期刊
ANESTHESIOLOGY
卷 121, 期 3, 页码 528-537出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/ALN.0000000000000316
关键词
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资金
- National Institutes of Health (Baltimore, Maryland) [GM084979, GM084979-02S1, GM056328, MH059937, K08-GM073224]
- March of Dimes Birth Defects Foundation Research (White Plains, New York) [12-FY08-167]
- Research Fund at the Department of Anesthesiology at the University of Pennsylvania (Philadelphia, Pennsylvania)
Background: Pharmacological evidence suggests that inhalational general anesthetics induce neurodegeneration in vitro and in vivo through overactivation of inositol trisphosphate receptor (InsP(3)R) Ca2+-release channels, but it is not clear whether these effects are due to direct modulation of channel activity by the anesthetics. Methods: Using single-channel patch clamp electrophysiology, the authors examined the gating of rat recombinant type 3 InsP(3)R (InsP(3)R-3) Ca2+-release channels in isolated nuclei (N = 3 to 15) from chicken lymphocytes modulated by isoflurane at clinically relevant concentrations in the absence and presence of physiological levels of the agonist inositol 1,4,5-trisphosphate (InsP(3)). The authors also examined the effects of isoflurane on InsP 3 R-mediated Ca2+ release from the endoplasmic reticulum and changes in intracellular Ca2+ concentration ([Ca2+](i)). Results: Clinically relevant concentrations (approximately 1 minimal alveolar concentration) of the commonly used general anesthetic, isoflurane, activated InsP(3)R-3 channels with open probability similar to channels activated by 1 mu M InsP(3) (P-o approximate to 0.2). This isoflurane modulation of InsP(3)R-3 P-o depended biphasically on [Ca2+](i). Combination of isoflurane with subsaturating levels of InsP(3) in patch pipettes resulted in at least two-fold augmentations of InsP(3)R-3 channel P-o compared with InsP(3) alone. These effects were not noted in the presence of saturating [InsP(3)]. Application of isoflurane to DT40 cells resulted in a 30% amplification of InsP(3)R-mediated [Ca2+](i) oscillations, whereas InsP(3)-induced increase in [Ca2+](i) and cleaved caspase-3 activity were enhanced by approximately 2.5-fold. Conclusion: These results suggest that the InsP(3)R may be a direct molecular target of isoflurane and plays a role in the mechanisms of anesthetic-mediated pharmacological or neurotoxic effects.
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