Microsoft word - siu 2012 silodosin prostate.doc
Combination of Silodosin and Tadalafil exerts an additive relaxant effect on contractions of
human and rat isolated prostates
Buono Roberta1, Villa Luca1, Benigni Fabio1, Rigatti Patrizio1, Montorsi Francesco1 and Hedlund
1Urological Research Institute, Milan, Italy
2Department of Clinical Pharmacology, Linköping, Sweden Introduction and objectives Lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) are associated with erectile dysfunction (ED). Alfa-1-adrenoceptor (α1-AR)-blockers are effective drugs for treating symptomatic BPH. Clinical data suggests meaningful improvements in LUTS by PDE5-inhibitors. This study aimed to evaluate effects of silodosin, a highly selective α1A-AR antagonist, alone or in combination with the PDE5-inhibitor tadalafil on contractions of isolated human and rat prostate. Materials and methods After Ethics Committee approval, normal prostatic tissue was obtained preoperatively from 37 patients (age: 67±2 years) undergoing surgery for prostate or bladder cancer. Prostatic rat tissue was obtained from 8 male Sprague Dawley rats (250 gram). By organ bath technique we investigated the effects of silodosin, tadalafil, silodosin + tadalafil, or vehicle on contractile responses to activation of nerves in prostate preparations. ANOVA was used for statistical comparisons. Results Silodosin concentration-dependently reduced nerve-induced contractions of human prostate preparations. At low frequencies (1-4 Hz) inhibitory effects were 0-5% (10nM), 10-17% (100nM), and 16-33% (1µM). At medium and high frequencies (8-32 Hz), inhibitory effects by silodosin were 6-17% (10nM), 29-35% (100nM), and 34-45% (1µM). Silodosin 1nM did not inhibit contractions. At 1-4Hz, tadalafil inhibited contractions by 3-17% (10µM) and 3-15% (100µM). At 8-32Hz, inhibitory effects by tadalafil were 5-13% (10µM) and 15-30% (100µM). Tadalafil 100nM and 1 µM did not inhibit contractions. Silodosin (1nM) + tadalafil (100nM) inhibited contractions by 35-42% (1-4Hz; p<0.05) and 26-31% (8-32Hz; p=0.06). Inhibitory effects of 40-58% (10nM silodosin + 1µM tadalafil; p<0.001-0.05), 56-67% (100nM silodosin + 10µM tadalafil; p<0.01-0.05), and 33-55% (1µM silodosin + 100µM tadalafil) were recorded at 1-4Hz. Corresponding values for 8-32Hz were 43-56% (10nM silodosin + 1µM tadalafil; p<0.01-0.05), 55-63% (100nM silodosin + 10µM tadalafil; p<0.05 vs tadalafil), and 47-52% (1µM silodosin + 100µM tadalafil). Similar findings were obtained in rat prostate preparations. At any frequency, silodosin inhibited contractions by 0-9% (1nM), 9-34% (10nM), 37-58% (100nM), and 40-68% (1µM). Tadalafil inhibited contractions by 0% (100nM), 0-9% (1µM), 0-26% (10µM), and 2-26% (100µM). Inhibitory effects of 23-34% (1nM silodosin + 100nM tadalafil; p<0.01-0.05), 42-53% (10nM silodosin + 1µM tadalafil; p<0.01-0.05), 56-72% (100nM silodosin + 10µM tadalafil; p<0.05) and 62-76% (1µM silodosin + 100µM tadalafil; p<0.01). Vehicles had no effects. Discussion The combination of silodosin and tadalafil exerts an additive effect of inhibiting nervous stimulation of prostatic tissue, exhibited 100-fold greater potency to inhibit contractions of prostates than each drug alone. Conclusion These experiments provide experimental support for the clinical investigation of the combination of α1-blockers and PDE-5 inhibitors in the treatment of LUTS.
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