s22ab_3

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

I.A. Tavares, F. Borrelli, N.J. Welsh¹

Academic Department of Surgery and Analytical Pharmacology¹, Guy's, Kings' and St. Thomas' School of Medicine, King's College, London, UK.

ABSTRACT
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; a, 0.64 ± 0.05) was inhibited by famotidine, and also by nimesulide (log r = 0.79 ± 0.10 at 30 mM). 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 mM). 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.

Key words
Nimesulide, COX-2, gastric acid, NSAID.

Please address correspondence to: I.A. Tavares, PhD, Academic Department of Surgery, GKT School of Medicine, King's College, The Rayne Institute, 123 Coldharbour Lane, London SE5 9NU, UK.
E-mail: ignatius.tavares@kcl.ac.uk