Effect of carbenoxolone on the biological activity of nitric oxide: relation to gastroprotection

Abstract

1 The interactions between carbenoxolone and nitric oxide (NO) were examined by investigating their effects on human platelet aggregation, on rat aortic strips precontracted by phenylephrine and on protection of rat gastric mucosa against ethanol-induced injury.2 Carbenoxolone (100-300,UM) caused a significant and concentration-dependent potentiation of rat peritoneal neutrophil (RPN)-, 3-morpholino-sydnonimine (SIN-1)-or iloprost-induced inhibition of platelet aggregation. Higher concentrations (5001uM) of carbenoxolone alone markedly inhibited platelet aggregation. Pretreatment with carbenoxolone (100-300pM) antagonized the reversal of the RPN-or SIN-1-induced antiaggregatory effect by oxyhaemoglobin (10Mm).3 Rat aortic strips with intact endothelium precontracted by phenylephrine (0.1-0.31uM) were relaxed by carbenoxolone (100-300,uM) in a concentration-dependent manner. Relaxations were abolished by mechanical removal of the endothelium or by incubation with methylene blue (10pM) or NG-nitro-L-arginine (L-NNA, 100pgM). Sodium nitroprusside (10 nM)-induced relaxations of endothelium-denuded rat aortic strips were potentiated by carbenoxolone (100 UM). 4 The carbenoxolone (200mg kg-1, p.o.)-induced gastroprotection against ethanol was antagonized by L-NNA (5-4Omgkg-1) in a dose-dependent manner. Pretreatment of rats with indomethacin (lOmgkg 1, s.c.) increased the effect of L-NNA. 5 The results suggest that the activity of carbenoxolone in the experimental systems tested is due to phosphodiesterase inhibition, although radical scavenging properties of the drug could contribute to some of the effects observed. In the rat gastric mucosa both increased prostaglandin levels and effects on the NO system could contribute to the protective action of carbenoxolone.

Role of Nitric Oxide in the Digestive System

“…7). Similar effects have been observed after administration o f 'cytoprotective' drugs such as carbenoxolone [76], sucralfate [77] or aluminum-containing antacids [78] whose protective activity was reduced by the inhibition of NOS and reversed by the addition of L-argi- 8 …”

Cytoprotective Action of L-Arginine against HCl-Induced Gastric Injury in Rats: Involvement of Nitric Oxide?

“…Recent studies showed that NO plays an important role in the modulation of the gastric mucosal integrity by interacting with sensory neuropeptides and endogenous prostaglandins (PGs) (3 5). It has been also shown that endogenous NO is involved in certain types of gastro protection as induced by capsaicin (6), carbenoxolone (7) and mild irritants (8). However, the effect of L-arginine, the precursor of NO, on the gastric mucosal integrity has not been much studied.…”

Multiple Mediators and Mechanisms Are Involved in the Adaptive Cytoprotection Provided by Certain Mild Irritants

“…Recent studies showed that NO could be involved in the protective actions of some antiulcer drugs such as car benoxolone and sucralfate (8,15). Lambrecht and Peskar (9) examined the effect of L-NNA pretreatment on the pro tective actions of some mild irritants against ethanol-in duced gatric lesions and found that L-NNA counteracted the protective action by 20% ethanol and 0.1 N NaOH but not that by 0.3 N HC1 and 5016 NaC1, suggesting that NO is involved in the protective activity of some but not all mild irritants.…”