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-R1a and GHS-R1b. The present study aimed: (i) to characterize the type of GHS-R involved in the central gastric inhibitory activity of ghrelin by using des-octanoyl ghrelin, and synthetic GHS-R1a agonist (EP 1572) and antagonist (D-Lys3-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 compds. with GHS-R1a were detd. by comparing their ability to displace labeled ghrelin or somatostatin from its receptors on rat hypothalamic membranes or on rat cardiomyocyte, resp. Intracerebroventricular administration of 0.01 and 1 nmol/rat des-octanoyl ghrelin did not affect gastric acid secretion in pylorus-ligated rats, whereas EP 1572 either i.c.v. (0.01-1 nmol/rat) or i.p. (10 and 20 nmol/kg) inhibited acid gastric secretion. Pretreatment with D-Lys3GHRP-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 vol. 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-Lys3GHRP-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-R1a antagonist.