Piboserod (SB 207266), a selective 5-HT₄ receptor antagonist, reduces serotonin potentiation of neurally-mediated contractile responses of human detrusor muscle

Abstract

The aim of this study is to evaluate the potency of piboserod (SB 207266), a selective 5-HT₄ receptor antagonist, at inhibiting the 5-HT₄-mediated potentiating effect of serotonin (5-HT) on the neurally-mediated contractile responses of human detrusor strips to electrical field stimulations (EFS). Strips of human detrusor muscle were mounted in Krebs-HEPES buffer under a resting tension of 500 mg and EFS (20 Hz, 1 ms duration at 300 mA for 5 s) was applied continuously at 1 min intervals. After stabilization of the EFS-induced contractions, concentration-response curves to 5-HT (0.1 nM–100 μM) were constructed in the absence or presence of 1 or 100 nM of piboserod. The experiments were performed in the presence of methysergide (1 μM) and ondansetron (3 μM) to block 5HT₁/5HT₂ and 5-HT₃ receptors, respectively. 5-HT potentiated the contractile responses to EFS of human bladder strips in a concentration-dependent manner, with a maximum mean of 60.0±19.9% of the basal EFS-evoked contractions. Piboserod did not modify the basal contractions but concentration-dependently antagonized the ability of 5-HT to enhance bladder strip contractions to EFS. In presence of 1 and 100 nM of piboserod, the maximal 5-HT-induced potentiations were reduced to 45.0±7.9 and 38.7±8.7%, respectively. A mean apparent antagonist dissociation constant value (K_B) of 0.56±0.09 nM was determined. These data show the ability of piboserod to antagonize with high potency the enhancing properties of 5-HT on neurally-mediated contractions of isolated human bladder strips. Therefore, the 5-HT₄ receptor might represent an attractive pharmacological target for the treatment of overactive bladder.