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Differences between the abilities of tegaserod and motilin receptor agonists to stimulate gastric motility in vitro
Author(s) -
Jarvie E M,
North Laidler V J,
Corcoran S,
Bassil A,
Sanger G J
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707118
Subject(s) - motilin , tegaserod , agonist , pharmacology , medicine , clobazam , prokinetic agent , chemistry , partial agonist , endocrinology , receptor , biology , constipation , neuroscience , epilepsy
Background and purpose: Motilin or 5‐HT 4 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‐HT 4 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) 0.003–0.3μM, [Nle 13 ]motilin 0.003–0.3μM, erythromycin 0.3–10μM and tegaserod 0.1–10μM 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 0.1μM [Nle 13 ]motilin were not different from those caused by the first application). Conclusions and implications: Prokinetic‐like activities of the 5‐HT 4 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). British Journal of Pharmacology (2007) 150 , 455–462. doi: 10.1038/sj.bjp.0707118