Responses of the ferret lower esophageal sphincter to 5-hydroxytryptamine: pathways and receptor subtypes. Blackshaw, L. A., V. Nisyrios, and J. Dent. Gastrointestinal Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, AUSTRALIA
APStracts 2:0010G, 1995.
This study in the urethane anesthetized ferret investigates the effects of 5 -HT on lower esophageal sphincter pressure (LESP), the receptor subtypes that mediate these effects, and the neural pathways which may be involved. Basal LESP was unaffected by the 5-HT3 receptor antagonist granisetron (0.5mg/kg), or by greater splanchnic nerve section (GSX) but increased significantly after bilateral vagotomy. This was independent of the order in which treatments were applied. Repetitive electrical stimulation of the cut peripheral vagal nerve caused rapid LES relaxation, often followed by a brief contraction and a prolonged inhibition of LESP. Close intraarterial injection of 5-hydroxytryptamine (5-HT, 5-100[mu]g) into the celiac axis had a biphasic effect on LESP, with a brief drop in LESP, followed by a prolonged increase. The threshold for response was 5[mu]g, and both phases showed a dose dependence. In the response to 50[mu]g 5-HT, blockade of 5-HT3 receptors with granisetron (0.5mg/kg IV) abolished the initial relaxation, and revealed an earlier peak of excitation. This effect was not influenced by subsequent vagotomy and GSX. In 8 further experiments (series 2), protocol order was changed so that granisetron was administered after vagotomy and GSX. In series 2, 5-HT -induced relaxation was unaffected by vagotomy, but was significantly reduced after GSX, and was further reduced after granisetron, indicating that 5-HT3 receptor mechanisms may lie on a sympathetic neural pathway. Vagotomy had no effect on the excitatory component of the response. GSX had no effect on the amplitude of the excitatory component, but reduced its latency. Granisetron had no further effect on excitation in series 2. In a further 13 experiments (series 3), the excitatory component of the LES response to 5-HT was found to be mediated via a peripheral 5-HT2 receptor mechanism, as this phase was abolished by administration of Ketanserin (2.5mg/kg IV), after which only relaxation could be observed. Administration of both 5-HT2 and 5-HT3 antagonists in combination abolished all effects of 5-HT on LESP. Atropine (400[mu]g/kg IV, n=4) had no effect on the 5-HT-induced LES response. Guanethidine (5mg/kg IV, n=4) had similar effects to GSX on the LES response to 5-HT. In 4 further experiments, the novel 5HT3 receptor antagonist BRL46470 (0.5mg/kg) was given in place of granisetron. Although this compound has been shown to have comparable affinity for the 5HT3 receptor to granisetron in other models, BRL46470 had no effect on 5-HT-induced LES responses in our study. Our data indicate that a specific subtype of 5-HT3 receptor is involved in reduction of LESP by 5-HT, and these effects may be mediated partly via a sympathetic pathway, and partly via an intrinsic pathway. 

Received 25 January 1993; accepted in final form 10 January 1995.
APS Manuscript Number G28-3.
Article publication pending Am. J. Physiol. (Gastrointest. Liver Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 February 1995.