Inhibition of gastric acid secretion by nimesulide: a possible factor in its gastric tolerability.

OBJECTIVE To study the effect of nimesulide on acid secretion in mouse isolated stomach. METHODS Isolated lumen-perfused mouse stomachs were monitored by pH-electrodes (1). Gastric acid secretion was stimulated with histamine or 5-methylfurmethide (5-MeF, a stable acetylcholine derivative), and the effect of nimesulide and indomethacin were studied alone and in combination with famotidine. RESULTS The concentration-dependent stimulation of gastric acid output by histamine (Hill equation fitting parameters: log[A]50 5.44 +/- 0.15; p, 1.01 +/- 0.11; alpha, 0.64 +/- 0.05) was inhibited by famotidine, and also by nimesulide (log r = 0.79 +/- 0.10 at 30 microM). However, nimesulide also reduced the maximum acid output. The shift produced by nimesulide and famotidine in combination indicated a greater than additive effect, suggesting that nimesulide was not acting at histamine H2-receptors (Shankley et al., 1988) (2). Indomethacin reduced acid secretion only at the highest concentration (100 microM). Furthermore, the histamine-receptor-independent stimulation of gastric acid output by 5-MeF was greatly inhibited by nimesulide, which also suggests that nimesulide was acting on the parietal cell signaling pathway at a non-histamine-receptor site. CONCLUSION The relatively low risk of gastric mucosal damage with nimesulide is thought to involve its weak inhibition of gastric prostaglandin synthesis and its weak acidity, but another factor might be the ability to reduce gastric acid production. However, the effect of nimesulide on human gastric acid secretion remains to be investigated.