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NEUROREGULATION AND MOTILITY

Effects of cholera toxin on the potential difference and motor responses induced by distension in the rat proximal small intestine in vivo

¹Department of Physiology, Sahlgren's Academy, University of Göteborg, Göteborg, Sweden; ²Department of Physiology, University of Melbourne, Parkville, Australia; ³Astra-Zeneca Research and Development, Mölndal, Sweden; and ⁴Department of Human Factors Engineering, Chalmers University of Technology, and ⁵Department of Internal Medicine, Sahlgren's Academy, University of Göteborg, Göteborg, Sweden

Submitted 9 June 2005 ; accepted in final form 10 December 2005

Cholera toxin (CT) may induce uncontrolled firing in recurrent networks of secretomotor neurons in the submucous plexus. This hypothesis was tested in chloralose-anesthetized rats in vivo. The secretory reflex response to graded intestinal distension was measured with or without prior exposure to luminal CT. The transmural potential difference (PD) was used as a marker for electrogenic chloride secretion. In controls, distension increased PD, and this response was reduced by the neural blocker tetrodotoxin given serosally and the vasoactive intestinal peptide (VIP) receptor antagonist [4Cl-D-Phe⁶,Leu¹⁷]VIP (2 µg·min^–1·kg^–1 iv) but unaffected by the serotonin 5-HT₃ receptor antagonist granisetron, by the nicotinic receptor antagonist hexamethonium, by the muscarinic receptor antagonist atropine, or by the cyclooxygenase inhibitor indomethacin. Basal PD increased significantly with time in CT-exposed segments, an effect blocked by granisetron, by indomethacin, and by [4Cl-D-Phe⁶,Leu¹⁷]VIP but not by hexamethonium or atropine. In contrast, once the increased basal PD produced by CT was established, [4Cl-D-Phe⁶,Leu¹⁷]VIP and indomethacin had no significant effect, whereas granisetron and hexamethonium markedly depressed basal PD. CT significantly reduced the increase in PD produced by distension, an effect reversed by granisetron, indomethacin, and atropine. CT also activated a specific motility response to distension, repeated cluster contractions, but only in animals pretreated with granisetron, indomethacin, or atropine. These data are compatible with the hypothesis that CT induces uncontrolled activity in submucous secretory networks. Development of this state depends on 5-HT₃ receptors, VIP receptors, and prostaglandin synthesis, whereas its maintenance depends on 5-HT₃ and nicotinic receptors but not VIP receptors. The motility effects of CT (probably reflecting myenteric activity) are partially suppressed via a mechanism involving 5-HT₃ and muscarinic receptors and prostaglandin synthesis.

enteric nervous system; vasoactive intestinal peptide

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