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 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 HCl (HCl-aspirin). Pretreatment with N(G)-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 HCl-aspirin, and T-593 inhibited this decrease. On the other hand, HCl-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 HCl-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.
Marubuchi
S
S
Research Laboratories, Toyama Chemical Co., Ltd., Japan.
Mori
Y
Y
Noto
M
M
Urata
N
N
Mizuo
M
M
Arai
H
H
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D004347:Drug Interactions; D004357:Drug Synergism; D005753:Gastric Mucosa / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000494:pharmacology*
D000897:Anti-Ulcer Agents; D006146:Guanidines; D013450:Sulfones; C088837:T 593; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D001241:Aspirin; D019331:NG-Nitroarginine Methyl Ester