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GENERAL ARTICLES

Sevoflurane Stimulates Inositol 1,4,5-Trisphosphate in Skeletal Muscle

Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan

Address correspondence and reprint requests to Akira Kudoh, MD, Department of Anesthesiology, University of Hirosaki School of Medicine, 5 Zaifucho, Hirosaki 036, Aomori, Japan.

Inositol 1,4,5-triphosphate (IP₃) plays an important role in excitation-contraction coupling and malignant hyperthermia in skeletal muscle. We investigated whether sevoflurane affects IP₃ formation in L₆ skeletal muscle cells and studied the mechanisms that modulate IP₃. Sevoflurane stimulated IP₃ production from a basal level of 78.4 ± 6.1 to 730.0 ± 53.1 pmol · mg · protein^-1 in 2 mM of sevoflurane in a dose-dependent manner. A dose of 10 µM of U73122 (a phospholipase C antagonist) significantly decreased 0.8 mM of sevoflurane-stimulated IP₃ production from 387.8 ± 24.7 to 247.8 ± 19.8 pmol · mg · protein^-1. A dose of 100 µM of (p-amylcinnamoyl) anthranilic acid (a PLA₂ antagonist) also significantly decreased sevoflurane-stimulated IP₃ production to 282.0 ± 24.0 pmol · mg · protein^-1. Exposure to 1 µM of genistein and tyrphostin A23 (tyrosine kinase inhibitors) significantly decreased sevoflurane-stimulated IP₃ production to 241.0 ± 35.3 and 267.4 ± 32.9 pmol · mg · protein^-1. Sevoflurane-stimulated IP₃ production was significantly decreased by 10 µM of 8-(N,N-diethylamino) octyl-3,4-5-trimathoxybenzoate (an intracellular calcium antagonist) and 100 µM and 1 mM of guanosine 5'-O-(2-thiodiphosphate) (GDPßS), a guanosine 5'triphosphate-binding protein inhibitor. Elevation of IP₃ production was significantly higher in halothane than in sevoflurane and isoflurane at the same concentration of 0.8 mM. We conclude that sevoflurane-stimulated IP₃ production involves phospholipase C, phospholipase A₂, tyrosine kinase, and guanosine 5'triphosphate-binding protein and the stimulation is associated with concentration of intracellular ionized calcium.

Implications: Inhaled anesthetics increase intracellular ionized calcium in the skeletal muscle cell and the ionized calcium increase is partly released from the intracellular store by inositol 1,4,5-triphosphate (IP₃) formation. IP₃ plays an important role in excitation-contraction coupling and malignant hyperthermia. We studied whether sevoflurane affects IP₃ formation and the mechanisms that modulate IP₃.

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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