title: Doxazosin and serotonin (5-HT) receptor (1A, 2A, and 4) antagonists inhibit 5-HT-mediated human cavernosal contraction.
abstract: Penile erection results from the balance between relaxation and contractile mechanisms of the corpus cavernosum. Only a few studies suggest a role for endogenous contractile agents such as 5-hydroxytryptamine (5-HT). Our aim was to confirm the possible role of 5-HT in human erection. The effect of 5-HT on human cavernosal tissues, as well as those of doxazosin (shown previously to have 5-HT inhibitory action), ketanserin (5-HT (2A) receptor antagonist), NAN-190 (5-HT (1A) receptor antagonist), and SB 203186 (5-HT (4) receptor antagonist) on 5-HT-mediated effects, were assessed using the organ bath technique, including electrical field stimulation study (EFS). Results are presented as median (mg/mg = mg contraction/mg of tissue). Consistent 5-HT-mediated (10(-3) M) contractions were demonstrated (n = 18; 63 mg/mg). These contractions were inhibited with ketanserin by 90% (n = 8), NAN-190 by 68% (n = 12), and SB 203186 by 55% (n = 12). Doxazosin showed a similar 5-HT inhibitory action in a concentration-dependent manner (10(-4) M; 94% reduction; n = 8, 10(-6) M; 68.3% reduction; n = 8). Our EFS studies indicated the presence of neuronally derived 5-HT and that a majority of the nonnoradrenogenic contraction (54%) was mediated via 5-HT(2A) receptors. These findings suggest that 5-HT may play a role in the human detumescence process via 5-HT(1A), 5-HT(2A), and 5-HT(4) receptors. Neuronally released 5-HT is probably an important contractile neurotransmitter in the erectile process. Doxazosin, ketanserin, and 5-HT(1A) and 5-HT(4) receptor antagonists may be useful as part of combination therapy used to treat erectile dysfunction.
authors.affiliation: Department of Urology, Royal Free Hospital and University College Medical School, University College London, United Kingdom.
authors.forename: David H W
authors.initials: DH
authors.lastname: Lau
authors.forename: Cecil S
authors.initials: CS
authors.lastname: Thompson
authors.forename: James F
authors.initials: JF
authors.lastname: Bellringer
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thomas
authors.forename: Faiz H
authors.initials: FH
authors.lastname: Mumtaz
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morgan
authors.forename: Dimitri P
authors.initials: DP
authors.lastname: Mikhailidis
mesh_terms: D000328:Adult; D001285:Atropine / Q000494:pharmacology; D017292:Doxazosin / Q000494:pharmacology*; D004558:Electric Stimulation; D006145:Guanethidine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology*; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: C088817:(1-piperidinyl)ethyl 1H-indole-3-carboxylate; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; D012701:Serotonin; D001285:Atropine; D007650:Ketanserin; D017292:Doxazosin; D019331:NG-Nitroarginine Methyl Ester; D006145:Guanethidine