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Inducible types of cyclooxygenase and nitric oxide synthase in adaptive cytoprotection in rat stomachs
H Yamamoto1, A Tanaka, T Kunikata
1Department of Pharmacology & Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Japan.
Abstract:
Roles of cyclooxygenases (COX-1 and COX-2) and nitric oxide (NO) synthases (nNOS and iNOS) in adaptive cytoprotection induced by 20 mM taurocholate dissolved in 50 mM HCl (TC) were investigated in rat stomachs. Intragastric administration of 0.6 N HCl caused haemorrhagic damage in the stomach. These lesions were prevented by pretreatment of the animals with TC p.o. 0.5 h before 0.6 N HCl, and a significant protection persisted for more than 5 h. The protection afforded by TC given 0.5 h before HCl was almost totally reversed by indomethacin and slightly mitigated by N(G)-nitro-L-arginine methyl ester (L-NAME) but not affected by NS-398 or aminoguanidine. By contrast, the mucosal protective action of TC given 5 h before HCl was significantly reversed by NS-398, L-NAME and aminoguanidine as well as indomethacin. Mucosal prostaglandin E2 (PGE2) contents were significantly increased for over 5 h after TC, while luminal NOx output tended to elevate at 0.5 h and be significantly increased at 5 h after TC. The increased PGE2 generation observed 0.5 h after TC was attenuated only by indomethacin, while that observed 5 h after TC was inhibited by NS-398 as well as indomethacin. On the other hand, the NOx output determined at 5 h after TC was significantly reduced by both L-NAME and aminoguanidine. The expression of mRNA for both COX-2 and iNOS was apparently detected in the stomach from 3 h after TC treatment. These results suggest that TC induced adaptive cytoprotection in the rat stomach against 0.6 N HCl, the effect lasting for over 5 h, and the underlying mechanism differs depending on the period after the irritation. The early phase is mediated mainly by COX-1/PGs, while the later phase is mediated by iNOS/NO, in addition to prostaglandins (PGs) produced by both COX-1 and COX-2.
Insights
Taurocholate (TC) protects rat stomachs from acid damage via adaptive cytoprotection. Early protection involves cyclooxygenase-1 (COX-1) and prostaglandins (PGs), while later protection involves inducible nitric oxide synthase (iNOS) and nitric oxide (NO).
Area of Science:
- Gastroenterology
- Pharmacology
- Cell Biology
Background:
- Gastric mucosal injury is a significant health concern.
- Adaptive cytoprotection mechanisms in the stomach are not fully understood.
- Taurocholate (TC) has shown potential in protecting the gastric mucosa.
Purpose of the Study:
- To investigate the roles of cyclooxygenases (COX-1, COX-2) and nitric oxide synthases (nNOS, iNOS) in taurocholate (TC)-induced adaptive cytoprotection in rat stomachs.
- To elucidate the temporal mechanisms underlying TC-mediated gastric protection against acid-induced injury.
Main Methods:
- Rat stomachs were subjected to 0.6 N HCl-induced hemorrhagic damage.
- Pretreatment with TC was administered at different time points (0.5 h and 5 h before HCl).
- Pharmacological inhibitors (indomethacin, NS-398, L-NAME, aminoguanidine) were used to block specific enzymes.
- Gastric mucosal prostaglandin E2 (PGE2) and luminal NOx output were measured.
- Messenger RNA (mRNA) expression for COX-2 and iNOS was analyzed.
Main Results:
- TC pretreatment significantly protected rat stomachs against HCl-induced damage for over 5 hours.
- Early protection (0.5 h post-TC) was primarily mediated by COX-1/prostaglandins (PGs), inhibited by indomethacin.
- Later protection (5 h post-TC) involved both PGs (via COX-1 and COX-2) and nitric oxide (NO) (via iNOS), as indicated by inhibition with indomethacin, NS-398, L-NAME, and aminoguanidine.
- TC increased PGE2 and NOx levels, and induced COX-2 and iNOS mRNA expression in a time-dependent manner.
Conclusions:
- TC induces significant adaptive cytoprotection in the rat stomach against acute acid injury.
- The protective mechanism is time-dependent, with early phase mediated by COX-1/PGs and the later phase involving iNOS/NO and COX-1/COX-2/PGs.
- Understanding these distinct temporal mechanisms can inform therapeutic strategies for gastric protection.
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