{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:55:33Z","timestamp":1791647733345,"version":"4.3.4"},"reference-count":19,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2016,12,30]],"date-time":"2016-12-30T00:00:00Z","timestamp":1483056000000},"content-version":"vor","delay-in-days":29,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Northwell Health and The Feinstein Institute for Medical Research (Manhasset, NY)."}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pulmonary hypertension (<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>) is a complex disease comprising a pathologic remodeling and thickening of the pulmonary vessels causing an after load on the right heart ventricle that can result in ventricular failure. Triggered by oxidative stress, episodes of hypoxia, and other undetermined causes,<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>is associated with poor outcomes and a high rate of morbidity. In the neonate, this disease has a similar etiology but is further complicated by the transition to breathing after birth, which requires a reduction in vascular resistance. Persistent pulmonary hypertension of the newborn (<jats:styled-content style=\"fixed-case\">PPHN<\/jats:styled-content>) is one form of<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>that is frequently unresponsive to current therapies including inhaled nitric oxide (due to lack of proper absorption and diffusion), and other therapeutics targeting signaling mediators in vascular endothelium and smooth muscle. The need for novel agents, which target distinct pathways in pulmonary hypertension, remains. Herein, we investigated the therapeutic effects of novel muscarinic receptor ligand C1213 in models of<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>. We demonstrated that via M3 muscarinic receptors, C1213 induced activating\u2010<jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>phosphorylation (serine\u20101177), which is known to lead to nitric oxide (<jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>) production in endothelial cells. Using signaling pathway inhibitors, we discovered that<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>and calcium signaling contributed to<jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>phosphorylation induced by C1213. As expected for an<jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>\u2010stimulating agent, in ex\u00a0vivo and in\u00a0vivo models, C1213 triggered pulmonary vasodilation and induced both pulmonary artery and systemic blood pressure reductions demonstrating its potential value in<jats:styled-content style=\"fixed-case\">PH<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">PPHN<\/jats:styled-content>. In brief, this proof\u2010of\u2010concept study provides evidence that an M3 muscarinic receptor functionally selective ligand stimulates downstream pathways leading to antihypertensive effects using in\u00a0vitro, ex\u00a0vivo, and in\u00a0vivo models of PH.<\/jats:p>","DOI":"10.14814\/phy2.13069","type":"journal-article","created":{"date-parts":[[2016,12,31]],"date-time":"2016-12-31T02:05:16Z","timestamp":1483149916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Effects of novel muscarinic M3 receptor ligand C1213 in pulmonary arterial hypertension models"],"prefix":"10.14814","volume":"4","author":[{"given":"Mohamed","family":"Ahmed","sequence":"first","affiliation":[{"name":"Northwell Health Pediatrics Department \u2010 Neonatology Division Cohens Children's Medical Center Manhasset New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya","family":"VanPatten","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Center for Molecular Innovation Manhasset New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satyan","family":"Lakshminrusimha","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics Physiology and Biophysics State University of New York at Buffalo Buffalo New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hardik","family":"Patel","sequence":"additional","affiliation":[{"name":"Northwell Health Pediatrics Department \u2010 Neonatology Division Cohens Children's Medical Center Manhasset New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Coleman","sequence":"additional","affiliation":[{"name":"The Feinstein Institute for Medical Research Manhasset New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Al\u2010Abed","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Center for Molecular Innovation Manhasset New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,12,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00098.2012"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00392.2014"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2011.00339"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.10.108"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00792.2006"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-23274-9_13"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2010.03.020"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3780385"},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.33549\/physiolres.930000.49.115","article-title":"Contemporary activation of different endothelial receptors accounts for a reserve mechanism of nitric oxide\u2010mediated relaxation","volume":"49","author":"Kysela S.","year":"2000","journal-title":"Physiol. 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