title: Effects of novel muscarinic M3 receptor ligand C1213 in pulmonary arterial hypertension models.
abstract: Pulmonary hypertension (PH) 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, PH 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 (PPHN) is one form of PH 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 PH We demonstrated that via M3 muscarinic receptors, C1213 induced activating- eNOS phosphorylation (serine-1177), which is known to lead to nitric oxide (NO) production in endothelial cells. Using signaling pathway inhibitors, we discovered that AKT and calcium signaling contributed to eNOS phosphorylation induced by C1213. As expected for an eNOS-stimulating agent, in ex vivo and in vivo models, C1213 triggered pulmonary vasodilation and induced both pulmonary artery and systemic blood pressure reductions demonstrating its potential value in PH and PPHN In brief, this proof-of-concept study provides evidence that an M3 muscarinic receptor functionally selective ligand stimulates downstream pathways leading to antihypertensive effects using in vitro, ex vivo, and in vivo models of PH.
authors.affiliation: Northwell Health, Pediatrics Department - Neonatology Division, Cohens Children's Medical Center, Manhasset, New York mahmed2@northwell.edu.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Medicinal Chemistry, Center for Molecular Innovation, Manhasset, New York.
authors.forename: Sonya
authors.initials: S
authors.lastname: VanPatten
authors.affiliation: Departments of Pediatrics, Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Satyan
authors.initials: S
authors.lastname: Lakshminrusimha
authors.affiliation: Northwell Health, Pediatrics Department - Neonatology Division, Cohens Children's Medical Center, Manhasset, New York.
authors.forename: Hardik
authors.initials: H
authors.lastname: Patel
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Coleman
authors.affiliation: Department of Medicinal Chemistry, Center for Molecular Innovation, Manhasset, New York.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001596:Benzylamines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000517:prevention & control; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D001596:Benzylamines; D006146:Guanidines; D043587:Receptor, Muscarinic M3; C000625002:compound 1213; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt
keywords: 
  PPHN
  ; C1213; muscarinic receptor; nitric oxide; pulmonary hypertension