{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T09:13:51Z","timestamp":1788081231708,"version":"build-2784847793"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,1,5]],"date-time":"2018-01-05T00:00:00Z","timestamp":1515110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R181\u20102014\u20104030"],"award-info":[{"award-number":["R181\u20102014\u20104030"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002808","name":"Carlsbergfondet","doi-asserted-by":"publisher","award":["CF16\u20100136"],"award-info":[{"award-number":["CF16\u20100136"]}],"id":[{"id":"10.13039\/501100002808","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>K<jats:sub>v<\/jats:sub>7.4 and K<jats:sub>v<\/jats:sub>7.5 channels are regulators of vascular tone. 4\u2010Aminopyridine (4\u2010AP) is considered a broad inhibitor of voltage\u2010gated potassium (K<jats:sub>V<\/jats:sub>) channels, with little inhibitory effect on K<jats:sub>v<\/jats:sub>7 family members at mmol concentrations. However, the effect of 4\u2010AP on K<jats:sub>v<\/jats:sub>7 channels has not been systematically studied. The aim of this study was to investigate the pharmacological activity of 4\u2010AP on K<jats:sub>v<\/jats:sub>7.4 and K<jats:sub>v<\/jats:sub>7.5 channels and characterize the effect of 4\u2010AP on rat resistance arteries.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Voltage clamp experiments were performed on<jats:styled-content style=\"fixed-case\"><jats:italic>Xenopus laevis<\/jats:italic><\/jats:styled-content>oocytes injected with cRNA encoding KCNQ4 or KCNQ5, HEK cells expressing K<jats:sub>v<\/jats:sub>7.4 channels and on rat, freshly isolated mesenteric artery smooth muscle cells. The effect of 4\u2010AP on tension, membrane potential, intracellular calcium and pH was assessed in rat mesenteric artery segments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>4\u2010AP increased the K<jats:sub>v<\/jats:sub>7.4\u2010mediated current in oocytes and HEK cells but did not affect K<jats:sub>v<\/jats:sub>7.5 current. 4\u2010AP also enhanced native mesenteric artery myocyte K<jats:sup>+<\/jats:sup>current at sub\u2010mmol concentrations. When applied to NA\u2010preconstricted mesenteric artery segments, 4\u2010AP hyperpolarized the membrane, decreased [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>and caused concentration\u2010dependent relaxations that were independent of 4\u2010AP\u2010mediated changes in intracellular pH. Application of the K<jats:sub>v<\/jats:sub>7 channel blocker XE991 and BK<jats:sub>Ca<\/jats:sub>channel blocker iberiotoxin attenuated 4\u2010AP\u2010mediated relaxation. 4\u2010AP also inhibited the NA\u2010mediated signal transduction to elicit a relaxation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These data show that 4\u2010AP is able to relax NA\u2010preconstricted rat mesenteric arteries by enhancing the activity of K<jats:sub>v<\/jats:sub>7.4 and BK<jats:sub>Ca<\/jats:sub>channels and attenuating NA\u2010mediated signalling.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14097","type":"journal-article","created":{"date-parts":[[2017,11,20]],"date-time":"2017-11-20T18:02:42Z","timestamp":1511200962000},"page":"501-516","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["4\u2010Aminopyridine: a pan voltage\u2010gated potassium channel inhibitor that enhances K<sub>v<\/sub>7.4 currents and inhibits noradrenaline\u2010mediated contraction of rat mesenteric small arteries"],"prefix":"10.1111","volume":"175","author":[{"given":"Makhala M","family":"Khammy","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark"},{"name":"Department of Biomedicine Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukhan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedicine Aarhus University Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0253-4992","authenticated-orcid":false,"given":"Bo H","family":"Bentzen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen 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