The sigma ligand, igmesine, inhibits cholera toxin and Escherichia coli enterotoxin induced jejunal secretion in the rat

Abstract

Background: Cholera toxin, and Escherichia coli heat labile (LT) and heat stable (STa) enterotoxins induce small intestinal secretion in part by activating enteric nerves. Igmesine is a novel sigma receptor ligand that inhibits neurally mediated secretion.

Aims: To assess the antisecretory potential of igmesine in cholera toxin, LT, and STa induced water and electrolyte secretion using an in vivo rat model of jejunal perfusion.

Methods: After pretreatment with igmesine, 0.03-10 mg/kg intravenously, jejunal segments of anaesthetised, adult male Wistar rats were incubated with cholera toxin (25 microg), LT (25 microg), or saline. Jejunal perfusion with a plasma electrolyte solution containing a non-absorbable marker was undertaken. In some cases 200 microg/l STa was added to the perfusate. After equilibration, net water and electrolyte movement was determined. In additional experiments rats received igmesine, intravenously or intrajejunally, after exposure to cholera toxin.

Results: Cholera toxin induced net water secretion was inhibited by 1 mg/kg igmesine (median -120 versus -31 microl/min/g, p<0.001). LT and STa induced secretion were also inhibited by 1 mg/kg igmesine (-90 versus -56, p<0.03; and -76 versus -29, p<0.01, respectively). Igmesine reduced established cholera toxin induced secretion.

Conclusion: The sigma ligand, igmesine, inhibits neurally mediated enterotoxigenic secretion. Its ability to inhibit established secretion makes it an agent with therapeutic potential.

Figure 1

Effect of pretreatment with igmesine on cholera toxin (CT) induced jejunal net water secretion. Data expressed as median and interquartile range. *p<0.04 compared with CT; †p<0.02 compared with CT + 0.03 mg/kg igmesine (Kruskal-Wallis).

Figure 2

Effect of igmesine (1 mg/kg intravenously) on established cholera toxin induced jejunal net water secretion. Net water secretion in individual rats (n=12) is represented at 45 minutes (pre-igmesine) and at 75 minutes (post-igmesine). p<0.04 compared with cholera toxin alone (Mann-Whitney test).

Figure 3

Effect of the addition of igmesine (40 µg/ml) to the perfusate, on established cholera toxin induced jejunal net water secretion. Net water secretion in individual rats (n=8) is represented on equilibration at 45 minutes and after receiving 6 mg/kg igmesine, intrajejunally, at 75 minutes. p<0.002 compared with cholera toxin perfused with standard plasma electrolyte solution (Mann-Whitney test).

Figure 4

Effect of pretreatment with igmesine (1 mg/kg intravenously) on heat labile (LT) and heat stable (STa) enterotoxin induced jejunal net water secretion. Data expressed as median and interquartile range. †p<0.03 compared with LT; **p<0.01 compared with STa (Mann-Whitney test).