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Evidence for an inhibitory 5‐HT 4 receptor in urinary bladder of Rhesus and Cynomolgus monkeys
Author(s) -
Waikar Manoj V.,
Ford Anthony P.D.W.,
Clarke David E.
Publication year - 1994
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 - 10.1111/j.1476-5381.1994.tb14046.x
Subject(s) - methysergide , receptor , stimulation , agonist , 5 ht receptor , inhibitory postsynaptic potential , 5 ht4 receptor , serotonin , medicine , endocrinology , urinary bladder , biology , chemistry
1 The present study shows that 5‐hydroxytryptamine (5‐HT) inhibits electrically‐evoked contractions of isolated urinary bladder strips from Rhesus and Cynomolgus monkeys via activation of 5‐HT 4 receptors. 2 5‐HT (0.1 nM‐10 μ m ) produced concentration‐dependent inhibition of the contractile response to electrical stimulation yielding a pEC 50 of 7.8 ( Rhesus monkey) and 7.6 ( Cynomolgus monkey). This action of 5‐HT was mimicked by 5‐methoxytryptamine, renzapride and BIMU 8, each of which behaved as a full agonist relative to 5‐HT. However, the potency estimate for BIMU 8 (pEC 50 = 6.5) in Cynomolgus monkey was low, relative to 5‐HT, indicating a possible heterogeneity of 5‐HT 4 receptors. 3 The inhibitory action of 5‐HT was resistant to antagonism by methysergide (1 μ m ) and ondansetron (5 μ m ), thereby eliminating a role for 5‐HT 1 , 5‐HT 2 and 5‐HT 3 receptors. The 5‐HT 4 receptor antagonists, GR 113808 (10 nM), DAU 6285 (1–10 μ m ) and RS 23597–190 (1 μ m ), produced parallel, dextral displacements of the concentration‐effect curves to 5‐HT and other related agonists with affinity estimates in agreement with those defined previously in other 5‐HT 4 receptor assay systems. 4 Experiments using direct electrical stimulation of bladder smooth muscle indicate that the 5‐HT 4 receptors are located post‐junctionally. 5 The inhibitory action of 5‐HT in isolated urinary bladder of monkey differs from the excitatory effect of 5‐HT in urinary bladder of man. Species variation and its implications for the development of therapeutic agents are discussed.