Received for publication April 24, 2006.
Revised July 24, 2006.
Accepted for publication July 24, 2006.

Prostaglandin/cyclooxygenase pathway in ghrelin-induced gastroprotection against ischemia-reperfusion injury

Abstract

Ghrelin is involved in the control of food intake but its role in gastroprotection against the formation of gastric mucosal injury has been little elucidated. We studied the effects of peripheral (i.p.) and central (i.c.v.) administration of ghrelin on gastric secretion and gastric mucosal lesions induced by 3 h of ischemia/reperfusion (I/R) with or without A) inhibition of ghrelin growth hormone secretagouge type 1a receptor (GHS-R1a) by using ghrelin antagonist, D-Lys³-GHRP-6; B) blockade of cyclooxygenase (COX)-1 (indomethacin, SC-560) and COX-2 (rofecoxib) and C) bilateral vagotomy or capsaicin denervation. I/R produced typical gastric erosions, a significant fall in the GBF, an increase in gastric MPO activity and MDA content and the upregulation of mucosal ghrelin mRNA. Ghrelin dose-dependently increased gastric acid secretion and significantly reduced I/R-induced gastric erosions, while producing a significant rise in the GBF and mucosal PGE₂ generation and a significant fall in MPO activity and MDA content. The protective and hyperemic activities of ghrelin were significantly attenuated in rats pretreated with D-Lys³-GHRP-6 and capsaicin denervation and completely abolished by vagotomy. Indomethacin, SC-560 and rofecoxib, selective COX-1 and COX-2 inhibitors, attenuated ghrelin-induced protection that was restored by supplying methyl analog of PGE₂. The expression of mRNA for COX-1 was unaffected by ghrelin but COX-2 mRNA and COX-2 protein were detectable in I/R injured mucosa and further upregulated by exogenous ghrelin. We conclude that ghrelin exhibits gastroprotective and hyperemic activities against I/R-induced erosions, the effects that are mediated by hormone activation of GHS-R1a receptors, COX-PG system, and vagal-sensory nerves.

Key words: cyclooxygenase, gastric ischemia-reperfusion, gastric mucosal blood flow, ghrelin, prostaglandin, vagal-sensory nerves

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