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 microM) 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 microM) and ondansetron (5 microM), 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 microM) and RS 23597-190 (1 microM), 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.