{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T03:06:41Z","timestamp":1768014401162,"version":"3.49.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL124338"],"award-info":[{"award-number":["HL124338"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Apelin-APJ receptor signaling regulates vascular tone in cerebral and peripheral arteries. We recently reported that apelin inhibits BK<jats:sub>Ca<\/jats:sub> channel function in cerebral arteries, resulting in impaired endothelium-dependent relaxations. In contrast, apelin causes endothelium-dependent relaxation of coronary arteries. However, the effects of apelin on BK<jats:sub>Ca<\/jats:sub> channel function in coronary arterial myocytes have not yet been explored. We hypothesized that apelin-APJ receptor signaling does not have an inhibitory effect on coronary arterial BK<jats:sub>Ca<\/jats:sub> channels and hence does not alter nitric oxide (NO)-dependent relaxation of coronary arteries. Patch clamp recording was used to measure whole cell K<jats:sup>+<\/jats:sup> currents in freshly isolated coronary smooth muscle cells. Apelin had no effect on the increases in current density in response to membrane depolarization or to NS1619 (a BK<jats:sub>Ca<\/jats:sub> channel opener). Moreover, apelin did not inhibit NO\/cGMP-dependent relaxations that required activation of BK<jats:sub>Ca<\/jats:sub> channels in isolated coronary arteries. Apelin-APJ receptor signaling caused a marked increase in intracellular Ca<jats:sup>2+<\/jats:sup> levels in coronary arterial smooth muscle cells, but failed to activate PI3-kinase to increase phosphorylation of Akt protein. Collectively, these data provide mechanistic evidence that apelin has no inhibitory effects on BK<jats:sub>Ca<\/jats:sub> channel function in coronary arteries. The lack of inhibitory effect on BK<jats:sub>Ca<\/jats:sub> channels makes it unlikely that activation of APJ receptors in coronary arteries would adversely affect coronary flow by creating a vasoconstrictive environment. It can be expected that apelin or other APJ receptor agonists in development will not interfere with the vasodilator effects of endogenous BK<jats:sub>Ca<\/jats:sub> channel openers.<\/jats:p>","DOI":"10.3389\/fphar.2021.679005","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T11:52:30Z","timestamp":1622202750000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Apelin Does Not Impair Coronary Artery Relaxation Mediated by Nitric Oxide-Induced Activation of BKCa Channels"],"prefix":"10.3389","volume":"12","author":[{"given":"Amreen","family":"Mughal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengwen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen T.","family":"O\u2019Rourke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1038\/368850a0","article-title":"Nitric Oxide Directly Activates Calcium-dependent Potassium Channels in Vascular Smooth Muscle","volume":"368","author":"Bolotina","year":"1994","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.1210\/en.2004-1427","article-title":"Apelin, a Newly Identified Adipokine Up-Regulated by Insulin and Obesity","volume":"146","author":"Boucher","year":"2005","journal-title":"Endocrinology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1161\/hypertensionaha.114.05099","article-title":"Design, Characterization, and First-In-Human Study of the Vascular Actions of a Novel Biased Apelin Receptor Agonist","volume":"65","author":"Brame","year":"2015","journal-title":"Hypertension"},{"key":"B4","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1126\/science.1373909","article-title":"Regulation of Arterial Tone by Activation of Calcium-dependent Potassium Channels","volume":"256","author":"Brayden","year":"1992","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1161\/01.res.78.3.415","article-title":"Identification of Epoxyeicosatrienoic Acids as Endothelium-Derived Hyperpolarizing Factors","volume":"78","author":"Campbell","year":"1996","journal-title":"Circ. 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