Effects of cholera toxin on the potential difference and motor responses induced by distension in the rat proximal small intestine in vivo.
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-Phe(6),Leu(17)]VIP (2 mug.min(-1).kg(-1) iv) but unaffected by the serotonin 5-HT(3) 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-Phe(6),Leu(17)]VIP but not by hexamethonium or atropine. In contrast, once the increased basal PD produced by CT was established, [4Cl-d-Phe(6),Leu(17)]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-HT(3) receptors, VIP receptors, and prostaglandin synthesis, whereas its maintenance depends on 5-HT(3) and nicotinic receptors but not VIP receptors. The motility effects of CT (probably reflecting myenteric activity) are partially suppressed via a mechanism involving 5-HT(3) and muscarinic receptors and prostaglandin synthesis.
Kordasti
Shirin
S
Dept. of Internal Medicine, Med pol 2, Sahlgren's University Hospital, University of Göteborg, S-413 45 Göteborg, Sweden.
Sapnara
Maria
M
Thomas
Evan A
EA
Lindstrom
Erik
E
Forsman
Mikael
M
Bornstein
Joel C
JC
Sjövall
Henrik
H
D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology*; D019054:Evoked Potentials, Motor / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007421:Intestine, Small / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology; D018005:Receptors, Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors; D013997:Time Factors
D018727:Muscarinic Antagonists; D011453:Prostaglandins; D011976:Receptors, Muscarinic; D044406:Receptors, Serotonin, 5-HT3; D018005:Receptors, Vasoactive Intestinal Peptide; D002772:Cholera Toxin