title: Ghrelin-related peptides exert protective effects in the cerebral circulation of male mice through a nonclassical ghrelin receptor(s).
abstract: The ghrelin-related peptides, acylated ghrelin, des-acylated ghrelin, and obestatin, are novel gastrointestinal hormones. We firstly investigated whether the ghrelin gene, ghrelin O-acyltransferase, and the ghrelin receptor (GH secretagogue receptor 1a [GHSR1a]) are expressed in mouse cerebral arteries. Secondly, we assessed the cerebrovascular actions of ghrelin-related peptides by examining their effects on vasodilator nitric oxide (NO) and superoxide production. Using RT-PCR, we found the ghrelin gene and ghrelin O-acyltransferase to be expressed at negligible levels in cerebral arteries from male wild-type mice. mRNA expression of GHSR1a was also found to be low in cerebral arteries, and GHSR protein was undetectable in GHSR-enhanced green fluorescent protein mice. We next found that exogenous acylated ghrelin had no effect on the tone of perfused cerebral arteries or superoxide production. By contrast, exogenous des-acylated ghrelin or obestatin elicited powerful vasodilator responses (EC50 < 10 pmol/L) that were abolished by the NO synthase inhibitor N(ω)-nitro-L-arginine methyl ester. Furthermore, exogenous des-acylated ghrelin suppressed superoxide production in cerebral arteries. Consistent with our GHSR expression data, vasodilator effects of des-acylated ghrelin or obestatin were sustained in the presence of YIL-781 (GHSR1a antagonist) and in arteries from Ghsr-deficient mice. Using ghrelin-deficient (Ghrl(-/-)) mice, we also found that endogenous production of ghrelin-related peptides regulates NO bioactivity and superoxide levels in the cerebral circulation. Specifically, we show that NO bioactivity was markedly reduced in Ghrl(-/-) vs wild-type mice, and superoxide levels were elevated. These findings reveal protective actions of exogenous and endogenous ghrelin-related peptides in the cerebral circulation and show the existence of a novel ghrelin receptor(s) in the cerebral endothelium.
authors.affiliation: Vascular Biology and Immunopharmacology Group (J.K., G.R.D., C.G.S., A.A.M.), Department of Pharmacology, and Department of Physiology (Z.B.A., A.R., M.B.L., M.W.S.), Monash University, Melbourne, Victoria 3800, Australia; and Schools of Health Sciences (S.J.S.) and Medical Sciences (T.B., A.A.M.), Health Innovations Research Institute, Royal Melbourne Institute of Technology (RMIT) University, Melbourne, Victoria 3083, Australia.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Ku
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
authors.forename: Tom
authors.initials: T
authors.lastname: Barsby
authors.forename: Alex
authors.initials: A
authors.lastname: Reichenbach
authors.forename: Moyra B
authors.initials: MB
authors.lastname: Lemus
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.forename: Mark W
authors.initials: MW
authors.lastname: Sleeman
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Spencer
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.forename: Alyson A
authors.initials: AA
authors.lastname: Miller
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects*; D054022:Cerebrum / Q000098:blood supply*; D005786:Gene Expression Regulation / Q000502:physiology; D054439:Ghrelin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides
chemical_list: D054439:Ghrelin; C571124:Ghsr1a protein, rat; D010880:Piperidines; D052999:Quinazolinones; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; C524424:YIL 781; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse