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

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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 μm) 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 (500 μm) of carbenoxolone alone markedly inhibited platelet aggregation. Pretreatment with carbenoxolone (100–300 μm) antagonized the reversal of the RPN- or SIN-1-induced antiaggregatory effect by oxyhaemoglobin (10 μm). 3 Rat aortic strips with intact endothelium precontracted by phenylephrine (0.1–0.3 μm) were relaxed by carbenoxolone (100–300 μm) in a concentration-dependent manner. Relaxations were abolished by mechanical removal of the endothelium or by incubation with methylene blue (10 μm) or NG-nitro-l-arginine (l-NNA, 100 μm). Sodium nitroprusside (10 nm)-induced relaxations of endothelium-denuded rat aortic strips were potentiated by carbenoxolone (100 μm). 4 The carbenoxolone (200 mg kg−1, p.o.)-induced gastroprotection against ethanol was antagonized by l-NNA (5–40 mg kg−1) in a dose-dependent manner. Pretreatment of rats with indomethacin (10 mg kg−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.