Selective cyclooxygenase (COX) inhibition causes damage to portal hypertensive gastric mucosa: roles of nitric oxide and NF-kappaB.
Portal hypertension (PHT) is associated with increased susceptibility of the gastric mucosa to injury by a variety of factors, including nonsteroidal anti-inflammatory drugs (NSAIDs) that nonselectively inhibit both isoforms of cyclooxygenase (COX-1 and -2). PHT gastric mucosa also has excessive nitric oxide (NO) production that contributes to the general increased susceptibility to injury. Using a rat model of PHT, we studied whether selective COX inhibition, which does not damage normal (normotensive) gastric mucosa, is sufficient to cause PHT gastric damage and, if so, whether and how excessive NO is involved. Indomethacin, a nonselective NSAID, caused 2.4-fold more gastric injury to PHT vs. normotensive sham-operated (SO) control rats. Neither NS-398 nor celecoxib, selective COX-2 inhibitors, caused gastric damage in either SO or PHT rats. SC-560, a selective COX-1 inhibitor, did not cause gastric damage in SO rats but dose-dependently caused gastric damage in PHT rats. There was a compensatory increase in COX-2 expression and activity in SC-560-treated SO rats but not SC-560-treated PHT rats. Partial inhibition of NO production restored gastric COX-2 expression and activity levels in SC-560-treated PHT rats to those of SC-560-treated SO rats, by a mechanism consistent with induction of NF-kappaB, and significantly reduced gastric damage. These studies indicate that, in contrast to normotensive gastric mucosa, inhibition of COX-1 alone is sufficient to cause PHT gastric damage as a result of excessive NO that prevents the induction of NF-kappaB and the compensatory increase in COX-2.
Akahoshi
Tomohiko
T
Department of Medicine, Department of Veterans Affairs Medical Center, Long Beach, California, USA.
Tanigawa
Tetsuya
T
Sarfeh
I James
IJ
Chiou
Shiun-Kwei
SK
Hashizume
Makoto
M
Maehara
Yoshihiko
Y
Jones
Michael K
MK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D051545:Cyclooxygenase 1 / Q000032:analysis; D051546:Cyclooxygenase 2 / Q000032:analysis; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006975:Hypertension, Portal / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D011720:Pyrazoles; C115461:SC 560; D009569:Nitric Oxide; D004247:DNA; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester