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-
(4-hydroxyphenyl)ethyl]-3-[2-[[[5-(methylamino)methyl-2-furyl]methyl]
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