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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.)