PMID- 24355434 OWN - NLM STAT- MEDLINE DCOM- 20140415 LR - 20211021 IS - 0006-3002 (Print) IS - 0006-3002 (Linking) VI - 1837 IP - 3 DP - 2014 Mar TI - Isoflurane modulates cardiac mitochondrial bioenergetics by selectively attenuating respiratory complexes. PG - 354-65 LID - S0005-2728(13)00198-9 [pii] LID - 10.1016/j.bbabio.2013.11.006 [doi] AB - Mitochondrial dysfunction contributes to cardiac ischemia-reperfusion (IR) injury but volatile anesthetics (VA) may alter mitochondrial function to trigger cardioprotection. We hypothesized that the VA isoflurane (ISO) mediates cardioprotection in part by altering the function of several respiratory and transport proteins involved in oxidative phosphorylation (OxPhos). To test this we used fluorescence spectrophotometry to measure the effects of ISO (0, 0.5, 1, 2mM) on the time-course of interlinked mitochondrial bioenergetic variables during states 2, 3 and 4 respiration in the presence of either complex I substrate K(+)-pyruvate/malate (PM) or complex II substrate K(+)-succinate (SUC) at physiological levels of extra-matrix free Ca(2+) (~200nM) and Na(+) (10mM). To mimic ISO effects on mitochondrial functions and to clearly delineate the possible ISO targets, the observed actions of ISO were interpreted by comparing effects of ISO to those elicited by low concentrations of inhibitors that act at each respiratory complex, e.g. rotenone (ROT) at complex I or antimycin A (AA) at complex III. Our conclusions are based primarily on the similar responses of ISO and titrated concentrations of ETC. inhibitors during state 3. We found that with the substrate PM, ISO and ROT similarly decreased the magnitude of state 3 NADH oxidation and increased the duration of state 3 NADH oxidation, DeltaPsim depolarization, and respiration in a concentration-dependent manner, whereas with substrate SUC, ISO and ROT decreased the duration of state 3 NADH oxidation, DeltaPsim depolarization and respiration. Unlike AA, ISO reduced the magnitude of state 3 NADH oxidation with PM or SUC as substrate. With substrate SUC, after complete block of complex I with ROT, ISO and AA similarly increased the duration of state 3 DeltaPsim depolarization and respiration. This study provides a mechanistic understanding in how ISO alters mitochondrial function in a way that may lead to cardioprotection. CI - Copyright (c) 2013. Published by Elsevier B.V. FAU - Agarwal, Bhawana AU - Agarwal B AD - Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA. FAU - Dash, Ranjan K AU - Dash RK AD - Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI, USA; Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA. FAU - Stowe, David F AU - Stowe DF AD - Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA; Research Service, Zablocki VA Medical Center, Milwaukee, WI, USA; Department of Biomedical Engineering, Marquette University, Milwaukee, WI, USA. FAU - Bosnjak, Zeljko J AU - Bosnjak ZJ AD - Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA. FAU - Camara, Amadou K S AU - Camara AK AD - Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA. LA - eng GR - R01-HL089514/HL/NHLBI NIH HHS/United States GR - R01-HL095122/HL/NHLBI NIH HHS/United States GR - P01-GM066730/GM/NIGMS NIH HHS/United States GR - R01 HL095122/HL/NHLBI NIH HHS/United States GR - R01 HL089514/HL/NHLBI NIH HHS/United States GR - P01 GM066730/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20131217 PL - Netherlands TA - Biochim Biophys Acta JT - Biochimica et biophysica acta JID - 0217513 RN - 0 (Malates) RN - 0 (Uncoupling Agents) RN - 03L9OT429T (Rotenone) RN - 0U46U6E8UK (NAD) RN - 642-15-9 (Antimycin A) RN - 817L1N4CKP (malic acid) RN - 8558G7RUTR (Pyruvic Acid) RN - AB6MNQ6J6L (Succinic Acid) RN - CYS9AKD70P (Isoflurane) RN - EC 1.3.5.1 (Electron Transport Complex II) RN - EC 7.1.1.2 (Electron Transport Complex I) RN - EC 7.1.1.8 (Electron Transport Complex III) SB - IM MH - Animals MH - Antimycin A/pharmacology MH - Electron Transport/drug effects MH - Electron Transport Complex I/*metabolism MH - Electron Transport Complex II/*metabolism MH - Electron Transport Complex III/*metabolism MH - Energy Metabolism/*drug effects MH - Isoflurane/*pharmacology MH - Malates/metabolism MH - Membrane Potential, Mitochondrial/drug effects MH - Mitochondria, Heart/*drug effects/metabolism/physiology MH - Models, Biological MH - NAD/metabolism MH - Oxidation-Reduction/drug effects MH - Oxygen Consumption/drug effects MH - Pyruvic Acid/metabolism MH - Rats MH - Rats, Wistar MH - Rotenone/pharmacology MH - Spectrometry, Fluorescence MH - Succinic Acid/metabolism MH - Uncoupling Agents/pharmacology PMC - PMC4084852 MID - NIHMS594155 OTO - NOTNLM OT - Cardiac IR injury OT - Cardioprotection OT - Electron transport chain OT - Isoflurane OT - Mitochondrial bioenergetics OT - Volatile anesthetic EDAT- 2013/12/21 06:00 MHDA- 2014/04/16 06:00 PMCR- 2015/03/01 CRDT- 2013/12/21 06:00 PHST- 2013/07/05 00:00 [received] PHST- 2013/10/28 00:00 [revised] PHST- 2013/11/13 00:00 [accepted] PHST- 2013/12/21 06:00 [entrez] PHST- 2013/12/21 06:00 [pubmed] PHST- 2014/04/16 06:00 [medline] PHST- 2015/03/01 00:00 [pmc-release] AID - S0005-2728(13)00198-9 [pii] AID - 10.1016/j.bbabio.2013.11.006 [doi] PST - ppublish SO - Biochim Biophys Acta. 2014 Mar;1837(3):354-65. doi: 10.1016/j.bbabio.2013.11.006. Epub 2013 Dec 17.