Combination of alfuzosin and tadalafil exerts an additive relaxant effect on human detrusor and prostatic tissues in vitro.
BACKGROUND
Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are highly prevalent in aging men and are strongly linked. Alpha₁-blockers such as alfuzosin are effective monotherapies for LUTS. Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil are the first-line treatment for ED. Both drugs act by two different mechanisms of action on common urogenital target organs and, thus, may have additive effects.


OBJECTIVE
We evaluated in vitro the effects of alfuzosin, tadalafil, and the combination of both on human detrusor and prostatic smooth muscle.


METHODS
Prostatic and bladder tissue were obtained from patients (n=20 and n=17, respectively) undergoing cystoprostatectomy for bladder cancer.


METHODS
In organ baths, isolated prostatic strips and isolated bladder strips were incubated with vehicle, tadalafil (10⁻⁶ M and 10⁻⁵ M), alfuzosin (3×10⁻⁸ M or 10⁻⁶ M and 10⁻⁵ M) or a combination. Concentration-response curves (CRCs) to norepinephrine were generated on prostatic strips and detrusor strips precontracted with carbachol. Strips were also submitted to electrical field stimulation (EFS).


CONCLUSIONS
When alfuzosin and tadalafil were combined, the maximal relaxation to norepinephrine on carbachol-precontracted detrusor strips was significantly increased compared with tadalafil alone, and EFS-induced detrusor contractions were better inhibited compared with each compound alone. Tadalafil significantly inhibited norepinephrine-induced prostatic strip contractions by reducing the maximal effect, whereas alfuzosin shifted the CRC of norepinephrine to the right. Combining both tadalafil and alfuzosin resulted in a greater relaxant effect. Likewise, the combination was more effective at reducing EFS-induced contractions compared with each compound alone.


CONCLUSIONS
The combination of alfuzosin and tadalafil exerts an additive effect of inhibiting adrenergic smooth muscle tone of prostatic tissue and EFS-induced detrusor contractions and conversely, of enhancing adrenergic relaxation of detrusor precontracted with carbachol. These experiments provide experimental support for the clinical investigation of the combination of α1-blockers and PDE5 inhibitors in the treatment of LUTS.
Pelvipharm, Orsay Parc, Batiment Cedre, 86 rue de Paris, 91400 Orsay, France.
Stephanie
S
Oger
Delphine
D
Behr-Roussel
Diane
D
Gorny
Thierry
T
Lebret
Yves
Y
Denoux
Laurent
L
Alexandre
François
F
Giuliano
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000368:Aged; D002217:Carbachol / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology*; D018679:Cholinergic Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004558:Electric Stimulation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects*; D011799:Quinazolines / Q000494:pharmacology*; D000068581:Tadalafil; D001743:Urinary Bladder / Q000187:drug effects*
D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D002243:Carbolines; D018679:Cholinergic Agonists; D058986:Phosphodiesterase 5 Inhibitors; D011799:Quinazolines; D000068581:Tadalafil; D002217:Carbachol; C047638:alfuzosin; D009638:Norepinephrine