{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T21:49:44Z","timestamp":1772747384904,"version":"3.50.1"},"reference-count":60,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T00:00:00Z","timestamp":1717632000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization (), possibly associated with disease\u2010related changes in sympathetic (\u03b1\u2010adrenergic) signaling. Thus, in seven patients with HFpEF (70\u00a0\u00b1\u00a06\u00a0years, 3 female\/4 male) and seven controls (CON) (66\u00a0\u00b1\u00a03\u00a0years, 3 female\/4 male), we examined changes (%\u0394) in leg blood flow (LBF, Doppler ultrasound) and leg  to intra\u2010arterial infusion of phentolamine (PHEN, \u03b1\u2010adrenergic antagonist) or phenylephrine (PE, \u03b1<jats:sub>1<\/jats:sub>\u2010adrenergic agonist) at rest and during single\u2010leg knee\u2010extension exercise (0, 5 and 10\u00a0W). At rest, the PHEN\u2010induced increase in LBF was not different between groups, but PE\u2010induced reductions in LBF were lower in HFpEF (\u221216%\u00a0\u00b1\u00a04% <jats:italic>vs<\/jats:italic>. \u221226%\u00a0\u00b1\u00a05%, HFpEF <jats:italic>vs<\/jats:italic>. CON; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). During exercise, the PHEN\u2010induced increase in LBF was greater in HFpEF at 10\u00a0W (16%\u00a0\u00b1\u00a08% <jats:italic>vs<\/jats:italic>. 8%\u00a0\u00b1\u00a05%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). PHEN increased leg  in HFpEF (10%\u00a0\u00b1\u00a03%, 11%\u00a0\u00b1\u00a06%, 15%\u00a0\u00b1\u00a07% at 0, 5 and 10\u00a0W; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) but not in controls (\u22121%\u00a0\u00b1\u00a09%, \u22124%\u00a0\u00b1\u00a02%, \u22121%\u00a0\u00b1\u00a05%; <jats:italic>P\u00a0=\u00a0<\/jats:italic>0.24). The \u2018magnitude of sympatholysis\u2019 (PE\u2010induced %\u0394 LBF at rest\u00a0\u2013\u00a0PE\u2010induced %\u0394 LBF during exercise) was lower in patients with HFpEF (\u22126%\u00a0\u00b1\u00a04%, \u22126%\u00a0\u00b1\u00a06%, \u22127%\u00a0\u00b1\u00a05% <jats:italic>vs<\/jats:italic>. \u221213%\u00a0\u00b1\u00a06%, \u221217%\u00a0\u00b1\u00a05%, \u221220%\u00a0\u00b1\u00a05% at 0, 5 and 10\u00a0W; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and was positively related to LBF, leg oxygen delivery, leg , and the PHEN\u2010induced increase in LBF (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Together, these data indicate that excessive \u03b1\u2010adrenergic vasoconstriction restrains blood flow and limits  of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group.\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\/tjp16134-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>Sympathetic (\u03b1\u2010adrenergic)\u2010mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The ability to adequately attenuate \u03b1<jats:sub>1<\/jats:sub>\u2010adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These observations extend our current understanding of HFpEF pathophysiology by implicating excessive \u03b1\u2010adrenergic restraint and impaired functional sympatholysis as important contributors to disease\u2010related impairments in exercising muscle blood flow and oxygen utilization in these patients.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp285526","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T18:40:23Z","timestamp":1717699223000},"page":"3401-3422","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["\u03b1\u2010Adrenergic regulation of skeletal muscle blood flow during exercise in patients with heart failure with preserved ejection fraction"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9769-4966","authenticated-orcid":false,"given":"Jeremy K.","family":"Alpenglow","sequence":"first","affiliation":[{"name":"Department of Nutrition and Integrative Physiology University of Utah  Salt Lake City UT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanokwan","family":"Bunsawat","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Geriatrics University of Utah  Salt Lake City UT USA"},{"name":"Geriatric Research, Education, and Clinical Center VAMC  Salt Lake City UT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael A.","family":"Francisco","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center VAMC  Salt Lake City UT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7388-2214","authenticated-orcid":false,"given":"Ryan M.","family":"Broxterman","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology University of Utah  Salt Lake City UT USA"},{"name":"Department of Internal Medicine, Division of Geriatrics University of Utah  Salt Lake City UT USA"},{"name":"Geriatric Research, Education, and Clinical Center VAMC  Salt Lake City UT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5959-4139","authenticated-orcid":false,"given":"Jesse C.","family":"Craig","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Geriatrics University of Utah  Salt Lake City UT USA"},{"name":"Geriatric Research, Education, and Clinical Center VAMC  Salt Lake City UT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jarred J.","family":"Iacovelli","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology University of Utah  Salt Lake City UT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2032-8498","authenticated-orcid":false,"given":"Joshua C.","family":"Weavil","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center VAMC  Salt Lake City UT 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