Sevoflurane stimulates inositol 1,4,5-trisphosphate in skeletal muscle.

Inositol 1,4,5-triphosphate (IP(3)) plays an important role in excitation-contraction coupling and malignant hyperthermia in skeletal muscle. We investigated whether sevoflurane affects IP(3) formation in L(6) skeletal muscle cells and studied the mechanisms that modulate IP(3). Sevoflurane stimulated IP(3) 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 microM of U73122 (a phospholipase C antagonist) significantly decreased 0.8 mM of sevoflurane-stimulated IP(3) production from 387. 8 +/- 24.7 to 247.8 +/- 19.8 pmol. mg. protein(-1). A dose of 100 microM of (p-amylcinnamoyl) anthranilic acid (a PLA(2) antagonist) also significantly decreased sevoflurane-stimulated IP(3) production to 282.0 +/- 24.0 pmol. mg. protein(-1). Exposure to 1 microM of genistein and tyrphostin A23 (tyrosine kinase inhibitors) significantly decreased sevoflurane-stimulated IP(3) production to 241.0 +/- 35.3 and 267.4 +/- 32.9 pmol. mg. protein(-1). Sevoflurane-stimulated IP(3) production was significantly decreased by 10 microM of 8-(N,N-diethylamino) octyl-3,4-5-trimathoxybenzoate (an intracellular calcium antagonist) and 100 microM and 1 mM of guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS), a guanosine 5'triphosphate-binding protein inhibitor. Elevation of IP(3) production was significantly higher in halothane than in sevoflurane and isoflurane at the same concentration of 0.8 mM. We conclude that sevoflurane-stimulated IP(3) production involves phospholipase C, phospholipase A(2), tyrosine kinase, and guanosine 5'triphosphate-binding protein and the stimulation is associated with concentration of intracellular ionized calcium.

CONCLUSIONS

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 (IP(3)) formation. IP(3) plays an important role in excitation-contraction coupling and malignant hyperthermia. We studied whether sevoflurane affects IP(3) formation and the mechanisms that modulate IP(3).