Jpn. J. Pharmacol. 79 (2), 195-202 (1999)

Implication of Endogenous Nitric Oxide in Gastric Mucosal Protective Effect of T-593, a Novel Anti-ulcer Agent, in Rats

Shigeki Marubuchi, Yukio Mori, Masahiko Noto, Noriko Urata, Midori Mizuo and Hirotoshi Arai

Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama 930-8508, Japan

Abstract: The relationship of endogenous nitric oxide (NO) to the gastric mucosal protective effect of the novel anti-ulcer agent T-593, (+/-)-(E)-1-[2-hydroxy-2-


thio]ethyl]-2-(methylsulfonyl) guanidine, was investigated in rats. T-593 (3 - 30 mg/kg, p.o.) dose dependently prevented the formation of gastric mucosal lesions induced by oral administration of aspirin (200 mg/kg) in 0.15 N HCI (HCI-aspirin). Pretreatment with NG-nitro-L-arginine methylester (L-NAME), a selective inhibitor of NO synthase (NOS), attenuated the mucosal protective effect of T-593. This effect of L-NAME was antagonized by pretreatment with L-arginine, a substrate of NOS, but not with D-arginine. Activity of total NOS composed of inducible and constitutive NOS in the gastric mucosa was decreased by HCI-aspirin, and T-593 inhibited this decrease. On the other hand, HCI-aspirin and T-593 did not affect inducible NOS activity in the gastric mucosa. Furthermore, we confirmed that T-593 inhibits the decrease in gastric mucosal blood flow (GMBF) induced by HCI-aspirin, and this effect is completely inhibited by pretreatment with L-NAME. These results suggest that the mucosal protective effect of T-593 is partly mediated by endogenous NO via improvement of GMBF and that a possible mechanism for the effect of T-593 is the maintenance of constitutive NOS activity in gastric mucosa.

Keywords: T-593, Anti-ulcer agent, Gastroprotection, Nitric oxide, Gastric mucosal blood flow

Copyrightę The Japanese Pharmacological Society 1999

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