Differences between the abilities of tegaserod and motilin receptor agonists to stimulate gastric motility in vitro

Background and purpose: Motilin or 5-HT4 receptor agonists stimulate gastrointestinal motility. Differences in activity are suggested but direct comparisons are few. A method was devised to directly compare the gastric prokinetic activities of motilin, the motilin receptor agonist, erythromycin, and the 5-HT4 receptor agonist, tegaserod. Experimental approach: Gastric prokinetic-like activity was assessed by measuring the ability to facilitate cholinergically-mediated contractions evoked by electrical field stimulation (EFS) in rabbit isolated stomach. Comparisons were made between potency, maximal activity and duration of responses. Key results: Rabbit motilin (r.motilin) 0.003-0.3 mu M, [Nle(13)] motilin 0.003-0.3 mu M, erythromycin 0.3-10 mu M and tegaserod 0.1-10 mu M caused concentration-dependent potentiation of EFS-evoked contractions. The potency ranking was r.motilin [Nle(13)] motilin > tegaserod > erythromycin. The E-max ranking was r.motilin = [Nle(13)] motilin = erythromycin > tegaserod. Responses to r.motilin and [Nle(13)] motilin faded rapidly (t(1/2) 9 and 11 min, respectively) whereas those to erythromycin and tegaserod were maintained longer (t(1/2) 24 and 28 min). The difference did not appear to be due to peptide degradation. A second application of [Nle(13)] motilin was excitatory after 60 min contact and fade of the initial response (responses to 0.03 and 0.1 mu M [Nle(13)] 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 E-max of motilin, compared with tegaserod) and for the first time, within each class ( short t(1/2) for motilin, compared with erythromycin).