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© Copyright 2004 The British Pharmacological Society

100P University of Newcastle
Winter Meeting December 2004

Species differences in oesophageal muscle responses to acetylcholine: implications for emetic control

Liu Y-L, Nicholson R.J, Hoyle C.H.V, Andrews P.L.R and Sanger G.J. GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW.

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Liu YL
Nicholson RJ
Hoyle CVH
Andrews PLR
Sanger GJ

In certain species, anatomical constraints in the upper gut are consistent with their inability to vomit (eg. Andrews et al., 2003). We have looked for functional differences which are also consistent with the presence or absence of an emetic reflex, by comparing responses to ACh, the major vagal excitatory neurotransmitter, in the isolated oesophagus and lower oesophageal sphincter of male Wistar rat (220-250g), adult male C57 BLK/6J mice (no emetic reflex) and male adult Suncusmurinus (emetic reflex).

Sections of abdominal (gastro-oesophageal junction to diaphragm) and infra-cardiac thoracic (above diaphragm) oesophagus, ~3-4 mm long, and lower oesophageal sphincter were suspended in Krebs solution (0.5 g load; 5 % CO2 in O2; 37°C) for isometric recording. Non-cumulative concentration-response curves were obtained for ACh (10 min cycle time). In other experiments, responses to ACh 10-6 M were examined after 10 min incubation firstly with atropine 10-3 M and then with atropine plus pancuronium 10-6 M. Peak contraction amplitudes were measured during the first 30s after ACh and at 30, 60 and 90 s after application. Results are expressed as g tension/ g wet weight of tissue. Paired data were analysed using t-test; One-way ANOVA followed by Dunnett’s test was used for multiple comparisons.

In all species and regions, ACh 10-6-10-2M evoked concentration-dependent contractions. Compared to rat and mouse, the thoracic oesophagus of Suncus generated a significantly greater rise in muscle tension in response to ACh (eg. respectively, 177.5 ± 6.6, 43.4 ± 7.16 and 40.1 ± 12.3 g /g wet weight during the first 30 s after ACh 10-2 M). In abdominal and thoracic oesophageal preparations of rat and mouse, ACh rapidly evoked contractions which partially and rapidly faded to sustained smaller contractions; in Suncus, the evoked contractions were monophasic and maintained. The latter were substantially reduced by atropine (eg. by 91 and 88 % respectively during the first 30 s in abdominal and thoracic oesophagus) whereas in the rat and mouse, the first component of the response to ACh (10-3 M) was unaffected by atropine but significantly reduced by atropine plus pancuronium (eg. 71 and 65 % reduction for rat, 50 and 60 % for mouse abdominal and thoracic oesophagus, respectively). In the rodent species, the second, more sustained phase of the contractions to ACh were greatly reduced (rat; eg. by 58 and 78 % at 30 s for abdominal and thoracic oesophagus) or abolished (mouse) by atropine alone. In the lower oesophageal sphincter of all species, the contractions to ACh (10-3 M) were greatly reduced or abolished by atropine; pancuronium had no additional effects.

ACh-induced contractions of the oesophagus of Suncus may be mediated predominantly by smooth muscle muscarinic receptors, whereas both striated and smooth muscles contribute to biphasic contractions in rat and mouse, involving nicotinic and muscarinic receptors. The ability of the thoracic oesophagus of Suncus to generate greater tension in response to ACh suggests that substantial shortening of the oesophagus plays an important role in reducing the length of the abdominal oesophagus during vomiting, and that the necessity for this function is reduced in non-emetic animals. Our data provides evidence for functional differences in the oesophagus between emetic and non-emetic species.

Andrews, P.L.R et al (2003) Neurogastroenterol Motil, 15, 25.