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Keywords:

  • adrenergic;
  • adrenoceptor;
  • BPH;
  • alpha blockers;
  • prostate;
  • benign prostatic hyperplasia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. α1-Adrenergic receptors
  5. Clinical use of αAR antagonists for treatment of LUTS
  6. Conclusions
  7. References

Abstract:  Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging men leading to lower urinary tract symptoms (LUTS). α1-Adrenoceptors (α1ARs) antagonists (blockers) have become a mainstay of LUTS treatment because they relax prostate smooth muscle and decrease urethral resistance, as well as relieving bladder LUTS symptoms. A review of key recent clinical trials suggests new insights into the role of specific α1AR subtypes in the treatment of LUTS.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. α1-Adrenergic receptors
  5. Clinical use of αAR antagonists for treatment of LUTS
  6. Conclusions
  7. References

Benign prostatic hyperplasia (BPH) is a common enlargement of the prostate gland that may lead to bladder outlet obstruction, lower urinary tract symptoms (LUTS) and reduced quality of life. BPH is present in 50% of men > 50 years. Until the 1990s, treatment of BPH predominantly involved surgery. However increasing understanding of α1-adrenergic receptor (α1AR) stress hormone receptors led to the use of α1AR-selective blocking drugs in treating LUTS.1α1ARs bind catecholamines adrenaline and noradrenaline; cellular responses include modulation of blood pressure and flow, neuronal activity, digestion, micturition, reproduction, pupil diameter, endocrine and metabolic processes and behavior. Several key clinical studies have demonstrated the effectiveness of α1AR blockade over other treatments, both in first-line therapy, combination therapy and extended treatment regimes. This review summarizes α1AR subtypes, their mechanistic role in BPH and LUTS and data demonstrating effectiveness in LUTS management.

α1-Adrenergic receptors

  1. Top of page
  2. Abstract
  3. Introduction
  4. α1-Adrenergic receptors
  5. Clinical use of αAR antagonists for treatment of LUTS
  6. Conclusions
  7. References

Subtypes and cell signaling

Adrenergic receptors were originally divided into αAR and βAR categories,2 but application of molecular biological methods has confirmed nine total AR subtypes: α1a (formerly named α1c), α1b, α1d, α2a, α2b, α2c, β1, β2, and β3.3 These subtypes are distinguished by their pharmacology, structure and interaction(s) with second messenger systems. α1ARs generally mediate their actions through members of the Gq/11 family of G proteins that stimulate inositol phosphate (membrane phospholipid) hydrolysis, with each subtype demonstrating different efficacy of coupling to phosphoinositide hydrolysis: α1a > α1b > α1d.4 In addition, α1AR subtypes can be pharmacologically distinguished on the basis of differential binding to α1-antagonists (blockers)5 as well as differential inactivation by the alkylating agent chloroethylclonidine (CEC).6 A concise review of α1AR subtype signaling can be found in Hawrylyshyn et al.4

Tissue distribution of α1-adrenoceptor subtypes

Although α1ARs consistently exist in specific organs/tissues, great variability exists across species (species heterogeneity) regarding which α1AR subtype is present in a given tissue. All three α1AR subtypes exist in a wide range of human tissues.7 The α1aAR subtype shows the highest levels of expression in the human liver, followed by slightly lower levels in the heart, cerebellum, and cerebral cortex; the α1bAR subtype has the highest expression in the human spleen, kidney, and fetal brain; whereas the α1dAR has the highest levels in the cerebral cortex and human aorta.7

In terms of LUTS, α1AR expression in the prostate, urethra, spinal cord and bladder is important. Molecular and contraction studies in human prostate tissue demonstrate the α1aAR subtype function predominates in prostate stroma8 in spite of demonstration of both α1a and α1dAR messenger ribonucleic acid (mRNA).9 Because baseline tone is present in prostate smooth muscle (due to its rich sympathetic innervation), blockade of prostate α1aARs results in the relaxation of prostate smooth muscle. Hence α1AR blockade is capable of modifying the dynamic (prostate smooth muscle contraction) component in BPH. Another tissue important in LUTS is the urethra. To date, most studies show that all regions of human urethra (including bladder neck and intraprostatic urethra) contain only α1aARs. Because of reflex arcs, spinal cord α1AR expression may be important in LUTS. Expression of α1ARs in the human spinal cord has been detected by in situ hybridization ribonucleic acid (RNA)/RNA hybridization technique in tissue slices to maintain anatomic structure), with α1dAR mRNA expression predominating over α1a and α1bAR at all spinal cord levels.10

An important role for the bladder in symptoms associated with LUTS is now appreciated. Normal detrusor (bladder smooth muscle tissue), obtained from surgical patients, expresses predominantly α1dARs, although other subtypes are present to a lesser extent.11 Furthermore, in vivo pharmacology using several highly α1aAR-selective agents (e.g. RS-17053) have been tested in animal and human bladders.12 Although these agents are effective at relaxing prostate smooth muscle and increasing urine flow in men (the expected response to an α1aAR antagonist), relief of outlet obstruction alone does not alter reported LUT symptom scores in men with BPH.12 Only when combined α1a1dAR blockers are used is LUTS also relieved.13 Indeed, commercially available α1AR antagonists that contain α1dAR antagonist activity (non-subtype selective α1AR blockers as well as subtype selective drugs such as tamsulosin and naftopidil, and to a lesser extent silodosin) improve bladder-based symptoms in humans.14 Of note, nocturia appears to respond to the blockade of α1dARs.14,15 Such findings confirm the important role of the α1dARs in LUTS. Studies demonstrating increased α1dAR expression and function in models of bladder hypertrophy provide a mechanistic explanation for increased symptoms associated with LUTS.13,16 In terms of the precise mechanism of bladder storage, symptoms remain unknown. However, unstable bladder smooth muscle contractions13,17,18 and a role for bladder urothelium α1dARs in initiating premature contractions, with filling (H2O) or mild irritation (ascorbic acid) are both being explored.19 Spinal afferents originating in the bladder have also been suggested to be modified by α1AR blockade.20

α1AR antagonists mediate vasodilation in vasculature; therefore one of the side-effects of treating LUTS with α1AR antagonists is hypotension. α1aARs predominate in human splanchnic (mesenteric, splenic, hepatic and distal omental) resistance arteries.21 Interestingly, α1AR expression increases two-fold in representative (mammary) arteries with aging, with the ratio of α1b/α1a increasing, whereas no alteration occurs in veins.21 These findings are consistent with the α1a1dAR-selective antagonist tamsulosin (which lacks α1bAR activity at clinical doses) having less effect on blood pressure in elderly men than a non-subtype-selective α1AR antagonist (which would block α1bARs).22,23 Studies of pharmacy databases in Europe suggest that the administration of α1AR blockers increases the incidence of hip fractures (chosen as a surrogate for clinically important orthostatic hypotension);23 further analysis regarding the precise α1AR antagonists prescribed suggests that the avoidance of α1bAR blockade may result in less overall blood pressure changes24 and hip fractures.25

In summary, for the treatment of LUTS, distribution studies suggest α1aAR-selective antagonists relieve obstructive outflow symptoms and improve urine flow via relaxation of prostate smooth muscle, whereas α1dAR-specific antagonists relieve bladder symptoms through either direct actions on the bladder and/or spinal cord reflexes (Table 1). The use of α1bAR antagonist drugs has little benefit with respect to LUTS and may promote blood pressure–related side-effects, particularly in elderly patients, in whom vascular α1bARs become predominant over α1aARs. Furthermore, these data hint that in the absence of bladder outlet obstruction (as in most female LUTS), bladder symptoms might be treated by targeting α1dARs selectively.26

Table 1.  α1-Adrenoceptors subtypes and function
  1. α1AR, α1-Adrenoceptors; LUTS, lower urinary tract symptoms; mRNA, messenger ribonucleic acid.

• Three α1AR subtypes: α1a, α1b, and α1d.
• α1AR subtype tissue expression varies with species
• α1aARs predominate in human prostate; blockade relaxes prostate smooth muscle and increases urine flow
• α1dARs predominate in human detrusor (bladder smooth muscle), spinal cord, and afferent nerves; blockade decreases LUTS symptoms
• Animal models of bladder outlet obstruction show detrusor α1dARs increase with bladder hypertrophy
• α1d > α1a, α1b mRNA in human spinal cord.
• α1AR subtypes vary in human vascular beds: α1aARs predominate in splanchnic resistance vessels, α1bARs present to lesser extent in some small arteries, α1d in conduit arteries (aorta)
• Aging increases vascular α1AR density two-fold (mammary artery) and α1b increasingly predominates over α1a; no change in α1d subtype

Clinical use of αAR antagonists for treatment of LUTS

  1. Top of page
  2. Abstract
  3. Introduction
  4. α1-Adrenergic receptors
  5. Clinical use of αAR antagonists for treatment of LUTS
  6. Conclusions
  7. References

Currently available α1AR antagonists

For the treatment of BPH/LUTS in the United States today, alfuzosin, doxazosin, terazosin, and tamsulosin are the most prescribed α1AR antagonists. Terazosin, doxazosin and alfuzosin are non-subtype selective in that they block all three α1AR subtypes. In contrast, tamsulosin blocks α1a = α1dARs with 10-fold greater affinity than α1bARs, and is therefore considered to be α1AR subtype selective. Two additional new subtype selective α1AR antagonists have been released only in Japan – naftopidil (α1d = α1a > α1b) and silodosin (α1a > α1d > α1b). General characteristics of α1AR antagonists are summarized in Table 2 and 3.27 All currently available α1ARs have similar efficacy and improve symptoms by approximately 35% and maximum urinary flow rate by 1.8–2.5 mL/s.2,14,28,29 What differentiates α1-selective antagonists therefore is their associated side-effects. The non-subtype-selective α1AR antagonist terazosin can cause asthenia, dizziness, somnolence, hypotension, nasal congestion/rhinitis, and impotence;30 doxazosin can cause dizziness, fatigue, edema, dyspnea and hypotension;31 and alfuzosin can produce dizziness, headache, nausea, dry mouth, diarrhea, and hypotension.32 Tamsulosin can cause abnormal ejaculation, dizziness, infection, headache and flu-like symptoms,33 but does not appear to affect blood pressure,22,33 particularly in elderly patients (probably due to its lack of α1b binding which is increasingly important in aging vessels). Interestingly, a recent study suggests that in the context of subtype specific α1AR antagonist therapy, α1a-mediated seminal vesicle contraction and emission is decreased, rather than having true retrograde ejaculation.34,35

Table 2.  Clinical pharmacology of α1-blockers used to treat lower urinary tract symptoms in the US
 TerazosinDoxazosinAlfuzosinTamsulosin
  • Registration in Europe has been withdrawn despite proven efficacy in lowering blood pressure in hypertension. α1AR, α1-Adrenoceptors; N, no; Y, yes.

α1AR subtype selectivityNon-subtype selectiveNon-subtype selectiveNon-subtype selectiveSubtype selective
Pharmacological selectivityNNNY
Clinical selectivityN (α1a = α1b = α1d)N (α1a = α1b = α1d)N (α1a = α1b = α1d)Y (α1a = α1d > α1b)
Registered for use in hypertension?YY(N)N
Reduces elevated blood pressure?YYYN
Usual daily dose, mg1–101–87.5–100.4
Regimen, doses/d111–31
Modified-release formulationNYN–YY
Side-effectsAsthenia, dizziness, somnolence, hypotension, nasal congestion/rhinitis, impotenceDizziness, fatigue, edema, dyspnea, hypotensionDizziness, headache, nausea, dry mouth, diarrhea, hypotensionAbnormal ejaculation, dizziness, headache, flu-like symptoms
Table 3.  Clinical pharmacology of additional α1-blockers used to treat lower urinary tract symptoms in Japan
 NaftopidilSilodosin
  • Note: Since naftopidil and silodosin are only marketed in Japan, they do not require FDA package inserts so side-effects have been summarized from published reports. α1AR, α1-Adrenoceptors; (N), conditional no.; N, no; Y, yes.

α1AR subtype selectivitySubtype selectiveSubtype selective
Pharmacological selectivityYY
Clinical selectivityY (α1d ≥ α1a > α1b)Y (α1a > α1d > α1b)
Registered for use in hypertension?NN
Reduces elevated blood pressure?NN
Usual daily dose, mg25–754
Regimen, doses/d1–22
Modified-release formulationNN
Side-effectsAbnormal ejaculation, nasal congestion, dizzinessAbnormal ejaculation, nasal congestion, dizziness

α1AR Antagonists for the treatment of hypertension (ALLHAT study results)

When α1AR antagonists first became widely used for the treatment of LUTS, some physicians suggested ‘monotherapy’ for LUTS and hypertension might be possible. Monotherapy was never seriously proposed for tamsulosin or alfuzosin as these drugs did not/do not lower blood pressure enough to be labeled an antihypertension drug by the US Food and Drug Administration. However, ever since results from The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study became available (http://www.allhat.org),36 the idea of monotherapy has been abandoned even for non-subtype selective α1AR antagonists. The doxazosin arm of this large antihypertension and lipid-lowering study was stopped early due to a higher rate of cardiovascular events (particularly the risk of congestive heart failure) compared with the diuretic chlorthalidone.36 Based on these results, α1AR blockers are not recommended as initial therapy in the management of hypertension, although they can still be added as additional agents in refractory hypertension (http://www.nhlbi.nih.gov/guidelines/hypertension/index.htm).36 Considering these findings, LUTS therapy is most appropriately initiated separately from antihypertension therapy.

α1AR Therapy versus other modalities for treating LUTS

In addition to α1AR antagonists, two 5α-reductase inhibitors (finasteride and dutasteride) have been used to treat LUTS. 5α-Reductase inhibitors inhibit the conversion of testosterone to dihydrotestosterone, a compound even more potent than testosterone in mediating prostatic hyperplasia, resulting in a gradual (over months) decrease in the size of the prostate gland by approximately 15–25%, and a concomitant improvement in symptoms and urinary flow rates. 5α-Reductase inhibitors appear most cost effective in patients with glands larger than 30 or 40 mL by transrectal ultrasound and/or a serum prostate-specific antigen (PSA) level above 1.5 ng/dL.37,38 The reason for this is likely to be a combination of increased efficacy and the fact that these patients are more likely to experience a worsening of symptoms and progression to urinary retention and surgery if left untreated. The risk for these two progression events is reduced with both drugs by approximately 50%.28,39,40

Many phytotherapeutic agents are in widespread use in both Europe and the US for the treatment of LUTS and clinical BPH, extracts of the Saw Palmetto berry and Pygeum Africanum are most commonly used. Cochran meta-analyses suggest a modest effect on certain symptoms associateds with BPH, however, the mechanisms of action remains unclear for all of these compounds.41–43

Emerging data suggest that antimuscarinics may also be efficacious and safe either alone or in combination with α1AR antagonists in the treatment of men with LUTS and mostly storage symptoms.44

Clinical trials of α1AR antagonists versus 5α-reductase inhibitors

Table 4 lists three key clinical trials that evaluated the efficacy of α1AR antagonists and 5α-reductase inhibitors, alone or in combination compared with a placebo in men with LUTS associated with BPH.45–47 The first key trial to directly address this question was the Veterans Affairs (VA) Cooperative Study Trial in which 1229 men with BPH 45–80 years of age were randomly assigned to receive terazosin, finasteride, combination terazosin/finasteride or a placebo for one year.46 The primary outcome measure was the American Urological Association (AUA) symptom score and peak urine flow rate. In this trial, α1AR antagonists were found most effective in treating LUTS associated with BPH; however, 5α-reductase inhibitor therapy did have some benefit in the subgroup of patients with extremely large prostates, although these patients required α1AR blocking drugs in addition to 5α-reductase inhibitors for complete symptom relief.45α1AR antagonists and combination therapy reduced serum PSA levels. Based on this trial, α1AR antagonists were recommended as first-line therapeutic agents for the treatment of LUTS associated with BPH. Another 12 month trial with a similar patient population comparing doxazosin, finasteride or combination therapy versus placebo, the Prospective European Doxazosin and Combination Therapy (PREDICT), was done in Europe with fundamentally similar results.47

Table 4.  Benign prostatic hyperplasia clinical trials comparing α1-adrenoceptors antagonists and 5-α-reductase inhibitors45–47
  1. α1AR, α1-Adrenoceptors; BPH, Benign prostatic hyperplasia; LUTS, lower urinary tract symptoms; MTOPS, Medical Therapy of Prostatic Symptoms; PREDICT, Prospective European Doxazosin and Combination Therapy; VA, Veterans Affairs;

VA Cooperative Trial
• Compared effect of 5α-reductase inhibitor, α1AR antagonist, combination, and placebo therapy on relief of LUTS, flowrate and other secondary endpoints
• n = 1229 men with LUTS associated with BPH, 1-year outcome
• Primary outcome: decrease in symptom score (American Urological Association score) Secondary: increase in peak urine flow rate and other endpoints
• Conclusion: α1AR antagonist therapy most effective in treating LUTS associated with BPH (alone or in combination); but 5α-reductase inhibitor therapy was beneficial in subgroup with extremely large prostates
MTOPS Trial
• Compared 5α-reductase inhibitor, α1AR antagonist, combination, and placebo therapy on clinical progression and symptom relief
• n = 3027 men with LUTS associated with BPH, 5-year outcome
• Primary outcome: effect on LUTS symptom progression (increase of = 4 units International Prostate Symptom Score) or complications
• Conclusion: both α1AR blocker and 5α-reductase inhibitor therapy slowed the progression of LUTS; combination therapy was the best approach in high-risk patients
PREDICT Trial
• Compared effect of 5α-reductase inhibitor, α1AR antagonist, combination, and placebo therapy on relief of LUTS, flowrate and other secondary endpoints.
• n = 1250 men with LUTS associated with clinical BPH, 1 years outcome.
• Primary outcome: decrease in symptom score (American Urological Association score). Secondary: increase in peak urine flow rate and other endpoints.
• Conclusion: Doxazosin was effective in improving urinary symptoms and urinary flow rate in men with benign prostatic hyperplasia, and was more effective than finasteride alone or placebo. The addition of finasteride did not provide further benefit to that achieved with doxazosin alone.

Another key longer-term trial, the Medical Therapy of Prostatic Symptoms (MTOPS),46 is a double-blind, randomized, placebo-controlled study designed to evaluate the effect of medical therapy on the clinical progression of LUTS associated with BPH, defined as an increase in total International Prostate Symptom Score of ≥4 points or the development of complications (e.g. acute urinary retention, incontinence, urinary tract infection, or renal insufficiency). The trial had a mean follow-up duration of five years for 3047 men with LUTS associated with BPH randomized to either placebo, doxazosin, finasteride, or the combination of doxazosin/finasteride. The overall risk of progression was reduced between 30 and 40% by both doxazosin and finasteride, but by 67% with combination therapy. Further analyses demonstrated that finasteride mainly reduced the risk of retention and surgery, while doxazosin reduced the risk of symptom progression.

The results of these pivotal trials have been integrated into the AUA BPH treatment guidelines updated in 2003 and are available online (Website for physician information regarding BPH management guidelines: http://www.auanet.org/timssnet/products/guidelines/main_reports/bph_managementchapt_1_appendix.pdf; website for patient information regarding BPH management: http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=3740).1 At present the AUA is in the process of updating the 2003 BPH guidelines with an anticipated completion date of late 2008 (C. G. Roehrborn, personal communication).

α1AR Antagonists and Type 5 phosphodiesterase (PDE) inhibitors

Erectile dysfunction can be treated medically with rapid onset vasodilators such as the type 5 PDE inhibitors sildenafil, vardenafil and tadalafil.48 Vasodilation is mediated via inhibition of the breakdown of cyclic guanosine monophospate (cGMP), ultimately through nitric oxide pathways. Patients with LUTS associated with BPH have elevated rates of erectile dysfunction compared with the general male population.49,50α1AR antagonists utilized to treat LUTS mediate smooth muscle relaxation and vasodilation, and alone have been shown to improve erectile dysfunction;51,52 in experimental models, this effect is mediated via the α1dAR subtype.52 Because LUTS patients are often elderly men with underlying coronary artery disease, interaction of α1AR blockers and type 5 PDE inhibitors is a potential concern since resultant lowered diastolic blood pressure might lead to decreased coronary perfusion and myocardial ischemia.53,54 There are specific warnings and precautions regarding the concomitant use of PDE5 inhibitors and α1AR antagonists. At present a 4 h window is recommended when using >25 mg sildenafil and α1AR antagonists, the concomitant use of vardenafil and α1AR antagonists is contraindicated, and only for tadalafil the warning was recently lifted and replaced by a precaution. Aside from the issue of combined use of α1AR antagonists and PDE5 inhibitors, there are also intriguing data suggesting that PDE5 inhibitors due to their muscle relaxing effect may be beneficial in the treatment of LUTS by themselves.55 Recently two trials have been published demonstrating efficacy and safety of once daily use of PDE5 inhibitors (sildenafil citrate and tadalafil) in the treatment of male LUTS in men with clinical BPH, and further Phase III trials are underway with at least one of these compounds (tadalafil).56,57 A summary of ways to treat LUTS is shown in Table 5.

Table 5.  New strategies to understand and treat lower urinary tract symptoms
StrategyPros/ConsLatest developmentWho is working on strategy
  1. Abbreviations: Asahi Chem, Asahi Chemical Industry (Japan); Labs, laboratories; LUTS, lower urinary tract symptoms; Rx, treatment; S.E., side-effects (for female LUTS this refers to urinary incontinence).

Female LUTS (α1d selective)Pro: Treats without S.E.  
Con: Disease heterogeneity  
New α1a1d blockersPro: Available, more comingNaftopidil, silodosin available only in JapanSeveral companies
Quality of life ascertainmentsPro: Better patient Rx  
Con: Takes time  
PhytotherapyPro: InexpensiveIneffective or very small effectsVarious academic labs
Con: May not be effectiveSafety and efficacy of 
AntimuscarinicsPro: Treat storage/OAB symptomscomb with α1a1d blockersPfizer, Astellas and others
Con: limited long-term safety data  
PDE5 InhibitorsPro: Treat BPH and EDPhase III trials underwayLilly, Pfizer
Con: price (?), AE spectrum (back pain, flushing, etc.)  
Growth factor inhibitorsPro: May prevent/regress BPH??
Con: Unproven, poor S.E. profile  

α1AR Antagonists and intraoperative floppy iris syndrome (IFIS)

In 2005 the first reports of small pupil and iris billowing during cataract surgery were reported in patients taking α1AR antagonists. Since iris hooks are required to dilate the pupil when intraoperative floppy iris syndrome (IFIS) occurs, some ophthalmologists feel this increases the risk of elective cataract surgery. Fortunately IFIS is relatively rare, occurring in 1–2% of all patients having cataract surgery.58 While original reports suggested IFIS only occurred in patients taking tamsulosin, it soon became apparent that this was a class effect, with all α1AR antagonists capable of producing these effects via the blockade of α1aARs in the iris dilator muscle.58,59 All of the effects of α1AR antagonists on pupil size are gone within 8 h of administration in the white albino rabbit model used in the most detailed study to date.59 However, one needs to be cautious about extrapolating such pharmacokinetic data to humans since iris pigment has been shown to sequester some drugs and such studies have not been performed for α1AR antagonists. Therefore stopping α1AR blockers one to two weeks prior to elective cataract surgery is probably prudent, with any urological complications during this interval referred to a urologist.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. α1-Adrenergic receptors
  5. Clinical use of αAR antagonists for treatment of LUTS
  6. Conclusions
  7. References

In conclusion α1AR antagonists are currently first-line therapy for LUTS associated with BPH. Successful use of α1AR blockers in treating patients with LUTS is based on targeting both prostate α1aARs and bladder α1dARs that are important in relieving obstructive and storage symptoms, respectively. 5α-reductase inhibitors may be added in patients with large prostates or higher serum PSA levels, as these patients are at greater risk of progression and may experience greater benefit from combination therapy. 5α-reductase inhibitor monotherapy may be considered in a preventive setting in mildly symptomatic patients who have a very large gland putting them at increased risk of progression. Furthermore, investigators are examining the role of α1AR blockers synergizing with type 5 PDE inhibitors for the treatment of erectile dysfunction, a condition which often accompanies LUTS. Knowledge of α1AR subtypes facilitates rational use of these important therapeutic agents.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. α1-Adrenergic receptors
  5. Clinical use of αAR antagonists for treatment of LUTS
  6. Conclusions
  7. References
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