Phosphodiesterase Type 5 Inhibitors in the Management of Non-neurogenic Male Lower Urinary Tract Symptoms: Critical Analysis of Current Evidence

Martínez-Salamanca, Juan Ignacio; Carballido, Joaquı́n; Eardley, Ian; Giuliano, François; Gratzke, Christian; Rosen, Raymond C.; Salonia, Andrea; Stief, Christian G.

doi:10.1016/j.eururo.2011.05.054

Cited by 51 publications

(26 citation statements)

References 70 publications

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“…Clinically, there is now good level 1 evidence of a beneficial effect of PDE5is on urinary symptoms, especially for men with LUTS and significant ED (42). To note, as mentioned previously, PDE5is provided only limited improvement in urinary flow rate, which gave rise to controversy regarding this therapy, although mounting and consistent evidence is showing their significant benefits in treating BPH/ LUTS (39,68). According to the American Urological Association guidelines, ␣ 1 -adrenergic blockers combined with 5␣-reductase inhibitors are considered the most effective therapy for the treatment of BPH, especially for larger prostates.…”

Section: E249 Testosterone Regulates Pde5 In Prostatic Smooth Musclementioning

confidence: 99%

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

Zhang

Zang

Wei

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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) plays a permissive role in the development of benign prostatic hyperplasia (BPH), and phosphodiesterase 5 inhibitors (PDE5is) have been found to be effective for BPH and lower urinary tract symptoms (LUTS) in clinical trials. This study investigated the effect of T on smooth muscle (SM) contractile and regulatory signaling pathways, including PDE5 expression and functional activity in prostate in male rats (sham-operated, surgically castrated, and castrated with T supplementation). In vitro organ bath studies, real-time RT-PCR, Western blot analysis, and immunohistochemistry were performed. Castration heavily attenuated contractility, including sensitivity to phenylephrine with SM myosin immunostaining revealing a disrupted SM cell arrangement in the stroma. PDE5 was immunolocalized exclusively in the prostate stroma, and orchiectomy signficantly reduced PDE5 immunopositivity, mRNA, and protein expression, along with nNOS and ROK␤ mRNA, whereas it increased eNOS plus ␣ 1a and ␣1b adrenoreceptor expression in castrated animals. The PDE5i zaprinast significantly increased prostate strip relaxation to the nitric oxide donor sodium nitroprusside (SNP) in control but not castrated rats. But SNP alone was more effective on castrated rats, comparable with sham treated with SNP plus zaprinast. T supplementation prevented or restored all above changes, including SNP and zaprinast in vitro responsiveness. In conclusion, our data show that T positively regulates PDE5 expression and functional activities in prostate, and T ablation not only suppresses prostate size but also reduces prostatic SM contractility, with several potential SM contraction/relaxation pathways implicated. Zaprinast findings strongly suggest a major role for PDE5/cGMP in this signaling cascade. PDE5 inhibition may represent a novel mechanism for treatment of BPH. benign prostatic hyperplasia; contraction; lower urinary tract symptoms; phosphodiesterase 5; phosphodiesterase 5 inhibitors; smooth muscle myosin; nitric oxide BENIGN PROSTATIC HYPERPLASIA (BPH), a cause of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in aging men, is a common pathological process with a histological prevalence of ϳ50 -60% for men in their 60s and 80 -90% for men in their 70s and 80s (54). Although the etiology of prostatic hyperplasia is not well understood, androgens and aging are necessary for the development of BPH (55) containing two physiological components, static (increased prostate size) (40) and dynamic [increased prostatic smooth muscle (SM) tone] (11).The dynamic tone of prostatic SM is regulated mainly by the ␣ 1 -adrenoreceptor (72), with up to 50% of the total urethral pressure in BPH patients being attributed to ␣-adrenoreceptormediated muscle tone (18), and ␣ 1 -blockers are the first-line therapy for BPH. Three major subtypes of adrenoreceptors have been identified to exist in the prostate at the molecular level (␣ 1a , ␣ 1b , and ␣ 1d ) (15). Eckert et al. (14), using a patch clamp combined with the fura-2 fluorescence calcium labelin...

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Section: E249 Testosterone Regulates Pde5 In Prostatic Smooth Musclementioning

confidence: 99%

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

Zhang

Zang

Wei

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

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“…Consistent evidence of improvements in LUTS has been shown with PDE5-Is, either alone or in combination with -blockers (Martinez-Salamanca, Carballido et al 2011). However, urodynamic results or objective measures of urinary flow are lacking (Martinez-Salamanca, Carballido et al 2011). …”

Section: Future Approaches To Bphmentioning

confidence: 86%

Benign Prostate Hyperplasia and Chronic Kidney Disease

Leão¹,

Pereira²,

Coelho³

2012

Chronic Kidney Disease

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“…The first-line pharmacologic treatment of OAB after conservative measures fail has been and remains anticholinergic pharmacotherapy, which has targeted the muscarinic receptors in the bladder. Other agents are still under investigation, and these include β 3 -adrenergic receptor agonists [5], phosphodiesterase inhibitors [6], neurokinin-1 receptor antagonists [7], and intravesical botulinum toxin [8]. In this review, we discuss the suggested mechanism of action of the various anticholinergic agents used to treat OAB and thereafter review the high-level evidence for their use.…”

Section: Introductionmentioning

confidence: 98%

Summary of Anticholinergic Pharmacotherapy Available for Overactive Bladder Dysfunction

Mangera

Chapple

2011

Curr Bladder Dysfunct Rep

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Bladder over activity affects many individuals worldwide. Anticholinergic therapy has become standard first-line pharmacotherapy for overactive bladder dysfunction after failure of conservative measures. Several different anticholinergic agents are currently utilized in clinical practice. In this article, we review the mechanism of action of these drugs. This review aims to summarize the contemporary evidence base behind the use of these agents in terms of efficacy, safety, and patient satisfaction. Anticholinergic agents lead to improvements in symptoms of urgency, frequency, and urgency incontinence; however, there are associated side effects related to dry mouth, pruritus, constipation, and the central nervous system.

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Phosphodiesterase Type 5 Inhibitors in the Management of Non-neurogenic Male Lower Urinary Tract Symptoms: Critical Analysis of Current Evidence

Cited by 51 publications

References 70 publications

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

Benign Prostate Hyperplasia and Chronic Kidney Disease

Summary of Anticholinergic Pharmacotherapy Available for Overactive Bladder Dysfunction

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