Induction of Small Intestinal Damage in Rats Following Combined Treatment with Cyclooxygenase-2 and Nitric-Oxide Synthase Inhibitors

摘要

Nitric oxide(NO)produced by constitutively expressed NO synthase(cNOS)plays an important role in maintaining the mucosal integrity of the small intestine,in collaboration with prostaglandins produced by cyclooxygenase(COX)-1.We examined whether intestinal damage is provoked in rats under inhibition of both cNOS and COX-2.The animals were given L-NAME(N~G-nitro-L-arginine methyl ester),aminoguanidine,or rofecoxib,either alone or in combination,and killed 24 h later.Neither L-NAME nor aminoguanidine alone provoked damage in the small intestinal mucosa within 24 h,yet L-NAME produced damage in a L-arginine-sensitive manner when administered together with rofecoxib.L-NAME up-regulated the expression of COX-2 mRNA,and the prostaglandin E_2(PGE_2)content following the L-NAME administration significantly increased 12 h later,in both a rofecoxib-and a L-arginine-inhib-itable manner.L-NAME enhanced intestinal motility,decreased mucus secretion,and increased the number of bacteria in the mucosa.The up-regulation of COX-2 expression and PGE_2 production by L-NAME was inhibited by prior administration of atropine,at a dose that inhibited the intestinal hypermotility.The intestinal lesions induced by L-NAME plus rofecoxib were prevented by pretreatment with ampicillin and aminoguanidine as well as atropine,indicating the involvement of bacteria,inducible nitric oxide synthase,and hypermotility in the patho-genesis.These results suggest that inhibition of both cNOS and COX-2 provokes intestinal damage,similar to inhibition of both COX-1 and COX-2.Inhibition of cNOS,similar to COX-1,up-regulates COX-2 expression,the process being associated with intestinal hypermotility and bacterial invasion,and this may be a key to the occurrence of intestinal damage associated with COX-2 inhibition.