Vagal stimulation triggers peripheral vascular protection through the cholinergic anti-inflammatory pathway in a rat model of myocardial ischemia/reperfusion

Myocardial ischemia/reperfusion (I/R) induces inflammatory response that may lead to remote vascular injury. Vagal nerve elicits the cholinergic anti-inflammatory pathway by activating alpha 7 nicotinic acetylcholine receptors (alpha 7nAChR). Nevertheless, the role of vagal nerve-mediated anti-inflammatory pathway in the vasculature has not been studied previously. Therefore, we aimed to clarify the potential role of vagal stimulation (VNS) in regulating remote vascular injury after myocardial I/R. Adult male Sprague-Dawley rats were subjected to VNS starting 15 min prior to ischemia until the end of reperfusion. VNS not only reduced infarct size and improved cardiac function, but also ameliorated myocardial I/R-induced dysfunctional vasoconstriction and vasodilatation and degradation of endothelial structure in mesenteric arteries. VNS decreased serum and vascular levels of tumor necrosis factor-alpha and IL-1 beta. Interestingly, in vivo microdialysis studies demonstrated that VNS increased ACh concentration in the mesenteric circulation. Furthermore, VNS up-regulated expressions of muscarinic ACh receptors-3 (M(3)AChR) and alpha 7nAChR in mesenteric arteries. Preserved endothelial relaxations by VNS were inhibited by atropine or methyllycaconitine, indicating that functional protection was associated with M-3 and alpha 7nAChR activation. Finally, VNS increased STAT3 phosphorylation and inhibited NF-kappa B activation in mesenteric arteries, and these effects were abolished by alpha 7nAChR shRNA treatment, indicating VNS-mediated anti-inflammatory effect mainly involved alpha 7nAChR. These results demonstrated for the first time that VNS protected against remote vascular dysfunction, through the cholinergic anti-inflammatory pathway which is dependent on alpha 7nAChR. Our findings represent a significant addition to the understanding of vagal nerve-mediated pathways and the potential roles they play in regulating the vasculature.