Isoflurane protects cardiomyocytes and mitochondria by immediate and cytosol-independent action at reperfusion. Br J Pharmacol 2010 May;160(2):220-32
Date
04/29/2010Pubmed ID
20423337Pubmed Central ID
PMC2874845DOI
10.1111/j.1476-5381.2010.00698.xScopus ID
2-s2.0-77951674239 (requires institutional sign-in at Scopus site) 42 CitationsAbstract
BACKGROUND AND PURPOSE: The volatile anaesthetic isoflurane protects the heart from ischaemia and reperfusion (I/R) injury when applied at the onset of reperfusion [anaesthetic postconditioning (APoC)]. However, the mechanism of APoC-mediated protection is unknown. In this study, we examined the effect of APoC on mitochondrial bioenergetics, mitochondrial matrix pH (pH(m)) and cytosolic pH (pH(i)), and intracellular Ca(2+).
EXPERIMENTAL APPROACH: Cardiac mitochondria from Wistar rats were isolated after in vivo I/R with or without APoC (1.4%-vol isoflurane, 1 minimum alveolar concentration), and mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (DeltaPsi(m)), and oxygen consumption were assessed. In isolated cardiomyocytes and isolated mitochondria I/R injury was produced in vitro, with or without APoC (0.5 mM isoflurane). Intracellular Ca(2+), pH(m), pH(i) and DeltaPsi(m) were monitored with SNARF-1, TMRE and fluo-4, respectively. Myocyte survival was assessed when APoC was induced at pH 7.4 and 7.8. In isolated mitochondria oxygen consumption and ATP synthesis were measured.
KEY RESULTS: In vivo APoC protected against mPTP opening, slowed mitochondrial respiration and depolarized mitochondria. APoC decreased the number of hypercontracted cardiomyocytes at pH 7.4, but not at pH 7.8. APoC attenuated intracellular Ca(2+) accumulation, maintained lower pH(m), and preserved DeltaPsi(m) during reoxygenation. Isoflurane did not affect the regulation of cytosolic pH. In mitochondria, APoC preserved ATP production rate and respiration.
CONCLUSIONS AND IMPLICATIONS: At reperfusion, APoC inhibited mitochondrial respiration, depolarized mitochondria and acidified pH(m). These events may lead to inhibition of mPTP opening and, consequently, to preserved DeltaPsi(m) and ATP synthesis. This reduces intracellular Ca(2+) overload and cell death.
Author List
Pravdic D, Mio Y, Sedlic F, Pratt PF, Warltier DC, Bosnjak ZJ, Bienengraeber MMESH terms used to index this publication - Major topics in bold
Adenosine TriphosphateAnesthetics, Inhalation
Animals
Calcium
Cell Death
Cytosol
Hydrogen-Ion Concentration
Isoflurane
Male
Membrane Potential, Mitochondrial
Mitochondria, Heart
Myocardial Reperfusion Injury
Myocytes, Cardiac
Oxygen Consumption
Rats
Rats, Wistar
