Substrate ‐dependent Action of Isoflurane on Electron Transport Chain Complexes

Abstract

The volatile anesthetic isoflurane (ISO) alters mitochondrial electron transport activity, which, in part, may underlie ISO‐induced cell protection. To unravel the mechanism of ISO effects on mitochondrial bioenergetics (ΔΨm, NADH and respiration), rat isolated cardiac mitochondria were energized with complex I (K+ ‐ pyruvate/malate; KPM) or complex II (K+ ‐succinate; KSuc) substrates ± sub‐maximal concentrations of ISO and the complex I and complex III blockers rotenone (ROT) and antimycin A (AA). Results showed that: (a) ISO decreased state 3 NADH oxidation and respiration, and increased the duration of state 3 ΔΨm with KPM; (b) ISO decreased state 3 respiration and the fall in ΔΨm, but did not decrease NADH oxidation with KSuc; (c) ISO increased state 3 ΔΨm duration but enhanced respiration with KSuc and ROT. These data indicate that: (1) ISO decreases the magnitude, while enhancing the duration, of state 3 NADH oxidation, ΔΨm and respiration, in part by inhibiting complex I activity with KPM; (2) ISO decreases KSuc supported production of NADH by attenuating complex I activity; (3) ISO increases state 3 ΔΨm duration but enhances respiration by attenuating complex III activity), with KSuc and ROT. Thus, isoflurane direct substrate‐dependent attenuation of complex I and complex III activities suggests a mitochondrial bioenergetic mechanism of cardioprotection during anesthetic exposure. (NIH Grants)