Pharmacological analysis of components of the change in transmural potential difference evoked by distension of rat proximal small intestine in vivo.
The reflex response to distension of the small intestine in vivo is complex and not well understood. The aim of this study was to characterize the neural mechanisms contributing to the complex time course of the intestinal secretory response to distension. Transmucosal potential difference (PD) was used as a marker for mucosal chloride secretion, which reflects the activity of the secretomotor neurons. Graded distensions (5, 10, and 20 mmHg) of distal rat duodenum with saline for 5 min induced a biphasic PD response with an initial peak (rapid response) followed by a plateau (sustained response). The rapid response was significantly reduced by the neural blockers tetrodotoxin and lidocaine (given serosally) and by intravenous (iv) administration of the ganglionic blocker hexamethonium and the NK(1) receptor antagonist SR-140333. Serosal TTX and iv SR-140333 significantly reduced the sustained response, which was also reduced by the NK(3) receptor antagonist talnetant and by the vasoactive intestinal polypeptide (VPAC) receptor antagonist [4Cl-d-Phe(6), Leu(17)]-VIP. Serosal lidocaine and iv hexamethonium had no significant effect on this component. Inhibition of nitric oxide synthase had no effect on any of the components of the PD response to distension. The PD response to distension thus seems to consist of two components, a rapidly activating and adapting component operating via nicotinic transmission and NK(1) receptors, and a slow component operating via VIP-ergic transmission and involving both NK(1) and NK(3) receptors.
Larsson
Marie H
MH
Department of Integrative Pharmacology, AstraZeneca R & D, Mölndal S-431 83, Sweden. marie.h.larsson@astrazeneca.com
Sapnara
Maria
M
Thomas
Evan A
EA
Bornstein
Joel C
JC
Lindström
Erik
E
Svensson
David J
DJ
Sjövall
Henrik
H
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D004386:Duodenum / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005730:Ganglionic Blockers / Q000494:pharmacology; D017829:Granisetron / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D007275:Injections, Intravenous; D007419:Intestinal Secretions / Q000187:drug effects*; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018727:Muscarinic Antagonists / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D018373:Peripheral Nervous System Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011312:Pressure; D011804:Quinolines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D018005:Receptors, Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D000779:Anesthetics, Local; D001285:Atropine; D002712:Chlorides; D004791:Enzyme Inhibitors; D005730:Ganglionic Blockers; D017829:Granisetron; D018738:Hexamethonium; D006727:Hormone Antagonists; D008012:Lidocaine; D018727:Muscarinic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D018373:Peripheral Nervous System Agents; D010880:Piperidines; D011804:Quinolines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3; D044406:Receptors, Serotonin, 5-HT3; D018005:Receptors, Vasoactive Intestinal Peptide; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D013779:Tetrodotoxin; D014660:Vasoactive Intestinal Peptide; C048507:vasoactive intestinal peptide, 4-chloro-Phe(6)-Leu(17)-; C085215:SR 140333; C106716:SB 223412