Combination of Doxazosin and Sildenafil Exerts an Additive Relaxing Effect Compared with Each Compound Alone on Human Cavernosal and Prostatic Tissue

Abstract

Introduction Phosphodiesterase 5 inhibitors (PDE5) such as sildenafil are first-line treatment for erectile dysfunction (ED). Alpha1 (α1)-adrenoceptor antagonists such as doxazosin are indicated for the treatment of patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). ED and LUTS/BPH are conditions that are often associated. Accordingly, α1-adrenoceptor antagonists and PDE5 inhibitors will be often prescribed in real life setting together. Aim To evaluate the effects of the combination of sildenafil and doxazosin on human cavernosal and prostatic tissue. Methods Prostatic and erectile tissues were obtained from nine to 12 patients, respectively. Patients underwent cystoprostatectomy for infiltrating bladder cancer or penile surgery for penile implant, congenital curvature or Peyronie’s disease. Main Outcome Measures In organ baths, prostatic and cavernosal strips were submitted to either concentration-response curves (CRC) to phenylephrine (Phe) or norepinephrine (NE), respectively, in presence of vehicle, sildenafil (10−6 M, 10−5 M), doxazosin (10−8 M, 3.10−8 M, or 10−7 M), or a combination of both. Continuous electrical field stimulation (EFS; 32 Hz, 5 ms, 5 seconds, 300 mA) was performed on prostatic strips which were incubated with sildenafil 10−6 M or vehicle before the successive addition of doxazosin (10−7 M, 10−6 M) or vehicle. Cavernosal strips were pre-incubated with doxazosin (10−9 M, 10−8 M) or vehicle, then CRC to sildenafil were constructed on NE (3.10−6 M) precontracted cavernosal strips. Results Combination of sildenafil and doxazosin exerted a greater relaxing effect on CRC to Phe or NE compared with each compound alone in both tissues. Sildenafil significantly enhanced the relaxing effect of doxazosin on EFS-induced contractions in prostatic strips. Doxazosin significantly increased the ability of sildenafil to inhibit NE-induced contractions in cavernosal strips. Conclusions Sildenafil and doxazosin reduced adrenergic tone of prostatic and cavernosal smooth muscle and their combination provided a significant benefit when targeting relaxation of both tissues. These experiments provide support for further clinical evaluation of the sildenafil and doxazosin combination in ED patients with LUTS/BPH.

Pathogenic mechanisms linking benign prostatic hyperplasia, lower urinary tract symptoms and erectile dysfunction

“…Increased adrenergic tonus also leads to enhanced expression of Rho-kinase pathway The presence of PDE-5 in the lower urinary tract of rats [Tinel et al 2006], the action of PDE-5i in the prostate muscles [Oger et al 2009[Oger et al , 2010 Angulo et al 2012] and clinical improvement of patients with LUTS/BPH using these drugs, which traditionally enable erection [Gacci et al 2012], demonstrated that, at least from a therapeutical point of view, ED and LUTS/BPH can be treated in the same manner.…”

“…Oger and colleagues verified the action of sildenafil [Oger et al 2009] and of tadalafil [Oger et al 2010] in muscle fibers of human prostate and penile tissues, obtained from surgical specimens and observed that the two drugs have a relaxing effect in both tissues.…”

“…More recently, the same group [Gur et al 2012] demonstrated alpha-adrenergic blockage produces relaxation of the muscle fibers of human cavernous body that is comparable to PDE-5i. Furthermore, in the past it was shown that the intracavernous and oral use of phentolamine and phenoxybenzamine caused erection in men with erectile dysfunction [Padma-Nathan et al 2002;Glina et al 2008].In the already cited study by Oger and colleagues, the authors assessed the effect of sildenafil and doxazosin in the smooth muscle fibers isolated from human prostate and cavernous body, and reported both drugs had a relaxing effect, reducing adrenergic tonus, on both tissues [Oger et al 2009]. The combination sildenafil-doxazosin presented a statistically superior effect compared with isolated compounds.…”

Efficacy and safety of combination therapy with mirodenafil and α1-blocker for benign prostatic hyperplasia-induced lower urinary tract symptoms accompanied by erectile dysfunction: a multicenter, open-label, prospective study

“…14 Furthermore, an in vitro study has reported that such combination therapy relaxes human prostate smooth muscles more potently than monotherapy. 15 Mirodenafil ( is the most recently developed oral PDE5i and has been shown to be potent, reversible and selective. 16 In Korea, this drug has been commercially available since 2007.…”

Combination therapy for erectile dysfunction: an update review

“…27,28 Researchers also have found that a-adrenergic receptor antagonists potentiates corporal vasodilators dependent on cyclic nucleotide second-messengers. 28 Applying these findings to human models, Oger et al 29 used cavernosal and prostatic tissue specimens from patients who underwent penile or prostatic surgery and demonstrated that combining sildenafil with doxazosin in tissue baths significantly increased overall tissue relaxation. This discovery has been the impetus for several randomized studies attempting to demonstrate the efficacy and safety of combining PDE5Is with a-adrenergic receptor antagonists to treat complex ED ( Table 5).…”