THE USE OFα-ADRENOCEPTOR ANTAGONISTS IN THE PHARMACOLOGICAL MANAGEMENT OF BENIGN PROSTATIC HYPERTROPHY: AN OVERVIEW

doi:10.1006/phrs.1996.0022

Pharmacological Research

Volume 33, Issue 3, March 1996, Pages 145-160

https://doi.org/10.1006/phrs.1996.0022 Get rights and content

Abstract

Benign prostatic hypertrophy (BPH) produces symptomatic urethral obstruction in a significant percentage of older men. Since the incidence of BPH is age related, the clinical and economic impact of this disease will continue to progress as average lifespan increases. BPH is associated with growth of both glandular and stromal elements of the prostate gland. Glandular hyperplasia can be partially reversed by withdrawal of androgenic tone with androgen receptor antagonists or steroid-5-α-reductase inhibitors. However, the reduction in prostatic size produced by these agents has little effect on the dynamic tone induced by nerve mediated contraction of stromal smooth muscle. This tone is mediated by activation ofα-adrenoceptors. Therefore theα-adrenoceptor antagonists represent a useful pharmacological approach to the treatment of BPH.

Studies in isolated strips of human prostate show that either exogenousα-adrenoceptor agonists or electrical field stimulation will induce contraction. Studies with selective antagonists such as prazosin show that this response is mediated by theα₁-adrenoceptor, even though radioligand binding studies show the presence ofα₁andα₂adrenoceptor subtypes in approximately equal density. Following the cloning of multipleα₁-adrenoceptors, the contractile response in human prostate has been assigned to theα_1Aadrenoceptor. However, recent data would suggest a functional role for another subtype, which has not yet been cloned, and designated asα_1Lbased on a relatively low affinity for prazosin.

Clinical trials have shown efficacy of a variety ofα-adrenoceptor antagonists in BPH, including non-selective agents such as phenoxybenzamine, as well as a variety of selectiveα₁-adrenoceptor antagonists, most structurally related to prazosin. The agents most commonly employed at the present time include the prazosin analogs terazosin, doxazosin and alfuzosin, as well as the structurally unrelated indoramin and tamsulosin. The design of newα₁-antagonists for BPH has concentrated on agents producing preferential blockage of urogenital vis-á-vis vascularα₁-adrenoceptors, based either on selectivity for theα_1A-adrenoceptor subtype or on functional uroselectivity in animal models. While these newer agents offer the prospect of reducing the incidence of the cardiovascular side effects associated with current therapy their superiority over nonselectiveα₁-adrenoceptor antagonists remains to be demonstrated in the clinical setting.

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Cited by (72)

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Citation Excerpt :
Similarly, no β-arrestin translocation was observed in cells transfected with β-arrestin2/Venus and CXCR2 upon treatment with vehicle (supplemental Fig. 3D) or NE (supplemental Fig. 3E); however, a punctate distribution was observed upon treatment with CXCL8 (supplemental Fig. 3F). Terazosin is a selective α1AR antagonist (43), and SB265610 has recently been characterized as a cell-permeable selective allosteric inverse agonist of CXCR2 believed to bind to the intracellular C-terminal tail (44, 45). With cells co-expressing CXCR2/Rluc8, β-arrestin2/Venus, and α1AAR, as expected, Terazosin did not inhibit the CXCL8-induced BRET signal (Fig. 4A), but did inhibit the NE-induced BRET signal (Fig. 4B).
We have provided the first evidence for specific heteromerization between the α_1A-adrenoceptor (α_1AAR) and CXC chemokine receptor 2 (CXCR2) in live cells. α_1AAR and CXCR2 are both expressed in areas such as the stromal smooth muscle layer of the prostate. By utilizing the G protein-coupled receptor (GPCR) heteromer identification technology on the live cell-based bioluminescence resonance energy transfer (BRET) assay platform, our studies in human embryonic kidney 293 cells have identified norepinephrine-dependent β-arrestin recruitment that was in turn dependent upon co-expression of α_1AAR with CXCR2. These findings have been supported by co-localization observed using confocal microscopy. This norepinephrine-dependent β-arrestin recruitment was inhibited not only by the α₁AR antagonist Terazosin but also by the CXCR2-specific allosteric inverse agonist SB265610. Furthermore, Labetalol, which is marketed for hypertension as a nonselective β-adrenoceptor antagonist with α₁AR antagonist properties, was identified as a heteromer-specific-biased agonist exhibiting partial agonism for inositol phosphate production but essentially full agonism for β-arrestin recruitment at the α_1AAR-CXCR2 heteromer. Finally, bioluminescence resonance energy transfer studies with both receptors tagged suggest that α_1AAR-CXCR2 heteromerization occurs constitutively and is not modulated by ligand. These findings support the concept of GPCR heteromer complexes exhibiting distinct pharmacology, thereby providing additional mechanisms through which GPCRs can potentially achieve their diverse biological functions. This has important implications for the use and future development of pharmaceuticals targeting these receptors.
Combination of Alfuzosin and Tadalafil Exerts an Additive Relaxant Effect on Human Detrusor and Prostatic Tissues In Vitro
2010, European Urology
Citation Excerpt :
PDE5 isoenzymes might also be involved in controlling relaxant and/or contractile processes of the human prostatic tissue. They are expressed in the transition zone of human prostate [17], and we showed in this experimental study that inhibition of PDE5 isoenzymes by tadalafil reduced prostatic tissue contractions induced by endogenous norepinephrine released by sympathetic nerves during EFS [23] and by exogenous norepinephrine. This effect is likely to be due to a subsequent increase in cyclic guanosine monophosphate (cGMP) levels, although an effect on the cyclic adenosine 3′,5′-monophosphate (cAMP) cascade cannot be excluded [21].
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.
We evaluated in vitro the effects of alfuzosin, tadalafil, and the combination of both on human detrusor and prostatic smooth muscle.
Prostatic and bladder tissue were obtained from patients (n = 20 and n = 17, respectively) undergoing cystoprostatectomy for bladder cancer.
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).
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.
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.
Effects of Phosphodiesterase Inhibitors on Tension Induced by Norepinephrine and Accumulation of Cyclic Nucleotides in Isolated Human Prostatic Tissue
2008, Urology
Citation Excerpt :
The results from the measurements of cyclic nucleotides are summarized in Figure 2. To date, various efforts have focused on new therapeutic options to reverse the sympathetic tone of prostate smooth muscle or inhibit the proliferation of stromal tissue.3,4,7–9 Awareness is increasing of the potential use of pharmacologic compounds to influence the activity of intracellular key enzymes related to the NO-cGMP pathway, such as NO synthase, guanylyl cyclase, or PDE5.
To further evaluate the mechanism of action of phosphodiesterase (PDE) inhibitors on the human prostate, the effects of PDE4 and PDE5 inhibitors on the tension induced by norepinephrine (NE) and on the intracellular levels of cyclic nucleotides in isolated human prostatic tissue were investigated.
Using the organ bath technique, the effects of increasing concentrations (1 nM to 10 μM) of the PDE5 inhibitors sildenafil, tadalafil, and vardenafil and the PDE4 inhibitors rolipram and RP 73401 on the tension induced by NE (40 μM) of prostate strip preparations were investigated. The accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate in response to drug exposure was determined by radioimmunoassays.
The tension induced by NE was dose dependently reversed by the drugs with the following rank order of efficacy: tadalafil greater than RP 73401 greater than rolipram greater than or equal to vardenafil greater than sildenafil. The maximal reversion of tension values ranged from 52.3% (tadalafil) to 17% (sildenafil). Of the PDE inhibitors, only tadalafil induced a 50% reversion of the initial tension. The most prominent enhancement in tissue cyclic adenosine monophosphate was registered in response to RP 73401 (11-fold), and cyclic guanosine monophosphate levels were significantly elevated by tadalafil, vardenafil, and sildenafil (28-fold, 12-fold, and 3-fold, respectively).
Our results have demonstrated that drugs interfering with the cyclic nucleotide-mediated pathways can reverse the tension induced by NE in isolated prostatic tissue and elevate cyclic adenosine monophosphate and cyclic guanosine monophosphate. Our findings serve to explain how PDE inhibitors can affect symptoms of lower urinary tract symptoms and benign prostatic hyperplasia.
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2007, Biological Psychiatry
Excessive brain responsiveness to norepinephrine appears to contribute to post-traumatic stress disorder (PTSD), particularly at night. Prazosin, a brain active alpha-1 adrenergic receptor antagonist, significantly reduced trauma nightmares and sleep disturbance in 10 Vietnam War combat veterans in a previous placebo-controlled crossover study. The current parallel group trial in a larger sample of veterans evaluated prazosin effects on trauma nightmares, sleep quality, global clinical status, dream characteristics, and comorbid depression.
Forty veterans (mean age 56 ± 9) with chronic PTSD and distressing trauma nightmares and sleep disturbance were randomized to evening prazosin (13.3 ± 3 mg/day) or placebo for 8 weeks.
In the evaluable sample (n = 34), primary outcome measures demonstrated that prazosin was significantly superior to placebo for reducing trauma nightmares and improving sleep quality and global clinical status with large effect sizes. Prazosin shifted dream characteristics from those typical of trauma-related nightmares toward those typical of normal dreams. Blood pressure changes from baseline to end study did not differ significantly between prazosin and placebo.
Prazosin is an effective and well-tolerated treatment for trauma nightmares, sleep disturbance and global clinical status in veterans with chronic PTSD.
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Regular ArticleTHE USE OFα-ADRENOCEPTOR ANTAGONISTS IN THE PHARMACOLOGICAL MANAGEMENT OF BENIGN PROSTATIC HYPERTROPHY: AN OVERVIEW

Abstract

Regular Article
THE USE OFα-ADRENOCEPTOR ANTAGONISTS IN THE PHARMACOLOGICAL MANAGEMENT OF BENIGN PROSTATIC HYPERTROPHY: AN OVERVIEW