{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T17:56:23Z","timestamp":1770832583482,"version":"3.50.1"},"reference-count":55,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,12,26]],"date-time":"2018-12-26T00:00:00Z","timestamp":1545782400000},"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":["R01HL119337"],"award-info":[{"award-number":["R01HL119337"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL119337"],"award-info":[{"award-number":["R01HL119337"]}],"id":[{"id":"10.13039\/100000050","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":[[2019,3]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>In humans, the vasodilatory response to skeletal muscle contraction is mediated in part by activation of inwardly rectifying potassium (K<jats:sub>IR<\/jats:sub>) channels. Evidence from animal models suggest that K<jats:sub>IR<\/jats:sub> channels serve as electrical amplifiers of endothelium\u2010dependent hyperpolarization (EDH).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We found that skeletal muscle contraction amplifies vasodilatation to the endothelium\u2010dependent agonist ACh, whereas there was no change in the vasodilatory response to sodium nitroprusside, an endothelium\u2010independent nitric oxide donor.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Blockade of K<jats:sub>IR<\/jats:sub> channels reduced the exercise\u2010induced amplification of ACh\u2010mediated vasodilatation. Conversely, pharmacological activation of K<jats:sub>IR<\/jats:sub> channels in quiescent muscle via intra\u2010arterial infusion of KCl independently amplified the vasodilatory response to ACh.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This study is the first in humans to demonstrate that specific endothelium\u2010dependent vasodilatory signalling is amplified in the vasculature of contracting skeletal muscle and that K<jats:sub>IR<\/jats:sub> channels may serve as amplifiers of EDH\u2010like vasodilatory signalling in humans.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The local vasodilatory response to muscle contraction is due in part to the activation of inwardly rectifying potassium (K<jats:sub>IR<\/jats:sub>) channels. Evidence from animal models suggest that K<jats:sub>IR<\/jats:sub> channels function as \u2018amplifiers\u2019 of endothelium\u2010dependent vasodilators. We tested the hypothesis that contracting muscle selectively amplifies endothelium\u2010dependent vasodilatation via activation of K<jats:sub>IR<\/jats:sub> channels. We measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra\u2010arterial infusion of ACh (endothelium\u2010dependent dilator) during resting conditions, handgrip exercise (5% maximum voluntary contraction) or sodium nitroprusside (SNP; endothelium\u2010independent dilator) which served as a high\u2010flow control condition (<jats:italic>n<\/jats:italic>\u00a0= 7, young healthy men and women). Trials were performed before and after blockade of K<jats:sub>IR<\/jats:sub> channels via infusion of barium chloride. Exercise augmented peak ACh\u2010mediated vasodilatation (\u0394FVC saline: 117\u00a0\u00b1 14; exercise: 236\u00a0\u00b1 21\u00a0ml\u00a0min<jats:sup>\u22121<\/jats:sup> (100\u00a0mmHg)<jats:sup>\u22121<\/jats:sup>; <jats:italic>P<\/jats:italic>\u00a0&lt; 0.05), whereas SNP did not impact ACh\u2010mediated vasodilatation. Blockade of K<jats:sub>IR<\/jats:sub> channels attenuated the exercise\u2010induced augmentation of ACh. In eight additional subjects, SNP was administered as the experimental dilator. In contrast to ACh, exercise did not alter SNP\u2010mediated vasodilatation (\u0394FVC saline: 158\u00a0\u00b1 35; exercise: 121\u00a0\u00b1 22\u00a0ml\u00a0min<jats:sup>\u22121<\/jats:sup> (100\u00a0mmHg)<jats:sup>\u22121<\/jats:sup>; n.s.). Finally, in a subset of six subjects, direct pharmacological activation of K<jats:sub>IR<\/jats:sub> channels in quiescent muscle via infusion of KCl amplified peak ACh\u2010mediated vasodilatation (\u0394FVC saline: 97\u00a0\u00b1 15, KCl: 142\u00a0\u00b1 16\u00a0ml\u00a0min<jats:sup>\u22121<\/jats:sup>\u00a0(100\u00a0mmHg)<jats:sup>\u22121<\/jats:sup>; respectively; <jats:italic>P<\/jats:italic>\u00a0&lt; 0.05). These findings indicate that skeletal muscle contractions selectively amplify endothelium\u2010dependent vasodilatory signalling via activation of K<jats:sub>IR<\/jats:sub> channels, and this may be an important mechanism contributing to the normal vasodilatory response to exercise in humans.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp276998","type":"journal-article","created":{"date-parts":[[2018,12,1]],"date-time":"2018-12-01T12:49:06Z","timestamp":1543668546000},"page":"1321-1335","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Amplification of endothelium\u2010dependent vasodilatation in contracting human skeletal muscle: role of K<sub>IR<\/sub> channels"],"prefix":"10.1113","volume":"597","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6561-3532","authenticated-orcid":false,"suffix":"Jr","given":"Christopher M.","family":"Hearon","sequence":"first","affiliation":[{"name":"Human Cardiovascular Physiology Laboratory Department of Health and Exercise Science Colorado State University  Fort Collins CO 80523 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer C.","family":"Richards","sequence":"additional","affiliation":[{"name":"Human Cardiovascular Physiology Laboratory Department of Health and Exercise Science Colorado State University  Fort Collins CO 80523 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8377-3556","authenticated-orcid":false,"given":"Mathew L.","family":"Racine","sequence":"additional","affiliation":[{"name":"Human Cardiovascular Physiology Laboratory Department of Health and Exercise Science Colorado State University  Fort Collins CO 80523 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary J.","family":"Luckasen","sequence":"additional","affiliation":[{"name":"Medical Center of the Rockies Foundation University of Colorado Health  Loveland CO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis G.","family":"Larson","sequence":"additional","affiliation":[{"name":"Medical Center of the Rockies Foundation University of Colorado Health  Loveland CO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4644-3213","authenticated-orcid":false,"given":"Frank A.","family":"Dinenno","sequence":"additional","affiliation":[{"name":"Human Cardiovascular Physiology Laboratory Department of Health and Exercise Science Colorado State University  Fort Collins CO 80523 USA"},{"name":"Center for Cardiovascular Research Colorado State University  Fort Collins CO 80523 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