Intracellular Mechanism of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channel Activation with Isoflurane

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Anesthesia & Analgesia (Impact Factor: 3.47). 11/2003; 97(4):1025-32, table of contents. DOI: 10.1213/01.ANE.0000077072.67502.CC
Source: PubMed


The precise mechanism of isoflurane and mitochondrial adenosine triphosphate-sensitive potassium channel (mitoK(ATp)) interaction is still unclear, although the mitoK(ATP) is involved in isoflurane-induced preconditioning. We examined the role of various intracellular signaling systems in mitoK(ATP) activation with isoflurane. Mitochondrial flavoprotein fluorescence (MFF) was measured to quantify mitoK(ATP) activity in guinea pig cardiomyocytes. To confirm isoflurane-induced MFF, cells were exposed to Tyrode's solution containing either isoflurane (1.0 +/- 0.1 mM) or diazoxide and then both drugs together (n = 10 each). In other studies, the following drugs were each added during isoflurane administration: adenosine or the idenosine receptor antagonist 8-(p-sulfophenyl)theophylline (SPT); the protein kinase C (PKC) activators phorbol-12-myristate-13-acetate (PMA) and phorbol-12,13-dibutyrate (PDBu); the PKC inhibitors polymyxin B and staurosporine; the tyrosine kinase inhibitor lavendustin A; or the mitogen-activated protein kinase inhibitor SB203580 (n = 10 each). Isoflurane potentiated MFF induced by diazoxide (100 muM), and diazoxide also increased isoflurane-induced MFF. PMA (0.2 muM), PDBu (1 muM), and adenosine (100 muM) induced MFF. However, SPT (100 muM), polymyxin B (50 muM), staurosporine (200 nM), lavendustin A (0.5 muM), and SB203580 (10 muM) all failed to inhibit the effect of isoflurane. Our results show that isoflurane, adenosine, and PKC activate mitoK(ATP). However, our data do not support an action of isoflurane through pathways involving adenosine, PKC, tyrosine kinase, or mitogen-activated protein kinase. These results suggest that isoflurane may directly activate mitoK(ATP).

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Available from: Zeljko Bosnjak
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    • "Early and late preconditioning probably involves different signalling pathways that have yet to be fully elucidated. Early preconditioning is thought to involve opening mitochondrial ATP dependent potassium channels [4,5,6,7,8,9], increasing mitochondrial reactive oxygen species [4,10,11], decreasing cytosolic and mitochon-drial calcium loading [12], protection of endothelial coronary cells by mediating nitric oxide release [13] and by suppressing neutrophil activation and the neutrophil-endothelium interactions that cause myocardial dysfunction [14,15]. "
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    • "However, the mechanism of Iso-induced preconditioning seems to have multiple complex signal transduction pathways and to share some of the mechanisms of IPC [4]. In particular, mitochondrial K ATP channels play a pivotal role in volatile anesthetic-induced preconditioning and in classic IPC [4] [9]. Diazoxide, a potent and specific mitochondrial K ATP channel opener, reduced neurologic injury in a rabbit model of SCI and decreased myocardial infarct size after coronary artery occlusion. "
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