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This study investigates expression and effect of stimulating the CaSR by increasing external Ca<jats:sup>2+<\/jats:sup> concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>o<\/jats:sub>) on contractility of rat mesenteric arteries. Immunofluorescence studies showed expression of the CaSR in perivascular nerves, vascular smooth muscle cells (VSMCs), and vascular endothelium cells. Using wire myography, increasing [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>o<\/jats:sub> from 1 to 10\u2009mM induced vasorelaxations which were inhibited by the calcilytic Calhex\u2010231 and partially dependent on a functional endothelium. [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>o<\/jats:sub>\u2010induced vasorelaxations were reduced by endothelial NO synthase (eNOS, L\u2010NAME) and large conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup> channels (BK<jats:sub>Ca<\/jats:sub>, iberiotoxin), with their inhibitory action requiring a functional endothelium. [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>o<\/jats:sub>\u2010induced vasorelaxations were also markedly inhibited by an ATP\u2010dependent K<jats:sup>+<\/jats:sup> channel (K<jats:sub>ATP<\/jats:sub>) blocker (PNU37883), which did not require a functional endothelium to produce its inhibitory action. Inhibitor studies also suggested contributory roles for inward rectifying K<jats:sup>+<\/jats:sup> channels (K<jats:sub>ir<\/jats:sub>), Kv7 channels, and small conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup> channels (SK<jats:sub>Ca<\/jats:sub>) on [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>o<\/jats:sub>\u2010induced vasorelaxations. These findings indicate that stimulation of the CaSR mediates vasorelaxations involving multiple pathways, including an endothelium\u2010dependent pathway involving NO production and activation of BK<jats:sub>Ca<\/jats:sub> channels and an endothelium\u2010independent pathway involving stimulation of K<jats:sub>ATP<\/jats:sub> channels.<\/jats:p>","DOI":"10.14814\/phy2.15926","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:49:25Z","timestamp":1706489365000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Stimulation of the calcium\u2010sensing receptor induces relaxations of rat mesenteric arteries by endothelium\u2010dependent and \u2010independent pathways via <scp>BK<sub>Ca<\/sub><\/scp> and <scp>K<sub>ATP<\/sub><\/scp> channels"],"prefix":"10.14814","volume":"12","author":[{"given":"Simonette R. 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