810 SILODOSIN (KMD-3213) IS A LONG-ACTING α-1A ADRENOCEPTOR ANTAGONIST WITH ACTIVITY IN THE HUMAN CORPUS CAVERNOSUM

Abstract

INTRODUCTION AND OBJECTIVES: Silodosin (KMD-3213, RapafloTM, Watson Pharmaceuticals, Inc. USA) is a new and highly selective 1A-adrenoreceptor (AR) antagonist for the treatment of lower urinary tract symptoms (LUTS) in men with BPH, a condition associated with erectile dysfunction (ED). Silodosin treats both irritative and obstructive symptoms. Silodosin induced responses on the human corpus cavernosum (HCC) needs further clarification. METHODS: HCC samples were obtained from patients (patient age: 50 66 yr) undergoing penile prosthesis surgery. Using the organ bath technique, drug effects were investigated with phenylephrine (PE, 10 M)-induced tension and electrically induced (0-40 Hz, 3 ms, 10 seconds, 60V) relaxation as well as on the acetylcholine (10 nM1000 nM) and sodium nitroprusside (SNP, 1 nM) induced relaxations of HCC strips (n 12). Direct EFS and KCl (100 mM) induced contractile responses were also generated in the presence of silodosin (0.01 M). RESULTS: Silodosin (0.01 M to 100 mM) induced relaxation (84.68 13.8 % and 37.62 10%) on PE and KCl precontracted strips. EFS-induced relaxant nitrergic responses (43.66 4.44% and 57.05 6.80%, p 0.1178) and contractile adrenergic (11.03 5.98%) neurogenic responses were not significantly affected by incubation with silodosin. ACh (40.01 1.41%, at 100 mM) and SNP (37.46 7.98, at 1 nM) induced relaxations were significantly enhanced (84.68 13.8%, 85.47 3.30%, p 0.0001, respectively) by silodosin. CONCLUSIONS: Inhibition of 1A-AR induces marked penile smooth muscle relaxation. The enhanced relaxation responses to ACh and SNP indicates the involvement of nitric oxide-cGMP pathways. However, silodosin does not target afferent nitrergic and adrenergic nerves in the HCC, and thereby does not act on the neurogenic erectile responses. Our results provide a rationale for the future use of silodosin as an oral treatment for ED. If approved for the human CC, silodosin may contribute to improved erectile function in patients treated for BPH-linked LUTS. Further clinical investigations of silodosin are necessary to evaluate the beneficial effect in ED patients who are not responding sufficiently to PDE5 inhibitors. It is still unknown whether the combination of silodosin and PDE-5 inhibitors is more effective than either mono-treatment.