{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:00:36Z","timestamp":1790838036569,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL142710"],"award-info":[{"award-number":["HL142710"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Smooth muscle voltage\u2010gated K<jats:sup>+<\/jats:sup> (Kv) channels in resistance arteries control vascular tone and contribute to the coupling of blood flow with local metabolic activity. Members of the Kv1 family are expressed in vascular smooth muscle and are modulated upon physiological elevation of local metabolites, including the glycolytic end\u2010product <jats:sc>l<\/jats:sc>\u2010lactate and superoxide\u2010derived hydrogen peroxide (H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>). Here, we show that <jats:sc>l<\/jats:sc>\u2010lactate elicits vasodilatation of small\u2010diameter mesenteric arteries in a mechanism that requires lactate dehydrogenase (LDH). Using the inside\u2010out configuration of the patch clamp technique, we show that increases in NADH that reflect LDH\u2010mediated conversion of <jats:sc>l<\/jats:sc>\u2010lactate to pyruvate directly stimulate the activity of single Kv1 channels and significantly enhance the sensitivity of Kv1 activity to H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>. Consistent with these findings, H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010evoked vasodilatation was significantly greater in the presence of 10\u00a0mM <jats:sc>l<\/jats:sc>\u2010lactate relative to lactate\u2010free conditions, yet was abolished in the presence of 10\u00a0mM pyruvate, which shifts the LDH reaction towards the generation of NAD<jats:sup>+<\/jats:sup>. Moreover, the enhancement of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced vasodilatation was abolished in arteries from double transgenic mice with selective overexpression of the intracellular Kv\u03b21.1\u00a0subunit in smooth muscle cells. Together, our results indicate that the Kv\u03b2 complex of native vascular Kv1 channels serves as a nodal effector for multiple redox signals to precisely control channel activity and vascular tone in the face of dynamic tissue\u2010derived metabolic cues.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15568-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Vasodilatation of mesenteric arteries by elevated external <jats:sc>l<\/jats:sc>\u2010lactate requires its conversion by lactate dehydrogenase.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Application of either NADH or H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> potentiates single Kv channel currents in excised membrane patches from mesenteric artery smooth muscle cells.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The binding of NADH enhances the stimulatory effects of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> on single Kv channel activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The vasodilatory response to H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> is differentially modified upon elevation of external <jats:sc>l<\/jats:sc>\u2010lactate or pyruvate.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The presence of <jats:sc>l<\/jats:sc>\u2010lactate enhances the vasodilatory response to H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> via the Kv\u03b2 subunit complex in smooth muscle.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp284195","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T12:31:51Z","timestamp":1682685111000},"page":"2621-2634","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Basal NAD(H) redox state permits hydrogen peroxide\u2010induced mesenteric artery dilatation"],"prefix":"10.1113","volume":"601","author":[{"given":"Sean M.","family":"Raph","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Louisville  Louisville KY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc M.","family":"Dwenger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Louisville  Louisville KY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Louisville  Louisville KY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8872-158X","authenticated-orcid":false,"given":"Matthew A.","family":"Nystoriak","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Environmental Medicine University of Louisville  Louisville KY 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