A second application of [Nle13]motilin was excitatory after 60 min contact and fade of the initial response (responses to 0

A second application of [Nle13]motilin was excitatory after 60 min contact and fade of the initial response (responses to 0.03 and 0.1M [Nle13]motilin were not different from those caused by the first application). Conclusions and implications: Prokinetic-like activities of the 5-HT4 agonist tegaserod and the motilin receptor agonists were compared by measuring changes in cholinergically-mediated contractions. min, respectively) whereas those to erythromycin and tegaserod were maintained longer (t1/2 24 and 28 min). The difference did not appear to be due to peptide degradation. A second application of [Nle13]motilin was excitatory after 60 min contact and fade of the initial Rabbit Polyclonal to Cytochrome P450 26C1 response (responses to 0.03 and 0.1M [Nle13]motilin were not different from those caused by the first application). Conclusions and implications: Prokinetic-like activities of the 5-HT4 agonist tegaserod and the motilin receptor agonists were compared by measuring changes in cholinergically-mediated contractions. This novel approach highlighted important differences between classes (greater Emax of motilin, compared with tegaserod) and for the first time, within each class (short t1/2 for motilin, compared with erythromycin). tension and allowed to equilibrate for at least 45?min during which time bath solutions were changed every 15?min. During this time, muscle tension stabilized at 1?but less than 1?(n) (M)(n) (M)p(M)may decline with repeated dosing, the literature to support this idea is not clear and indeed, the duration of the response to erythromycin may depend around the dose used. Studies that suggest a possible reduction in the therapeutic benefit of erythromycin after long-term dosing used doses of 250C400?mg, four times a day (Richards em et al /em ., 1993). However, Dhir and Richter (2004) investigated the effects of a LY2334737 relatively low dose of erythromycin (50C100?mg, three times a day and at bedtime) on symptoms of dyspepsia in patients with gastroparesis, and found a significant correlation between short- and long-term responses to the beneficial effects of this drug. Similarly, LY2334737 symptoms LY2334737 associated with gastroparesis may be improved by repeated intravenous administration of erythromycin, provided the dose was titrated to achieve both efficacy and tolerance in each patient (DiBaise and Quigley, 1999). Finally LY2334737 in a single case report, long-term, low-dose erythromycin (250?mg twice daily for 12 months) was found to be an effective treatment of the vomiting associated with gastric stasis and resistant to cisapride, domperidone and metoclopramide (Hunter em et al /em ., 2005). These long-lasting prokinetic effects of erythromycin may be reflected by the current experiments em in vitro /em , in which the ability of erythromycin to potentiate EFS-evoked contractions faded relatively slowly, compared with motilin. Interestingly, the long-lasting nature of this response to erythromycin contrasts with a short-lasting ability to directly evoke muscle contraction (Dass em et al /em ., 2003), an assay commonly cited within the literature to support a belief that this prokinetic activity of motilin receptor agonists must be short-lasting (e.g., Thielemans em et al /em ., 2005). The reasons for this difference are not comprehended. The use of low concentrations of motilin and erythromycin to activate motilin receptors naturally expressed by neurones within the gut may minimise desensitization of the receptor. Alternatively, if it can be assumed that at all concentrations of all motilin receptor agonists, the receptor is usually desensitized and possibly internalized (e.g., Lamian em et al /em ., 2006), then the long-lasting responses observed may be related to maintain changes evoked within the nerves, downstream from the receptor. Further work is required to resolve this difficult question. In summary, our studies have shown that it is possible to measure and directly compare the prokinetic and desensitization abilities of different motilin receptor agonists and the 5-HT4 receptor agonist, tegaserod, using an assay which reflects the abilities of these agents to increase neuronal activity rather than to contract the muscle directly. This novel approach highlighted marked differences in the maximal activities of tegaserod and the motilin receptor agonists and for the first time, marked differences in the durations of responses to peptide and non-peptide motilin receptor agonists. These data indicate a need for great caution, when using a single agent, to comment on prokinetic drugs in general and especially when judging the potential of motilin receptor agonists as therapeutic drugs. Acknowledgments We thank Martin Chesterman, Jon Bester, Elaine Bowden, Susan Moore, Kim Gerson, Nick Jones and Claire Taylor for providing technical support during the course of this study. Abbreviations EFSelectrical field stimulation em E /em maxmaximally effective responser. motilinrabbit motilin Notes Conflict of interest The authors state no conflict of interest..