Article

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: 3.42). 11/2003; 97(4):1025-32, table of contents. DOI: 10.1213/01.ANE.0000077072.67502.CC
Source: PubMed

ABSTRACT 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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