title: Activation of M3 cholinoceptors attenuates vascular injury after ischaemia/reperfusion by inhibiting the Ca2+/calmodulin-dependent protein kinase II pathway.
abstract: OBJECTIVE
  The activation of M3 cholinoceptors (M3 receptors) by choline reduces cardiovascular risk, but it is unclear whether these receptors can regulate ischaemia/reperfusion (I/R)-induced vascular injury. Thus, the primary goal of the present study was to explore the effects of choline on the function of mesenteric arteries following I/R, with a major focus on Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulation.
  
  
  METHODS
  Rats were given choline (10 mg · kg(-1), i.v.) and then the superior mesenteric artery was occluded for 60 min (ischaemia), followed by 90 min of reperfusion. The M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), was injected (0.12 μg · kg(-1), i.v.) 5 min prior to choline treatment. Vascular function was examined in rings of mesenteric arteries isolated after the reperfusion procedure. Vascular superoxide anion production, CaMKII and the levels of Ca(2+)-cycling proteins were also assessed.
  
  
  RESULTS
  Choline treatment attenuated I/R-induced vascular dysfunction, blocked elevations in the levels of reactive oxygen species (ROS) and decreased the up-regulated expression of oxidised CaMKII and phosphorylated CaMKII. In addition, choline reversed the abnormal expression of Ca(2+)-cycling proteins, including Na(+)Ca(2+) exchanger, inositol 1,4,5-trisphosphate receptor, sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban. All of these cholinergic effects of choline were abolished by 4-DAMP.
  
  
  CONCLUSIONS
  Our data suggest that inhibition of the ROS-mediated CaMKII pathway and modulation of Ca(2+)-cycling proteins may be novel mechanisms underlying choline-induced vascular protection. These results represent a significant addition to the understanding of the pharmacological roles of M3 receptors in the vasculature, providing a new therapeutic strategy for I/R-induced vascular injury.
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Xing-Zhu
authors.initials: XZ
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Bi
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Man
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Zheng-Hang
authors.initials: ZH
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Wei-Jin
authors.initials: WJ
authors.lastname: Zang
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002794:Choline / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018679:Cholinergic Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D007511:Ischemia / Q000150:complications*; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D057772:Vascular System Injuries / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D018679:Cholinergic Agonists; D010880:Piperidines; D043587:Receptor, Muscarinic M3; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002794:Choline