Regional differences in neurogenic signal transduction pathway of cholera toxin-induced fluid, electrolyte and serotonin accumulation in the porcine jejunum

Serotonin, acetylcholine and substance P are mediators involved in the secr etory response to cholera toxin in the small intestine. The aim of this stu dy was to investigate the regional difference in the effect of a serotonin receptor type 3 antagonist (ondansetron), a nicotinic receptor antagonist ( hexamethonium), and a substance P antagonist (the neurokinin receptor type 1 antagonist, CP 99,994) on the cholera toxin-induced fluid accumulation in the porcine jejunum. A dose-range of cholera toxin (0.32-56.00 mu g/loop) was instilled for 4 hr in ligated loops in two regions of the proximal jeju num in 6-8-week-old pigs. Ondansetron (200 mu g/kg), hexamethonium (10 mg/k g), CP 99,994 (1 mg/kg), or saline alone (control) were given intravenously 10 min, before cholera toxin instillation. Cardiovascular parameters, bloo d gas data, net fluid accumulation, serotonin and electrolyte concentration in the accumulated fluid were measured. Cardiovascular and blood gas param eters were within the normal range in all treatments. The apparent maximal response in fluid accumulation was reduced 20% in case of ondansetron, and by 33% using CP 99,994 in the aboral region compared to control, whereas no effect was observed in the oral region. Hexamethonium reduced the apparent maximal secretory response in both the oral and aboral regions by 45%. Non e of the treatments with antagonists changed the luminal content of seroton in or the electrolyte concentrations in the accumulated fluid. The results demonstrate that the involvement of serotonin receptor type 3 and neurokini n type 1 receptors in the transductional pathway of cholera toxin-induced f luid accumulation vary significantly within the jejunum, while the choliner gic (nicotinic) transmission plays an even role.