{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:48:57Z","timestamp":1793040537457,"version":"4.5.0"},"reference-count":27,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T00:00:00Z","timestamp":1761350400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["23DIVSUP1069441"],"award-info":[{"award-number":["23DIVSUP1069441"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["T32AG020494"],"award-info":[{"award-number":["T32AG020494"]}],"id":[{"id":"10.13039\/100000049","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":[[2025,11]]},"abstract":"\n Abstract<\/jats:title>\n \n Voltage\u2010dependent potassium (K\n V<\/jats:sub>\n ) channels play a pivotal role in regulating vascular tone via negative feedback control of membrane potential. Despite substantial evidence in animal models, many aspects of their regulation are not fully understood in humans, particularly within the skeletal muscle microcirculation. Therefore, we tested the hypothesis that K\n V<\/jats:sub>\n channel antagonism would attenuate pharmacologically induced vasodilatation in skeletal muscle of humans. We utilised microdialysis to directly measure the local hyperaemic response to methacholine (55\u00a0m\n m<\/jats:sc>\n ; endothelium\u2010dependent) and sodium nitroprusside (42\u00a0m\n m<\/jats:sc>\n ; endothelium\u2010independent) in the vastus lateralis muscle of 17\u00a0healthy adults (seven women). At separate sites, the K\n V<\/jats:sub>\n channel antagonist, 4\u2010aminopyridine (26.6\u00a0m\n m<\/jats:sc>\n ), was co\u2010perfused with each vasodilator agent. Local skeletal muscle blood flow was assessed using the ethanol washout technique. Baseline blood flow did not differ between probes perfused with 0.9% saline and those perfused with 4\u2010aminopyridine (\n P\u00a0=\u00a0<\/jats:italic>\n 0.375). However, the hyperaemic response to methacholine (\u0394 28\u00a0\u00b1\u00a012\u00a0mL\u00a0min\n \u22121<\/jats:sup>\n 100\u00a0g\n \u22121<\/jats:sup>\n ) was abolished when co\u2010perfused with 4\u2010aminopyridine (\u0394 3\u00a0\u00b1\u00a09\u00a0mL\u00a0min\n \u22121<\/jats:sup>\n \u00a0100\u00a0g\n \u22121<\/jats:sup>\n ,\n P\u00a0<\u00a0<\/jats:italic>\n 0.001). Likewise, the hyperaemic response to sodium nitroprusside (\u0394 59\u00a0\u00b1\u00a027\u00a0mL\u00a0min\n \u22121<\/jats:sup>\n \u00a0100\u00a0g\n \u22121<\/jats:sup>\n ) was reduced when co\u2010perfused with 4\u2010aminopyridine (\u0394 14\u00a0\u00b1\u00a010\u00a0mL\u00a0min\n \u22121<\/jats:sup>\n \u00a0100\u00a0g\n \u22121<\/jats:sup>\n ,\n P<\/jats:italic>\n \u00a0<\u00a00.001). These data suggest that K\n V<\/jats:sub>\n channels play a major role in pharmacologically induced vasodilatation in skeletal muscle of humans and serve as major downstream effectors in the nitric oxide\u2010cyclic guanosine monophosphate\u2010protein kinase G (i.e. NO\/cGMP\/PKG) signalling pathway.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Voltage\u2010dependent potassium (K\n V<\/jats:sub>\n ) channels play a pivotal role in regulating vascular tone via negative feedback control of membrane potential. Despite substantial evidence in animal models, many aspects of their regulation are not fully understood in humans, particularly within the skeletal muscle microcirculation.\n <\/jats:p>\n <\/jats:list-item>\n \n \n We tested the hypothesis that K\n V<\/jats:sub>\n channel antagonism would attenuate the vasodilatation induced by methacholine and sodium nitroprusside in the vastus lateralis muscle of young healthy humans.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Utilising microdialysis, we found that K\n V<\/jats:sub>\n channel antagonism, via perfusion of 4\u2010aminopyridine, blunted the hyperaemic response to methacholine and sodium nitroprusside in the vastus lateralis muscle.\n <\/jats:p>\n <\/jats:list-item>\n \n \n We identified a critical role for K\n V<\/jats:sub>\n channels in the vasodilatation induced by methacholine and sodium nitroprusside in skeletal muscle of humans. Because both pharmacological agents induce vasodilatation via nitric oxide\u2010cyclic guanosine monophosphate\u2010protein kinase G (i.e. NO\/cGMP\/PKG) signalling, these findings suggest that K\n V<\/jats:sub>\n channels are major downstream effectors of this pathway.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp289720","type":"journal-article","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T11:49:51Z","timestamp":1761392991000},"page":"6801-6810","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["K\n V<\/sub>\n channel antagonism blunts vasodilatation in skeletal muscle of humans"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4701-9943","authenticated-orcid":false,"given":"Ysabella I.","family":"Ruiz\u2010Pick","sequence":"first","affiliation":[{"name":"Human Vascular Physiology Laboratory, Department of Physiology and Anatomy UNT Health Fort Worth Fort Worth TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7090-1782","authenticated-orcid":false,"given":"Rauchelle E.","family":"Richey","sequence":"additional","affiliation":[{"name":"Human Vascular Physiology Laboratory, Department of Physiology and Anatomy UNT Health Fort Worth Fort Worth TX USA"},{"name":"Department of Human Physiology University of Oregon Eugene OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyson C.","family":"Garfield","sequence":"additional","affiliation":[{"name":"Division of Geriatric Medicine University of Colorado Anschutz Medical Campus Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asim","family":"Kichloo","sequence":"additional","affiliation":[{"name":"Department of Medicine UNT Health Fort Worth Fort Worth TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert H.","family":"Olivencia\u2010Yurvati","sequence":"additional","affiliation":[{"name":"Human Vascular Physiology Laboratory, Department of Physiology and Anatomy UNT Health Fort Worth Fort Worth TX USA"},{"name":"Department of Surgery UNT Health Fort Worth Fort Worth TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1444-6436","authenticated-orcid":false,"given":"Gregory M.","family":"Dick","sequence":"additional","affiliation":[{"name":"Human Vascular Physiology Laboratory, Department of Physiology and Anatomy UNT Health Fort Worth Fort Worth TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2014-7806","authenticated-orcid":false,"given":"Steven A.","family":"Romero","sequence":"additional","affiliation":[{"name":"Human Vascular Physiology Laboratory, Department of Physiology and Anatomy UNT Health Fort Worth Fort Worth TX 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