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Here we have studied the direct actions of nutrients on mesenteric arterial tone and the underlying molecular mechanisms in healthy and colitis mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Colitis in C57BL\/6 mice was induced with dextran sodium sulphate. Nutrient\u2010induced vasorelaxation of mesenteric arterioles from humans and mice was studied with wire myograph assays. Ca<jats:sup>2+<\/jats:sup> and Na<jats:sup>+<\/jats:sup> imaging were performed in human vascular endothelial cells and vascular smooth muscle cells, using selective pharmacological agents and shRNA knockdown of TRPV1 channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Glucose, sodium and mannitol concentration\u2010dependently induced endothelium\u2010dependent relaxation of human and mouse mesenteric arterioles via hyperosmotic action,. Hyperosmosis\u2010induced vasorelaxation was almost abolished by selective blockers for TRPV1, IK<jats:sub>Ca<\/jats:sub> and SK<jats:sub>Ca<\/jats:sub> channels. Glucose markedly stimulated Ca<jats:sup>2+<\/jats:sup> influx through endothelial TRPV1 channels, an effect attenuated by selective blockers and shRNA knockdown of TRPV1 channels. Capsaicin synergised the glucose\u2010induced vasorelaxation. Nutrient\u2010induced hyperosmosis also activated Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPase and the Na\/Ca exchanger (NCX) to decrease [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> in VSMCs. Glucose\u2010induced vasorelaxation was impaired in mouse colitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Nutrient\u2010induced hyperosmosis evoked endothelium\u2010dependent mesenteric vasorelaxation via the TRPV1\/Ca<jats:sup>2+<\/jats:sup>\/ endothelium\u2010dependent hyperpolarisation pathway to increase normal mucosal perfusion, which is impaired in our model of colitis. The TRPV1\/Ca<jats:sup>2+<\/jats:sup>\/ endothelium\u2010dependent hyperpolarisation pathway could provide novel drug targets for gastrointestinal diseases with hypoperfusion, such as chronic colitis and mesenteric ischaemia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15322","type":"journal-article","created":{"date-parts":[[2020,11,10]],"date-time":"2020-11-10T04:11:21Z","timestamp":1604981481000},"page":"689-708","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Nutrient\u2010induced hyperosmosis evokes vasorelaxation via TRPV1 channel\u2010mediated, endothelium\u2010dependent, hyperpolarisation in healthy and colitis mice"],"prefix":"10.1111","volume":"178","author":[{"given":"Yanjun","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Xinqiao Hospital, Army Medical University  Chongqing 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