University of SaskatchewanHARVEST
  • Login
  • Submit Your Work
  • About
    • About HARVEST
    • Guidelines
    • Browse
      • All of HARVEST
      • Communities & Collections
      • By Issue Date
      • Authors
      • Titles
      • Subjects
      • This Collection
      • By Issue Date
      • Authors
      • Titles
      • Subjects
    • My Account
      • Login
      JavaScript is disabled for your browser. Some features of this site may not work without it.
      View Item 
      • HARVEST
      • Electronic Theses and Dissertations
      • Graduate Theses and Dissertations
      • View Item
      • HARVEST
      • Electronic Theses and Dissertations
      • Graduate Theses and Dissertations
      • View Item

      Vasodilator action of ghrelin

      Thumbnail
      View/Open
      bam119.pdf (763.3Kb)
      Date
      2007-06-08
      Author
      Moazed, Banafsheh
      Type
      Thesis
      Degree Level
      Doctoral
      Metadata
      Show full item record
      Abstract
      Ghrelin is a 28-amino acid peptide predominantly produced in the stomach and secreted into the circulation. Ghrelin is found in plasma and tissues in two major forms of n-octanoyl-modified at its N-terminal third serine residue and des-acyl ghrelin. The n-octanoyl group of ghrelin is essential for its growth hormone (GH)-releasing activity and appetite regulation mediated through growth hormone secretagogue receptor (GHS-R). We demonstrated that both ghrelin and des-acyl ghrelin evoke vasodilatation at remarkably low concentrations compared to acetylcholine (ACh) in phenylephrine (PE)-constricted perfused rat mesenteric vascular bed (MVB). This was abolished in endothelium-denuded preparations and in endothelium-intact preparations exposed to either a calcium-activated potassium channel (KCa) blocker or a depolarizing stimulus. While KATP channel blockade, nitric oxide synthase and cyclooxygenase inhibition had no effect, the responses were abolished in the presence of combinations of apamin and charybdotoxin, apamin and TRAM-34, and ouabain and Ba2+. The GHS-R antagonist, [D-Lys3]-GHRP-6, per se evoked vasodilatation. Inclusion of L-756867, a peptide antagonist of classical GHS-R, failed to evoke any vasodilator response or to affect vasodilatation evoked by ghrelin. Both non-peptide agonists of GHS-R, L-166446 and L-163255, demonstrated concentration-dependent decreases in perfusion pressure. All short peptides encompassing the first 20, 16, 10, 6, 4, and 3 residues of des-acyl ghrelin were able to evoke vasodilator responses to the same extent as des-acyl ghrelin. However, vasodilatation to single amino acids, L-serine and glycine, were significantly attenuated. Streptozotocin (STZ)-induced diabetes increased plasma ghrelin concentration. Diabetes for 4-weeks did not cause any significant reduction in ghrelin-evoked vasodilatation, whereas 8-weeks diabetes significantly reduced ghrelin-evoked vasodilatation. In contrast to ghrelin, there was a duration-dependent fall in vasodilator response to ACh from 4- to 8-weeks diabetes. These data suggest that the vasodilatation evoked by ghrelin is mediated by endothelium-dependent hyperpolarization (EDHF) by mechanism(s) that are independent of classical GHS-R activation. In addition, EDHF-dependent ghrelin-evoked vasodilator responses may not be affected, at least in the early stages of STZ diabetes, whereas the responses to ACh, predominantly mediated through nitric oxide, are progressively diminished right from the early stages of endothelial dysfunction in STZ diabetic rats.
      Degree
      Doctor of Philosophy (Ph.D.)
      Department
      Pharmacology
      Program
      Pharmacology
      Supervisor
      Gopalakrishnan, Venkat
      Committee
      Richardson, J. Steven; Hiebert, Linda M.; Hickie, Robert A.; Desai, Kaushik; Tuchek, John M.
      Copyright Date
      June 2007
      URI
      http://hdl.handle.net/10388/etd-06072007-144506
      Subject
      Vasodilation
      Ghrelin
      Collections
      • Graduate Theses and Dissertations
      University of Saskatchewan

      University Library

      The University of Saskatchewan's main campus is situated on Treaty 6 Territory and the Homeland of the Métis.

      © University of Saskatchewan
      Contact Us | Disclaimer | Privacy