Serotonin-induced potentiation of cholinergic responses to electrical field stimulation in normal and neurogenic overactive human detrusor muscle

OBJECTIVE: To compare the serotonin (5-HT)₄-receptor-mediated effects of 5-HT on the potentiation of cholinergic responses to electrical-field stimulation (EFS) in isolated strips of detrusor muscle from patients with normal or neurogenic overactive bladders. MATERIAL AND METHODS: Strips of detrusor muscle were field-stimulated (10 Hz, 0.01 ms duration, 60 V for 5 s) at 100-s intervals until consistent responses were obtained. In the presence of methiothepin, ketanserin and ondansetron (all 1 μmol/L) to block 5-HT₁, 5-HT₂ and 5-HT₃ receptors, respectively, the cumulative administration of 5-HT or the selective 5-HT₄ agonist cisapride, produced concentration-dependent enhancement of responses to EFS in both types of tissue. RESULTS: The maximum potentiation induced by 5-HT in neurogenic overactive detrusor muscle was reduced (P < 0.05) by about half compared to normal detrusor muscle, but EC₅₀ values obtained in normal and overactive tissue were not significantly different. Cisapride was less potent than 5-HT and acted as a partial agonist relative to 5-HT. The selective 5-HT₄ receptor antagonist RS-100235 was a potent antagonist of the 5-HT-induced potentiation of responses to EFS. At 3 nmol/L RS-100235 antagonized the effects of 5-HT in both groups of tissues without affecting the maximum responses. The affinity estimates (apparent pK _B values of 9.2-9.5) for this antagonist were similar in normal and overactive detrusor muscle. CONCLUSIONS: These results indicate that 5-HT ₄ receptor-mediated potentiation of field-stimulated responses is lower in the neurogenic overactive detrusor muscle than in normal tissue. 5-HT₄ receptor antagonist affinity is unchanged in the neurogenic overactive bladder.