Gastroprotective and ulcer healing effects of nitric oxide-releasing non-steroidal anti-inflammatory drugs.
OBJECTIVE
New class of nitric oxide-releasing non-steroidal anti-inflammatory drugs was shown to inhibit cyclooxygenase and prostaglandin generation without causing mucosal damage but whether these agents are capable of affecting gastric mucosal damage induced by strong irritants and healing of chronic gastric ulcers remains to be studied. In this investigation, effects of nitric oxide-releasing aspirin and nitric oxide-releasing naproxen were compared with those of native agents on gastric lesions provoked by 100% ethanol and on healing of chronic acetic acid ulcers.


RESULTS
Both, nitric oxide-releasing aspirin and naproxen dose-dependently attenuated ethanol-induced damage and produced a significant rise in gastric blood flow but did not delay healing of gastric ulcers while native aspirin and naproxen had no influence on ethanol-induced gastric damage but significantly prolonged ulcer healing, reduced gastric blood flow and suppressed mucosal generation of prostaglandin E2. The gastroprotective and hyperaemic effects of both nitric oxide-non-steroidal anti-inflammatory drugs were completely abolished by ODQ, an inhibitor of guanylyl cyclase-cGMP system but not influenced by suppression of nitric oxide-synthase with L-NNA. The damaging effects of native acetyl salicylate acid or naproxen were aggravated by acidification of these non-steroidal anti-inflammatory drugs but the exogenous acid added to nitric oxide-acetyl salicylate acid or nitric oxide-naproxen failed to influence their effect. Despite inhibiting of PGE2 generation, both nitric oxide-releasing derivatives and native aspirin and naproxen failed to affect expression of cyclooxygenase-1 mRNA but upregulated the cyclooxygenase-2 mRNA. Concurrent inhibition of cyclooxygenase-2 by selective inhibitor NS-398 which by itself delayed ulcer healing and attenuated the gastric blood flow at ulcer margin, significantly worsened the effects of these nitric oxide-non-steroidal anti-inflammatory drugs and their parent drugs on ulcer healing and the gastric blood flow at the ulcer margin.


CONCLUSIONS
1) Coupling of nitric oxide to aspirin or naproxen attenuates ethanol-induced damage, possibly due to an increase in gastric microcirculation mediated by excessive release and action of nitric oxide that probably compensates for PG deficiency induced by non-steroidal anti-inflammatory drugs; and 2) nitric oxide-non-steroidal anti-inflammatory drug, unlike classic non-steroidal anti-inflammatory drugs, does not affect intact gastric mucosa and fails to delay the healing of pre-existing ulcers.
Brzozowski
T
T
Department of Physiology, Jagiellonian University School of Medicine, Cracow, Poland.
Konturek
P C
PC
Konturek
S J
SJ
Sliwowski
Z
Z
Drozdowicz
D
D
Kwiecień
S
S
Pajdo
R
R
Ptak
A
A
Pawlik
M
M
Hahn
E
E
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001241:Aspirin / Q000494:pharmacology* / Q000627:therapeutic use; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000096:biosynthesis; D000431:Ethanol; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins; D008833:Microcirculation; D023421:Models, Animal; D009288:Naproxen / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000494:pharmacology* / Q000502:physiology; D009578:Nitrobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D009603:Nitroso Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000098:blood supply; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D009603:Nitroso Compounds; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009569:Nitric Oxide; D000431:Ethanol; D009288:Naproxen; C024942:S-nitrosopenicillamine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone; D001241:Aspirin