title: Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway.
abstract: On-site mortality in crush syndrome remains high due to lack of effective drugs based on definite diagnosis. Anisodamine (Ani) is widely used in China for treatment of shock, and activation of α7 nicotinic acetylcholine receptor (α7nAChR) mediates such antishock effect. The present work was designed to test whether activation of α7nAChR with Ani decreased mortality in crush syndrome shortly after decompression. Sprague-Dawley rats and C57BL/6 mice with crush syndrome were injected with Ani (20 mg/kg and 28 mg/kg respectively, i.p.) 30 min before decompression. Survival time, serum potassium, insulin, and glucose levels were observed shortly after decompression. Involvement of α7nAChR was verified with methyllycaconitine (selective α7nAChR antagonist) and PNU282987 (selective α7nAChR agonist), or in α7nAChR knockout mice. Effect of Ani was also appraised in C2C12 myotubes. Ani reduced mortality and serum potassium and enhanced insulin sensitivity shortly after decompression in animals with crush syndrome, and PNU282987 exerted similar effects. Such effects were counteracted by methyllycaconitine or in α7nAChR knockout mice. Mortality and serum potassium in rats with hyperkalemia were also reduced by Ani. Phosphorylation of Na/K-ATPase was enhanced by Ani in C2C12 myotubes. Inhibition of tyrosine kinase on insulin receptor, phosphoinositide 3-kinase, mammalian target of rapamycin, signal transducer and activator of transcription 3, and Na/K-ATPase counteracted the effect of Ani on extracellular potassium. These findings demonstrated that activation of α7nAChR could decrease on-site mortality in crush syndrome, at least in part based on the decline of serum potassium through insulin signaling-Na/K-ATPase pathway.
authors.affiliation: Department of Pharmacology, Second Military Medical University Shanghai, China.
authors.forename: Bo-Shi
authors.initials: BS
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, Second Military Medical UniversityShanghai, China; The 406th Hospital of Chinese People's Liberation ArmyDalian, China.
authors.forename: En-Hui
authors.initials: EH
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Second Military Medical University Shanghai, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Wu
authors.affiliation: Jinan Military General Hospital Jinan, China.
authors.forename: Jin-Min
authors.initials: JM
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Second Military Medical University Shanghai, China.
authors.forename: Ding-Feng
authors.initials: DF
authors.lastname: Su
authors.affiliation: Department of Pharmacology, Second Military Medical University Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Second Military Medical University Shanghai, China.
authors.forename: Jian-Guang
authors.initials: JG
authors.lastname: Yu
keywords: Na/K-ATPase; crush syndrome; hyperkalemia; insulin sensitivity; mortality; α7 nicotinic acetylcholine receptor