title: Functional and in situ hybridization evidence that preganglionic sympathetic vasoconstrictor neurons express ghrelin receptors.
abstract: Agonists of ghrelin receptors can lower or elevate blood pressure, and it has been suggested that the increases in blood pressure are caused by actions at receptors in the spinal cord. However, this has not been adequately investigated, and the locations of neurons in the spinal cord that express ghrelin receptors, through which blood pressure increases may be exerted, are not known. We investigated the effects within the spinal cord of two non-peptide ghrelin receptor agonists, GSK894490 and CP464709, and two peptide receptor agonists, ghrelin and des-acyl ghrelin, and we used polymerase chain reaction (PCR) and in situ hybridization to examine ghrelin receptor expression. I.v. application of the non-peptide ghrelin receptor agonists caused biphasic changes in blood pressure, a brief drop followed by a blood pressure increase that lasted several minutes. The blood pressure rise, but not the fall, was antagonized by i.v. hexamethonium. Application of these agonists or ghrelin peptide directly to the spinal cord caused only a blood pressure increase. Des-acyl ghrelin had no significant action. The maximum pressor effects of agonists occurred with application at spinal cord levels T9 to T12. Neither i.v. nor spinal cord application of the agonists had significant effect on heart rate or the electrocardiogram. Ghrelin receptor gene expression was detected by PCR and in situ hybridization. In situ hybridization localized expression to neurons, including autonomic preganglionic neurons of the intermediolateral cell columns at all levels from T3 to S2. The numbers of ghrelin receptor expressing neurons in the intermediolateral cell columns were similar to the numbers of nitric oxide synthase positive neurons, but there was little overlap between these two populations. We conclude that activation of excitatory ghrelin receptors on sympathetic preganglionic neurons increases blood pressure, and that decreases in blood pressure caused by ghrelin agonists are mediated through receptors on blood vessels.
authors.affiliation: Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: D M
authors.initials: DM
authors.lastname: Ferens
authors.forename: L
authors.initials: L
authors.lastname: Yin
authors.forename: R
authors.initials: R
authors.lastname: Bron
authors.forename: B
authors.initials: B
authors.lastname: Hunne
authors.forename: K
authors.initials: K
authors.lastname: Ohashi-Doi
authors.forename: P D
authors.initials: PD
authors.lastname: Kitchener
authors.forename: G J
authors.initials: GJ
authors.lastname: Sanger
authors.forename: J
authors.initials: J
authors.lastname: Witherington
authors.forename: Y
authors.initials: Y
authors.lastname: Shimizu
authors.forename: J B
authors.initials: JB
authors.lastname: Furness
mesh_terms: D000320:Adrenergic Fibers / Q000378:metabolism*; D000818:Animals; D001339:Autonomic Fibers, Preganglionic / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D054439:Ghrelin / Q000378:metabolism / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D017403:In Situ Hybridization; D008297:Male; D009474:Neurons / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000031:analogs & derivatives / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D054439:Ghrelin; D010879:Piperazines; D011725:Pyridines; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; D012694:Serine; D013449:Sulfonamides; C546352:5-(2-methylalanyl)-O-((2,4difluorophenyl)methyl)-seryl-3-oxo-3a-(2 pyridinylmethyl)-2-(2,2,2 trifluoroethyl)-3,3a,4,5,6,7-hexahydro-2H pyrazolo(4,3-c)pyridine; C546351:N-(5-(3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl)-4-(5-methyl-2-furanyl) benzenesulfonamide; D000096926:Benzenesulfonamides