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K<jats:sub>ATP<\/jats:sub> channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional K<jats:sub>ATP<\/jats:sub> channels as verified by electrophysiological techniques.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Global deletion of Kir6.1 or SUR2 subunits results in severely impaired lymphatic contractile responses to pinacidil.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Smooth muscle\u2010specific expression of Kir6.1 gain\u2010of\u2010function mutant (GoF) subunits results in profound lymphatic contractile dysfunction and LSM hyperpolarization that is partially rescued by the K<jats:sub>ATP<\/jats:sub> inhibitor glibenclamide. In contrast, lymphatic endothelial\u2010specific expression of Kir6.1 GoF has essentially no effect on lymphatic contractile function.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The high sensitivity of LSM to K<jats:sub>ATP<\/jats:sub> channel GoF offers an explanation for the lymphoedema observed in patients with Cant\u00fa syndrome, a disorder caused by gain\u2010of\u2010function mutations in genes encoding Kir6.1 or SUR2, and suggests that glibenclamide may be an appropriate therapeutic agent.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>This study aimed to understand the functional expression of K<jats:sub>ATP<\/jats:sub> channel subunits in distinct lymphatic cell types, and assess the consequences of altered K<jats:sub>ATP<\/jats:sub> channel activity on lymphatic pump function. K<jats:sub>ATP<\/jats:sub> channel subunits Kir6.1 and SUR2B were expressed in mouse lymphatic muscle by PCR, but only Kir6.1 was expressed in lymphatic endothelium. Spontaneous contractions of popliteal lymphatics from wild\u2010type (WT) (C57BL\/6J) mice, assessed by pressure myography, were very sensitive to inhibition by the SUR2\u2010specific K<jats:sub>ATP<\/jats:sub> channel activator pinacidil, which hyperpolarized both mouse and human lymphatic smooth muscle (LSM). In vessels from mice with deletion of Kir6.1 (Kir6.1<jats:sup>\u2212\/\u2212<\/jats:sup>) or SUR2 (SUR2[STOP]) subunits, contractile parameters were not significantly different from those of WT vessels, suggesting that basal K<jats:sub>ATP<\/jats:sub> channel activity in LSM is not an essential component of the lymphatic pacemaker, and does not exert a strong influence over contractile strength. However, these vessels were &gt;100\u2010fold less sensitive than WT vessels to pinacidil. Smooth muscle\u2010specific expression of a Kir6.1 gain\u2010of\u2010function (GoF) subunit resulted in severely impaired lymphatic contractions and hyperpolarized LSM. Membrane potential and contractile activity was partially restored by the K<jats:sub>ATP<\/jats:sub> channel inhibitor glibenclamide. In contrast, lymphatic endothelium\u2010specific expression of Kir6.1 GoF subunits had negligible effects on lymphatic contraction frequency or amplitude. Our results demonstrate a high sensitivity of lymphatic contractility to K<jats:sub>ATP<\/jats:sub> channel activators through activation of Kir6.1\/SUR2\u2010dependent channels in LSM. In addition, they offer an explanation for the lymphoedema observed in patients with Cant\u00fa syndrome, a disorder caused by gain\u2010of\u2010function mutations in genes encoding Kir6.1\/SUR2.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp279612","type":"journal-article","created":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T04:26:07Z","timestamp":1588739167000},"page":"3107-3127","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Kir6.1\u2010dependent K<sub>ATP<\/sub> channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain\u2010of\u2010function"],"prefix":"10.1113","volume":"598","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7992-9300","authenticated-orcid":false,"given":"Michael J.","family":"Davis","sequence":"first","affiliation":[{"name":"Department of Medical Pharmacology and Physiology University of Missouri School of Medicine  Columbia MO 65212 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