Doxazosin and Serotonin (5-HT) Receptor (1A, 2A, and 4) Antagonists Inhibit 5-HT-Mediated Human Cavernosal Contraction

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.