title: Effects of the 5-HT4 receptor agonist, cisapride, on neuronally evoked responses in human bladder, urethra, and ileum.
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.
authors.affiliation: Urogenix Inc./Astellas 801 Capitola Dr., Durham, NC, USA. aura240@yahoo.com
authors.forename: F Aura
authors.initials: FA
authors.lastname: Kullmann
authors.forename: Ryoko
authors.initials: R
authors.lastname: Kurihara
authors.forename: Lan
authors.initials: L
authors.lastname: Ye
authors.forename: Grace I
authors.initials: GI
authors.lastname: Wells
authors.forename: David G
authors.initials: DG
authors.lastname: McKenna
authors.forename: Edward C
authors.initials: EC
authors.lastname: Burgard
authors.forename: Karl B
authors.initials: KB
authors.lastname: Thor
mesh_terms: D000328:Adult; D000368:Aged; D020117:Cisapride / Q000494:pharmacology*; D004558:Electric Stimulation / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology*; D014521:Urethra / Q000187:drug effects / Q000502:physiology*; D001743:Urinary Bladder
chemical_list: D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D020117:Cisapride