Motilin and the motilin receptor agonist erythromycin, act pre-junctionally to facilitate cholinergically-mediated contractions of rabbit isolated gastric antrum (Van Assche et al., 1997; Dass et al., 2003; Depoortere et al., 2003); this activity is consistent with an ability to increase gastric emptying. Agonists at the 5-HT₄ receptor (metoclopramide, tegaserod) also increase gastric emptying and although acting as partial agonists at the receptor, behave as full agonists in terms of the ability to facilitate cholinergically-mediated contractions in stomach preparations from several species (see Sanger, 1998). We have now compared the actions of agonists at the two receptors in the same preparation, the rabbit gastric antrum.Methods: Circular muscle sections from rabbit gastric antrum were suspended between 2 platinum ring electrodes in Krebs solution (5% CO₂/ 95% O₂; pH 7.4; 37^oC) under 10 mN tension for isometric recording (Dass et al., 2003). Contractions were evoked by electrical field stimulation (EFS; ±50 V, 0.5 ms) applied for 30 s at 1 min intervals for 30 min. The frequency of EFS was the minimum which evoked clear muscle contractions (1-10 Hz), to optimise an ability of drugs to facilitate contraction amplitudes. Contractions were prevented by tetrodotoxin 1 µM (n=4) and reduced by atropine 1 µM (n=4). The effects of [Nle¹³]-motilin and metoclopramide were determined using single concentrations applied to each tissue for 5 min. Other agents were applied cumulatively at 8 min intervals.

Results: [Nle¹³]-Motilin 0.1 nM - 3 µM concentration-dependently increased the amplitude of EFS-evoked contractions (pEC₅₀ 8.1 ± 0.4, n=3-5), the response fading rapidly during the contact period; the maximum potentiation (E_max) was 2305 ± 821%, at 0.1 µM. Erythromycin 0.3-100 µM also increased EFS-evoked contractions (pEC₅₀ 5.4 ± 0.13, n=6; E_max = 1878 ± 316 % at 10 µM), but in contrast to [Nle¹³]-motilin, this effect did not fade during the contact period at all but the highest concentration. At high concentrations, both [Nle¹³]-motilin and erythromycin caused a short-lived increase in muscle tension. Metoclopramide 1 nM - 100 µM and tegaserod 0.1 nM - 1.0 µM each increased EFS-evoked contractions (respectively, pEC₅₀ 5.51 ± 0.49, n=5 and 8.6 ± 1.0, n=2-6) in a sustained manner, E_max = 434 ± 149 % (10-100 µM) and 69 ± 38 % (1 µM), respectively. No increase in muscle tension was observed in the presence of either of these agonists at any of the concentrations used.

Conclusions: Compared with agonists at the 5-HT₄ receptor, motilin receptor agonists evoked marked gastric prokinetic-like activity which, at the highest concentrations are likely to aggressively evoke gastric emptying. The small response to tegaserod may reflect low intrinsic activity or a more selective action at the 5-HT₄ receptor, relative to metoclopramide.

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Sanger, G.J (1998). In: 5-HT4 Receptors in the Brain and Periphery. Ed., Eglen, R.M., Springer-Verlag, pp 213-226.
Van Assche, G., et al., (1997). Eur. J. Pharmacol., 337, 267-274.