Combination of Alfuzosin and Tadalafil Exerts an Additive Relaxant Effect on Human Detrusor and Prostatic Tissues In Vitro

Abstract

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.

Objectives

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

Design, setting, and participants

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

Measurements

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).

Results and limitations

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.

Introduction

Lower urinary tract symptoms (LUTS) increase with advancing age [1]. LUTS comprise storage symptoms, often related to detrusor overactivity, and voiding symptoms. The latter could result either from bladder outlet obstruction as a result of benign prostatic enlargement resulting from the histologic condition of benign prostatic hyperplasia (BPH) or from impaired detrusor contractility.

Alpha-adrenoceptor antagonists are considered to be the most effective monotherapy for LUTS suggestive of BPH [2]. They improve both voiding and storage symptoms of BPH and are characterized by a rapid onset of action [3]. All α1-adrenoceptor antagonists are considered to have a comparable efficacy in LUTS. Nevertheless, alfuzosin offers the advantages of good cardiovascular tolerability, even in elderly and hypertensive patients, and less deleterious effect on sexual function [4].

Phosphodiesterase type 5 (PDE5) inhibitors are the first-line treatment of erectile dysfunction (ED) [5]. Moreover, randomized placebo-controlled trials have shown that the three available PDE5 inhibitors (ie, sildenafil, vardenafil, or tadalafil), also improve voiding and storage LUTS in patients with BPH [6], [7], [8], [9]. A recent pilot study has also shown that a single vardenafil administration (20 mg) can improve urodynamic parameters in men with spinal cord injuries [10].

LUTS and ED are strongly linked independent of age and cardiovascular comorbidities, as shown in several epidemiologic studies [11], [12]. Thus, coprescription of α-adrenoceptor antagonists and PDE5 inhibitors is likely to increase. The concept is currently emerging that treatment with a combination of an α1-adrenoceptor antagonist and a PDE5 inhibitor is the most effective therapy to treat LUTS related to BPH. Specific precautions, however, should be taken regarding the concomitant use of these two therapeutic classes due to their potential additive hypotensive effects. Interestingly, alfuzosin (10 mg once daily [OD]) shows no relevant hemodynamic interaction with tadalafil at the highest prescribed dose (20 mg OD) [13]. Moreover, very recent reports of combination of α-adrenoceptor antagonists and PDE5 inhibitors have each reported no symptomatic hemodynamic effects [14], [15]. Finally, a pilot clinical study has shown that combining sildenafil 25 mg OD with alfuzosin 10 mg OD was superior to each therapy alone (same dosages) in relieving LUTS and ED in BPH patients [16].

The mechanism of action responsible for the greater benefit of the combination in LUTS is not yet fully understood and should be explored. Increasing recent data indicate that the benefit observed from the combination in clinical practice on LUTS could be due to an effect of both drugs, not only on the prostate but also on the smooth muscle of the bladder [17], [18], [19]. Thus, our goal was to evaluate in vitro whether the combination of alfuzosin and tadalafil was more effective than each compound alone in inhibiting pharmacologically induced or electrical field stimulation (EFS)–induced contractions of human prostatic smooth muscle and/or in enhancing pharmacologically induced relaxation of human bladder smooth muscle.