Evidence for a role of the GHS-R1a receptors in ghrelin inhibition of gastric acid secretion in the rat.
Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R) has been previously shown to inhibit gastric acid secretion in pylorus-ligated rats. Two isoforms of GHS-R have been identified: GHS-R(1a) and GHS-R(1b). The present study aimed: (i) to characterise the type of GHS-R involved in the central gastric inhibitory activity of ghrelin by using des-octanoyl ghrelin, and synthetic GHS-R(1a) agonist (EP1572) and antagonist (D-Lys(3)-GHRP-6) and (ii) to investigate the relationship between ghrelin and cortistatin (CST) in the control of gastric acid secretion by using the natural neuropeptide CST-14 and the synthetic octapeptide CST-8. The specific interactions of all the compounds with GHS-R(1a) were determined by comparing their ability to displace labelled ghrelin or somatostatin from its receptors on rat hypothalamic membranes or on rat cardiomyocyte, respectively. Intracerebroventricular administration of 0.01 and 1 nmol/rat des-octanoyl ghrelin did not affect gastric acid secretion in pylorus-ligated rats, whereas EP1572 either i.c.v. (0.01-1 nmol/rat) or i.p. (10 and 20 nmol/kg) inhibited acid gastric secretion. Preteatment with D-Lys(3)GHRP-6 (3 nmol/rat, i.c.v.) was able to remove the inhibitory action of ghrelin (0.01 nmol/rat, i.c.v.) on gastric acid volume and acid output, thus indicating that the type 1a GHS-R likely mediates the gastric inhibitory action of ghrelin. This is supported by binding data showing that D-Lys(3)GHRP-6, but not des-octanoyl ghrelin, binds to hypothalamic GHS-R. CST-14 (1 nmol/rat, i.c.v.) did not affect either basal or ghrelin inhibition of gastric acid secretion. CST-8 (1 nmol/rat, i.c.v.) was able to counteract the gastric ghrelin response. The observation that CST-14 binds both GHR-S and somatostatin receptors, whereas CST-8 specifically displaces only ghrelin binding, indicates that CST-8 behaves as a GHS-R(1a) antagonist.
Sibilia
V
V
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milano, Milano, Milan, Italy. valeria.sibilia@unimi.it
Muccioli
G
G
Deghenghi
R
R
Pagani
F
F
De Luca
V
V
Rapetti
D
D
Locatelli
V
V
Netti
C
C
D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive; D015891:Cystatins / Q000378:metabolism; D015536:Down-Regulation; D005744:Gastric Acid / Q000378:metabolism*; D054439:Ghrelin; D007031:Hypothalamus / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D036361:Peptide Hormones / Q000502:physiology*; D010455:Peptides / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D054440:Receptors, Ghrelin; D017481:Receptors, Somatostatin / Q000378:metabolism*
C489715:Cst8 protein, rat; D015891:Cystatins; D054439:Ghrelin; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides; D036361:Peptide Hormones; D010455:Peptides; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D017481:Receptors, Somatostatin; C467796:cortistatin 14; C054598:corticostatin