Involvement of prostacyclin/IP receptors in decreased acid response of damaged stomachs--mediation by somatostatin/SST2 receptors.

AIMS: We examined the effect of a prostacyclin (PGI(2)) analog iloprost on histamine-induced acid secretion and investigated how endogenous PGI(2) mediated the decreased secretory response in the damaged stomach after exposure to taurocholate (TC). MAIN METHODS: Male C57BL/6 mice, both wild-type (WT) and IP receptor knockout (IP-KO) animals, were used after 18 h of fasting. Under urethane anesthesia, the abdomen was incised, and an acute fistula was provided in the stomach. KEY FINDINGS: Acid secretion in WT and IP-KO mice was similarly and dose-dependently increased by histamine. Iloprost decreased the histamine-stimulated secretion in WT but not IP-KO mice. The inhibitory effect of iloprost in WT mice was totally abrogated by the prior administration of CYN154806, a selective somatostatin SST2 receptor antagonist. On the other hand, the acid secretion in WT mice was decreased after exposure of the stomach to 20 mM TC for 20 min, with an increase in mucosal PGI(2) content, but the decrease was significantly less marked in IP-KO mice. The decreased acid response to TC in WT mice was totally prevented by the prior administration of CYN154806 as well as indomethacin. Somatostatin contents in the stomach were reduced after the administration of iloprost or the mucosal exposure to TC, while the blood levels increased. SIGNIFICANCE: Somatostatin/SST2 receptors are involved in the decreased acid response of the damaged stomach, in addition to PGI(2)/IP receptors. It is assumed that PGI(2) releases somatostatin from D cells, which in turn decreases acid secretion via the activation of SST2 receptors.

Healing impairment effect of cyclooxygenase inhibitors on dextran sulfate sodium-induced colitis in rats.

We examined the effects of various cyclooxygenase (COX) inhibitors on the healing of colonic lesions induced by dextran sulfate sodium (DSS) in the rat. Colonic lesions were induced by 2.5% DSS in the drinking water for 7 days, and then the animals were fed with tap water for subsequent 7 days. Indomethacin (a nonselective COX inhibitor), SC-560 (a selective COX-1 inhibitor), or rofecoxib (a selective COX-2 inhibitor) was given orally twice daily after termination of the DSS treatment. DSS treatment caused severe colonic lesions with a decrease in body weight gain and colon length as well as an increase in myeloperoxidase activity and thiobarbituric acid reactant levels. The severity of colitis gradually reduced, with an improvement of morphological and histological alterations. Daily administration of indomethacin and rofecoxib significantly delayed the healing of colitis with deleterious influences on histological restitution as well as mucosal inflammation, while SC-560 had no effect. Although COX-1 mRNA was expressed in the colon without much alteration during the test period, the expression of COX-2 was upregulated with a peak on day 3 and decreased thereafter. The mucosal prostaglandin E2 content in the colon showed a biphasic change, in parallel with that of the COX-2 expression. The increased prostaglandin E2 production in the injured mucosa was attenuated by indomethacin and rofecoxib, but not by SC-560. These results suggest that endogenous prostaglandins produced by COX-2 play an important role in the healing of DSS-induced colonic lesions. Caution should be paid to the use of selective COX-2 inhibitors as well as nonsteroidal anti-inflammatory drugs in patients with colitis.

Role of endogenous nitric oxide in mucosal defense of inflamed rat stomach following iodoacetamide treatment.

Nitric oxide (NO) plays a role in regulating the mucosal integrity of the stomach. However, its part in the mucosal defense of the inflamed stomach remains unclear. In the present study, we examined the effects of various NO synthase (NOS) inhibitors on gastric ulcerogenic and acid secretory responses following daily exposure of the stomach to iodoacetamide and investigated the role of each NOS isozyme in gastric protection from subchronic mucosal irritation. Gastric mucosal irritation was induced in rats by addition of 0.1% iodoacetamide to drinking water, and the gastric mucosa was examined on the 6th day. L-NAME (a nonselective NOS inhibitor: 20 mg/kg) or aminoguanidine (a selective iNOS inhibitor: 20 mg/kg) was given s.c. twice 24 h and 3 h before the termination of iodoacetamide treatment. Giving iodoacetamide in drinking water for 5 days produced minimal damage in the stomach with an increase in myeloperoxidase (MPO) activity and lipid peroxidation. Iodoacetamide treatment up-regulated the expression of iNOS mRNA and NO production in the stomach, without affecting nNOS expression. Both L-NAME and aminoguanidine markedly aggravated gastric lesions induced by iodoacetamide treatment, with a further enhancement in MPO activity and lipid peroxidation. Basal acid secretion as determined in pylorous-ligated stomachs was decreased following iodoacetamide treatment, but the response was significantly restored by both L-NAME and aminoguanidine. These results suggest that endogenous NO derived from both cNOS and iNOS is involved in mucosal defense of the inflamed stomach, partly by decreasing acid secretion, and contributes to maintaining mucosal integrity under such conditions.