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5‐hydroxyindalpine, an agonist at the putative 5‐HT 1P receptor, has no activity on human recombinant monoamine receptors but accelerates distension‐induced peristalsis in mouse isolated colon
Author(s) -
Mitchell N. A.,
Pepperell E.,
Ociepka S.,
Brown J. D.,
Witherington J.,
Tuladhar B.,
Sanger G. J.,
Lee K.,
Cellek S.
Publication year - 2009
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/j.1365-2982.2009.01275.x
Subject(s) - peristalsis , agonist , receptor , medicine , endocrinology , distension , 5 ht receptor , chemistry , receptor antagonist , serotonin , antagonist , biology
Although the putative 5‐HT 1P receptor has been implicated to have a role in peristalsis, experiments which suggest this function are preliminary or have measured only components of the reflex. We have, therefore, further characterized a reported agonist at this receptor (5‐hydroxyindalpine; 5‐OHIP) and investigated the effects of 5‐OHIP and 5‐hydroxytrytophan‐dipeptide (5‐HTP‐DP), a reported 5‐HT 1P receptor antagonist, on distension‐induced peristalsis in mouse colon. The effects of 5‐OHIP on intracellular calcium, cyclic adenosine monophosphate concentrations or GTPγS binding were measured in cell lines expressing human recombinant 5‐HT 1A, 1B, 1D, 2A, 2B, 2C, 3, 4, 6, 7 and α 1A , α 1B , D 1 , D 2 , D 3 , H 1 , H 3 receptors. The effects of 5‐OHIP and 5‐HTP‐DP on peristalsis were assessed by measuring changes in frequency and times to reach threshold of peristaltic contractions, as well as the threshold and maximum pressures of each peristaltic stroke. 5‐hydroxyindalpine (1 nmol L −1 –10 μ mol L −1 ) had no significant activity at any of the receptors studied. However, 5‐OHIP (0.1 nmol L −1 –1 μ mol L −1 ) concentration‐dependently increased the frequency of peristalsis (EC 50 = 4.4 nmol L −1 ) and reduced the time taken to reach threshold and threshold pressure, without altering maximum pressures. The maximum effect of 5‐OHIP was at 1 μ mol L −1 (68.0 ± 14.5% increase in frequency); 10 μ mol L −1 decreased peristalsis. 5‐hydroxytrytophan‐dipeptide (1–300 nmol L −1 ) also increased the frequency of peristalsis and prevented the actions of 5‐OHIP. The higher concentration (1 μ mol L −1 ) transiently inhibited peristalsis and after recovery, prevented the actions of 5‐OHIP but not the excitatory activity of the cholinesterase inhibitor neostigmine. In summary, the present data demonstrate an interaction of ‘5‐HT 1P ‐ligands’ with the peristaltic reflex. However, the absence of an effect of 5‐OHIP on a range of different monoamine receptors continues to highlight the need to investigate the identity of the putative 5‐HT 1P receptor.