Abstract

Mechanisms of cytotoxicity induced by the anesthetic isoflurane: the role of inositol 1,4,5-trisphosphate receptors

Author(s): W.-H. Zhai, J. Zhao, S.-P. Huo, X.-G. Chen, Y.-D. Li, Z.-L. Zhang, L.-L. Yu, S. Song and Q.-J. Wang

Isoflurane can induce widespread cytotoxicity. We hypothesized that isoflurane induces apoptosis partly by causing excessive calcium release from the endoplasmic reticulum (ER) via direct activation of inositol 1,4,5-trisphosphate receptors (IP3 R). Rat pheochromocytoma cells cultured for seven days with nerve growth factor were divided into four groups: control group (C), IP3 R antagonist group (X), isoflurane group (I) and isoflurane + IP3 R antagonist group (I+X). Groups I and I+X were treated with 1 MAC isoflurane for 12 h. Groups X and I+X were pretreated with IP3 R antagonist. Annexin V/PI apoptosis and TUNEL assays were performed to evaluate cell apoptosis. TEM was used to observe changes in cell ultrastructure. Changes in calcium concentration ([Ca2+]i ) in the cytoplasm were measured by flow cytometry. RT-PCR was performed to evaluate IP3 R mRNA expression. TEM showed that isoflurane treatment altered cell ultrastructure. Compared to group C, cell apoptosis rate and [Ca2+]i increased in groups I and I+X (P < 0.05). Compared to group C, IP3 R mRNA expression was lower in group X and higher in group I (P < 0.05). Compared to group X, cell apoptosis rate, [Ca2+]i and IP3 R mRNA expression increased in groups I and I+X (P < 0.05). Compared to group I, cell apoptosis rate, [Ca2+]i and IP3 R mRNA expression decreased in group I+X (P < 0.05). These results suggest that exposure to 1 MAC isoflurane for 12 h causes excessive calcium release partly by direct activation of IP3 R on the ER membrane and triggers cell apoptosis.

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