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Substance P hyperpolarized smooth muscle and endothelium ~ \u221215\u00a0mV; smooth muscle hyperpolarization was abolished by endothelial disruption or NO synthase inhibition. Blocking K<jats:sub>Ca<\/jats:sub> channels (apamin\u00a0+\u00a0charybdotoxin) attenuated hyperpolarization in both cell types. CGRP hyperpolarized endothelium and smooth muscle ~ \u221230\u00a0mV; smooth muscle hyperpolarization was independent of endothelium. Blocking K<jats:sub>Ca<\/jats:sub> channels prevented hyperpolarization to CGRP in endothelium but not smooth muscle. Inhibiting K<jats:sub>ATP<\/jats:sub> channels with glibenclamide or genetic deletion of K<jats:sub>IR<\/jats:sub>6.1 attenuated hyperpolarization in smooth muscle but not endothelium. Pinacidil (K<jats:sub>ATP<\/jats:sub> channel agonist) hyperpolarized smooth muscle more than endothelium (~ \u221235 vs. ~ \u221220\u00a0mV).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Calcitonin gene\u2010related peptide elicits greater hyperpolarization than substance P. Substance P hyperpolarizes both cell layers through K<jats:sub>Ca<\/jats:sub> channels and involves endothelium\u2010derived NO in smooth muscle. Endothelial hyperpolarization to CGRP requires K<jats:sub>Ca<\/jats:sub> channels, while K<jats:sub>ATP<\/jats:sub> channels mediate hyperpolarization in smooth muscle. Differential K<jats:sup>+<\/jats:sup> channel activation in smooth muscle and endothelium through sensory neurotransmission may selectively tune mesenteric blood flow.<\/jats:p><\/jats:sec>","DOI":"10.1111\/micc.12733","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T13:00:22Z","timestamp":1633957222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Differential hyperpolarization to substance P and calcitonin gene\u2010related peptide in smooth muscle versus endothelium of mouse mesenteric artery"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9442-4039","authenticated-orcid":false,"given":"Charles E.","family":"Norton","sequence":"first","affiliation":[{"name":"Department of Medical Pharmacology and Physiology University of Missouri Columbia Missouri 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