Abstract
This study evaluated the effects of a 5-HT4 agonist, cisapride, on neuronally evoked smooth muscle responses in bladder, urethra
and ileum and compared these effects with those of an acetylcholinesterase inhibitor,
distigmine.
Electrical field stimulation (EFS) was applied to human bladder and ileum smooth muscle
strips from human organ transplant donors and to urethral strips from prostatectomy
patients, to evoke neuronally mediated smooth muscle responses.
EFS induced contractions in bladder and mixed responses, consisting of contractions
and relaxations, in urethra and ileum. Relaxations were mediated by nitric oxide while
contractions were partially cholinergic (i.e. atropine sensitive). This atropine sensitive
component amounted to ~ 95% in bladder and ~75% in ileum, and it was enhanced by distigmine in a concentration dependent manner
(0.1–3 μM; ~100–600% increase in bladder and ~50–250% increase in ileum). Cisapride (0.0003–1 μM) also enhanced bladder contractions (~75–100% increase) but had no effect on urethral contractions or relaxations, and modestly
enhanced ileum contractions (~10–40% increase). Facilitatory effects of cisapride were reversed by the specific
5-HT4 receptor antagonist, SB-203186 (3 μM), but were resistant to repeated washing in the bladder.
These data indicate that 5-HT4 receptor agonists enhanced EFS-induced contractions in bladder and ileum without
an effect on urethra and suggest that it may be possible to enhance bladder activity
with a dose of cisapride that is at, or below, those producing gastrointestinal (GI)
effects. Although distigmine's maximal facilitation of bladder and GI tract function
was greater than that of cisapride, at clinically relevant concentrations cisapride
showed much greater efficacy.
Abbreviations:
GI (gastrointestinal), ACh (acetylcholine), LUT (lower urinary tract), NO (nitric oxide), TXA(2) (thromboxane A2)Keywords
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Article info
Publication history
Published online: March 18, 2013
Accepted:
February 19,
2013
Received in revised form:
December 12,
2012
Received:
August 16,
2012
Identification
Copyright
© 2013 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
