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ANESTHETIC PHARMACOLOGY

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

Yuri Nakae, MD PhD^*, Shinji Kohro, MD PhD^*, Quinn H. Hogan, MD^*, and Zeljko J. Bosnjak, PhD^*,

Departments of *Anesthesiology and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin

Address correspondence and reprint requests to Quinn H. Hogan, MD, Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Address e-mail to qhogan{at}mcw.edu

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 adenosine 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 µM), and diazoxide also increased isoflurane-induced MFF. PMA (0.2 µM), PDBu (1 µM), and adenosine (100 µM) induced MFF. However, SPT (100 µM), polymyxin B (50 µM), staurosporine (200 nM), lavendustin A (0.5 µM), and SB203580 (10 µM) 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.

IMPLICATIONS: Our results show that isoflurane activates mitochondrial adenosine triphosphate-sensitive potassium (mitoK_ATP) channels, but not through pathways involving adenosine, protein kinase C, tyrosine kinase, or p38 mitogen-activated protein kinase. Isoflurane may directly activate mitoK_ATP channels.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999