title: Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor.
abstract: OBJECTIVE
  Some agonists of ghrelin receptors cause rapid decreases in BP. The mechanisms by which they cause hypotension and the pharmacology of the receptors are unknown.
  
  
  METHODS
  The effects of ligands of ghrelin receptors were investigated in rats in vivo, on isolated blood vessels and on cells transfected with the only molecularly defined ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a).
  
  
  RESULTS
  Three agonists of GHSR1a receptors, ulimorelin, capromorelin and CP464709, caused a rapid decrease in BP in the anaesthetized rat. The effect was not reduced by either of two GHSR1a antagonists, JMV2959 or YIL781, at doses that blocked effects on colorectal motility, in vivo. The rapid hypotension was not mimicked by ghrelin, unacylated ghrelin or the unacylated ghrelin receptor agonist, AZP531. The early hypotension preceded a decrease in sympathetic nerve activity. Early hypotension was not reduced by hexamethonium or by baroreceptor (sino-aortic) denervation. Ulimorelin also relaxed isolated segments of rat mesenteric artery, and, less potently, relaxed aorta segments. The vascular relaxation was not reduced by JMV2959 or YIL781. Ulimorelin, capromorelin and CP464709 activated GHSR1a in transfected HEK293 cells at nanomolar concentrations. JMV2959 and YIL781 both antagonized effects in these cells, with their pA2 values at the GHSR1a receptor being 6.55 and 7.84.
  
  
  CONCLUSIONS
  Our results indicate a novel vascular receptor or receptors whose activation by ulimorelin, capromorelin and CP464709 lowered BP. This receptor is activated by low MW GHSR1a agonists, but is not activated by ghrelin.
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Vic., Australia.
authors.forename: Brid
authors.initials: B
authors.lastname: Callaghan
authors.forename: Samin
authors.initials: S
authors.lastname: Kosari
authors.forename: Ruslan V
authors.initials: RV
authors.lastname: Pustovit
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Sartor
authors.forename: Dorota
authors.initials: D
authors.lastname: Ferens
authors.forename: Kung
authors.initials: K
authors.lastname: Ban
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baell
authors.forename: Trung V
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Leni R
authors.initials: LR
authors.lastname: Rivera
authors.forename: James A
authors.initials: JA
authors.lastname: Brock
authors.forename: John B
authors.initials: JB
authors.lastname: Furness
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D054439:Ghrelin / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists* / Q000502:physiology
chemical_list: C433143:CP 424391; D054439:Ghrelin; C571124:Ghsr1a protein, rat; D047028:Macrocyclic Compounds; D010880:Piperidines; D011720:Pyrazoles; D054440:Receptors, Ghrelin; C528884:ulimorelin
keywords: BP; ghrelin; ghrelin receptors; vasodilation