title: Silodosin and tadalafil have synergistic inhibitory effects on nerve-mediated contractions of human and rat isolated prostates.
abstract: Lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) are associated with erectile dysfunction. Alpha-1-adrenoceptor antagonists are effective drugs for treating symptomatic BPH. Clinical data show improvements in LUTS by phosphodiesterase 5 inhibitors. This study aimed to evaluate effects of silodosin, a highly selective α1A-adrenoceptor antagonist, alone or in combination with the phosphodiesterase 5 inhibitor tadalafil on contractions of isolated human and rat prostates. In organbath studies, effects of increasing concentrations of silodosin (1 nM-1 µM) and tadalafil (100 nM-100 µM) on contractions by electrical field stimulation or phenylephrine of human and rat prostate strip preparations were investigated. The combination silodosin and tadalafil reduced electrically-induced contractions of human prostate preparations better than single drugs alone. At any frequencies (1-32 Hz), inhibitory effects of combined therapy (P-values vs single drug) in human tissue were 26-42% (1 nM silodosin+100 nM tadalafil; P<0.05), 40-58% (10 nM silodosin+1 µM tadalafil; P<0.001-0.05), 56-67% (100 nM silodosin+10 µM tadalafil; P<0.01-0.05), and 33-55% (1 µM silodosin+100 µM tadalafil P<0.01-0.05). Similar findings were obtained in rat prostate preparations. In human and rat prostate tissue, the drug combination exerted similar inhibitory effect on phenylephrine contractions as silodosin alone. Silodosin plus tadalafil had greater potency than each drug alone to inhibit prostate contractions to electrical field stimulation but not to phenylephrine. This study supports the clinical application of a combination of an α1A-adrenoceptor antagonist and a phosphodiesterase 5 inhibitor for symptomatic BPH and suggests that the drug combination requires endogenous nerve-activity for optimal effect.
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy. Electronic address: buono.roberta@hsr.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Buono
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Briganti
authors.affiliation: Division of Oncology/Unit of Pathology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Freschi
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Villa
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden.
authors.forename: Giovanni
authors.initials: G
authors.lastname: La Croce
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Moschini
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benigni
authors.affiliation: Università Vita-Salute San Raffaele, Milan, Italy; Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden.
authors.forename: Fabio
authors.initials: F
authors.lastname: Castiglione
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Montorsi
authors.affiliation: Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Department of Clinical Pharmacology, Linköping University, Linköping, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Hedlund
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000368:Aged; D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D004357:Drug Synergism; D004558:Electric Stimulation / Q000379:methods; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D059411:Lower Urinary Tract Symptoms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068581:Tadalafil
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D002243:Carbolines; D007211:Indoles; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010656:Phenylephrine; D000068581:Tadalafil; C095285:silodosin
keywords: Alfa-1A-adrenoceptor; Contraction; Inhibition; Phosphodiesterase 5; Prostate; Smooth muscle