhibited succinate oxidation (and succinate dehydrogenase), albeit to a lesser extent. To test the hypothesis that complex I is a target of volatile anaesthetics, we examined the effects of these agents on NADH:ubiquinone oxidoreductase (EC 1.6.99.3) activity using the ubiquinone analogue DBQ (decylubiquinone) as substrate. Halothane, isoflurane and sevoflurane dose‐dependently inhibited NADH:DBQ oxidoreductase activity. Unlike the classical inhibitor rotenone, none of the anaesthetics completely inhibited enzyme activity at high concentration, suggesting that these agents bind weakly to the ‘hydrophobic inhibitory site’ of complex I. In conclusion, halothane, isoflurane and sevoflurane inhibit complex I (NADH:ubiquinone oxidoreductase) of the electron transport chain. At concentrations of ≈2 MAC (minimal alveolar concentration), the activity of NADH:ubiquinone oxidoreductase was reduced by about 20 % in the presence of halothane or isoflurane, and by about 10 % in the presence of sevoflurane. These inhibitory effects are unlikely to compromise cardiac performance at usual clinical concentrations, but may contribute to the mechanism by which volatile anaesthetics induce pharmacological preconditioning.

Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice

“…Although there is no direct evidence that NS-1619 could inhibit mitochondrial function in cardiac cells, we cannot completely rule out the possibility that the cardioprotective effect of this drug is mediated in part through inhibition of complex I of the mitochondrial respiratory chain. In fact, a recent study suggested that the cardioprotective effects of volatile anesthetics (such as halothane, isoflurane, and sevoflu-rane) may be mediated through inhibition of complex I of the cardiac mitochondrial respiratory chain (21). There is also evidence that paxilline inhibits sarco/endoplasmic reticulum Ca 2ϩ -ATPase (SERCA) in vitro (7).…”

Quantitative characterization of changes in the cardiac mitochondrial proteome during anesthetic preconditioning and ischemia

“…Although it is known that mitochondria play a vital role in the cardioprotection conferred by volatile anesthetics, the exact target proteins have not been identified. It has long been established that drugs with anesthetic properties have a depressant effect on mitochondrial function (9,11). The slowing of respiration rates at various complexes in the respiratory chain may cause an electron leak and subsequently lead to augmented generation of ROS.…”

Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review

“…29 Fatal halothane rechallenge is widely attributed to immunomediated liver injury with rapid injury with rechallenge, associated fever, eosinophilia, anti-CYP2E1, anti-liver-kidney-microsomal and adduct antibodies, 24,28 and association with HLA A-11. 29 Halothane also causes mitochondrial impairment, due to inhibition of complex I and II, 30 as well as fatty acid and pyruvate oxidation in nonclinical studies. 31 Therefore, halothane's high fatality rate on rechallenge appears related to its combined mitochondrial impairment and immunoallergic injury, most frequently observed with rechallenge occurring within 1 month of initial injury.…”