Implication of endogenous nitric oxide in gastric mucosal protective effect of T-593, a novel anti-ulcer agent, in rats

The relationship of endogenous nitric oxide (NO) to the gastric mucosal pro tective effect of the novel anti-ulcer agent T-593, (+/-)-(E)-l-[2-hydroxy- 2-(4-hydroxyphenyl)-3[2-[[[5-(methylamino) methyl-2-furyl] methyl]thio]ethy l]-2-(methylsulfonyl) guanidine, was investigated in rats. T-593 (3 - 30 mg /kg, p.o.) dose dependently prevented the formation of gastric mucosal lesi ons induced by oral administration of aspirin (200 mg/kg) in 0.15 N HCI (HC l-aspirin). Pretreatment with NG-nitro-L-arginine methylester (L-NAME), a s elective 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 d ecreased by HCl-aspirin, and T-593 inhibited this decrease. On the other ha nd, HCl-aspirin and T-593 did not affect inducible NOS activity in the gast ric mucosa. Furthermore, we confirmed that T-593 inhibits the decrease in g astric mucosal blood flow (GMBF) induced by HCl-aspirin, and this effect is completely inhibited by pretreatment with L-NAME. These results suggest th at 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.