title: Mechanisms of cytotoxicity induced by the anesthetic isoflurane: the role of inositol 1,4,5-trisphosphate receptors.
abstract: 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 (IP3R). Rat pheochromocytoma cells cultured for seven days with nerve growth factor were divided into four groups: control group (C), IP3R antagonist group (X), isoflurane group (I) and isoflurane + IP3R 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 IP3R 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 ([Ca(2+)]i) in the cytoplasm were measured by flow cytometry. RT-PCR was performed to evaluate IP3R mRNA expression. TEM showed that isoflurane treatment altered cell ultrastructure. Compared to group C, cell apoptosis rate and [Ca(2+)]i increased in groups I and I+X (P < 0.05). Compared to group C, IP3R mRNA expression was lower in group X and higher in group I (P < 0.05). Compared to group X, cell apoptosis rate, [Ca(2+)]i and IP3R mRNA expression increased in groups I and I+X (P < 0.05). Compared to group I, cell apoptosis rate, [Ca(2+)]i and IP3R 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 IP3R on the ER membrane and triggers cell apoptosis.
authors.affiliation: Department of Anesthesiology, Affiliated Hospital of Jining Medical University, Jining, China.
authors.forename: W-H
authors.initials: WH
authors.lastname: Zhai
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: S-P
authors.initials: SP
authors.lastname: Huo
authors.affiliation: Department of Anesthesiology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: X-G
authors.initials: XG
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Affiliated Hospital of Jining Medical University, Jining, China.
authors.forename: Y-D
authors.initials: YD
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Affiliated Hospital of Jining Medical University, Jining, China.
authors.forename: Z-L
authors.initials: ZL
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China.
authors.forename: L-L
authors.initials: LL
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Yuhuanding Hospital, Yantai, China.
authors.forename: S
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Anesthesiology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China qiujunwang@126.com.
authors.forename: Q-J
authors.initials: QJ
authors.lastname: Wang
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D020287:In Situ Nick-End Labeling; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017136:Ion Transport; D007530:Isoflurane / Q000633:toxicity*; D047028:Macrocyclic Compounds / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D016716:PC12 Cells; D012333:RNA, Messenger / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D018685:Anesthetics, Inhalation; D017304:Annexin A5; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D012333:RNA, Messenger; C511704:xestospongin C; D020932:Nerve Growth Factor; D007530:Isoflurane; D002118:Calcium