title: Analysis of the ghrelin receptor-independent vascular actions of ulimorelin.
abstract: Ulimorelin (TZP101) is a ghrelin receptor agonist that stimulates intestinal motility, but also reduces blood pressure in rodents and humans and dilates blood vessels. It has been proposed as a treatment for intestinal motility disorders. Here we investigated the mechanisms through which ulimorelin affects vascular diameter. Actions of ulimorelin on wall tension of rodent arteries were investigated and compared with other ghrelin receptor agonists. Saphenous, mesenteric and basilar arteries were obtained from Sprague-Dawley rats (male, 8 weeks) and saphenous arteries were obtained from wild type or ghrelin receptor null mice. These were mounted in myography chambers to record artery wall tension. Ulimorelin (0.03-30µM) inhibited phenylephrine-induced contractions of rat saphenous (IC50=0.6µM; Imax=66±5%; n=3-6) and mesenteric arteries (IC50=5µM, Imax=113±16%; n=3-4), but not those contracted by U46619, ET-1 or 60mM [K(+)]. Relaxation of phenylephrine-constricted arteries was not observed with ghrelin receptor agonists TZP102, capromorelin or AZP-531. In rat saphenous and basilar arteries, ulimorelin (10-100µM) and TZP102 (10-100µM) constricted arteries (EC50=9.9µM; Emax=50±7% and EC50=8µM; Emax=99±16% respectively), an effect not attenuated by the ghrelin receptor antagonist YIL 781 3µM or mimicked by capromorelin or AZP-531. In mesenteric arteries, ulimorelin, 1-10µM, caused a surmountable rightward shift in the response to phenylephrine (0.01-1000µM; pA2=5.7; n=3-4). Ulimorelin had similar actions in mouse saphenous artery from both wild type and ghrelin receptor null mice. We conclude that ulimorelin causes vasorelaxation through competitive antagonist action at α1-adrenoceptors and a constrictor action not mediated via the ghrelin receptor.
authors: Neurogastroenterology group, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address: j.broad@qmul.ac.uk.
authors: John
authors: J
authors: Broad
authors: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Brid
authors: B
authors: Callaghan
authors: Neurogastroenterology group, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: Gareth J
authors: GJ
authors: Sanger
authors: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: James A
authors: JA
authors: Brock
authors: Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia.
authors: John B
authors: JB
authors: Furness
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D008297:Male; D051379:Mice; D051381:Rats; D054440:Receptors, Ghrelin / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D047028:Macrocyclic Compounds; D054440:Receptors, Ghrelin; C528884:ulimorelin
keywords: Ghrelin (PubChem CID: 71728433); Myography; Peripheral arteries; Ulimorelin (PubChem CID: 11526696);; Vasodilatation