Evidence for an inhibitory 5‐HT4 receptor in urinary bladder of Rhesus and Cynomolgus monkeys

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‐HT4 receptors. 2 5‐HT (0.1 nM‐10 μm) produced concentration‐dependent inhibition of the contractile response to electrical stimulation yielding a pEC50 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 (pEC50 = 6.5) in Cynomolgus monkey was low, relative to 5‐HT, indicating a possible heterogeneity of 5‐HT4 receptors. 3 The inhibitory action of 5‐HT was resistant to antagonism by methysergide (1 μm) and ondansetron (5 μm), thereby eliminating a role for 5‐HT1, 5‐HT2 and 5‐HT3 receptors. The 5‐HT4 receptor antagonists, GR 113808 (10 nM), DAU 6285 (1–10 μm) and RS 23597–190 (1 μm), 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‐HT4 receptor assay systems. 4 Experiments using direct electrical stimulation of bladder smooth muscle indicate that the 5‐HT4 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.