Activation of M3 cholinoceptors attenuates vascular injury after ischaemia/reperfusion by inhibiting the Ca2+/calmodulin-dependent protein kinase II pathway.

Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE

Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.

Calcium-Calmodulin-Dependent Protein Kinase Type 2/*antagonists & inhibitors ; Cholinergic Agonists/*pharmacology ; Ischemia/*complications ; Receptor, Muscarinic M3/*metabolism ; Reperfusion Injury/*complications ; Vascular System Injuries/*drug therapy; Administration, Intravenous ; Animals ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Choline/administration & dosage ; Choline/pharmacology ; Choline/therapeutic use ; Cholinergic Agonists/administration & dosage ; Cholinergic Agonists/therapeutic use ; Dose-Response Relationship, Drug ; Male ; Piperidines/administration & dosage ; Piperidines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Structure-Activity Relationship ; Vascular System Injuries/chemically induced ; Vascular System Injuries/metabolism

Background and Purpose: 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.
Experimental Approach: 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.
Key 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 and Implications: 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.
(© 2015 The British Pharmacological Society.)

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0 (Cholinergic Agonists)
0 (Piperidines)
0 (Receptor, Muscarinic M3)
81405-11-0 (4-diphenylacetoxy-1,1-dimethylpiperidinium)
EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
N91BDP6H0X (Choline)

Date Created: 20150509 Date Completed: 20160919 Latest Revision: 20181113

20250114

PMC4667848

10.1111/bph.13183

25953628