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.


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 mumol/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 pKB values of 9.2-9.5) for this antagonist were similar in normal and overactive detrusor muscle.


CONCLUSIONS
These results indicate that 5-HT4 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.
Chapple
C R
CR
Department of Urology, Royal Hallamshire Hospital, Sheffield, UK. c.r.chapple@sheffield.ac.uk
Radley
S C
SC
Martin
S W
SW
Sellers
D J
DJ
Chess-Williams
R
R
D000328:Adult; D020117:Cisapride / Q000494:pharmacology; D004558:Electric Stimulation; D006801:Humans; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation; D001745:Urinary Bladder Diseases / Q000503:physiopathology; D001750:Urinary Bladder, Neurogenic / Q000503:physiopathology
D010880:Piperidines; C485189:RS100235; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D011407:Propane; D020117:Cisapride