Combination of doxazosin and sildenafil exerts an additive relaxing effect compared with each compound alone on human cavernosal and prostatic tissue.
BACKGROUND
Phosphodiesterase 5 inhibitors (PDE5) such as sildenafil are first-line treatment for erectile dysfunction (ED). Alpha1 (alpha1)-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, alpha1-adrenoceptor antagonists and PDE5 inhibitors will be often prescribed in real life setting together.


OBJECTIVE
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.


METHODS
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.
Oger
Stéphanie
S
Pelvipharm, Orsay Parc, Orsay, France.
Behr-Roussel
Delphine
D
Gorny
Diane
D
Lecoz
Olivier
O
Lebret
Thierry
T
Denoux
Yves
Y
Faix
Antoine
A
Leriche
Albert
A
Wayman
Chris
C
Alexandre
Laurent
L
Giuliano
François
F
D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D017292:Doxazosin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004338:Drug Combinations; D007172:Erectile Dysfunction / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D010410:Penile Erection; D010413:Penis / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011467:Prostate / Q000187:drug effects*; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use*
D000317:Adrenergic alpha-Antagonists; D004338:Drug Combinations; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D017292:Doxazosin