Pathophysiology Of Lower Urinary Tract Symptoms Research Articles

Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction.

Intraurethral inoculation of mice with uropathogenic Escherichia coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of a mast cell stabilizer, cromolyn sodium, and the histamine 1 receptor antagonist cetirizine di-hydrochloride in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.NEW & NOTEWORTHY LUTS-associated benign prostatic hyperplasia is derived from a combination of immune activation, extracellular matrix remodeling, hyperplasia, and smooth muscle cell contraction in prostates of men. Using a mouse model, we describe the importance of mast cells in regulating these multiple facets involved in the pathophysiology of LUTS. Mast cell inhibition alleviates both pathology and urinary dysfunction in this model, suggesting the potential for mast cell inhibition as a therapeutic that prevents and reverses pathology and associated symptomology.

LUTS in pelvic ischemia: a new concept in voiding dysfunction.

Lower urinary tract symptoms (LUTS) are a group of voiding symptoms affecting both genders as they age. Traditionally, LUTS in men were commonly attributed to bladder outlet obstruction (BOO) due to benign prostatic enlargement (BPE). It was later shown that, in approximately one-third to more than one-half of cases, LUTS in men are not associated with BOO. Urodynamic changes in the male bladder and symptom scores in aging men were found to be identical to their age-matched female counterparts. These observations suggested that LUTS in the elderly do not necessarily relate to BOO and may result from local changes in bladder muscle, nerves, and blood vessels. However, aging factors predisposing to bladder dysfunction and LUTS remain unknown. Growing evidence suggests that aging-associated pelvic ischemia may be a primary factor in the development of nonobstructed nonneurogenic overactive bladder and LUTS. First identified in experimental models and later in clinical studies, pelvic ischemia has been shown to compromise the lower urinary tract structure and lead to dysfunction. Structural and functional consequences of bladder and prostate ischemia have been documented in animal models. Clinical studies have shown that bladder and prostate blood flow decreases with aging. The severity of LUTS in elderly patients correlates with the degrees of bladder ischemia. LUTS improvement with α blockers has been associated with increased bladder blood flow. Pelvic ischemia may be an independent factor in nonobstructed nonneurogenic bladder instability and LUTS. Further research into the pathophysiology of LUTS in pelvic ischemia may lead to better management of this problem in the elderly population.

Inhibition of smooth muscle force generation by focal adhesion kinase inhibitors in the hyperplastic human prostate.

Smooth muscle contraction may be critical for lower urinary tract symptoms (LUTS) in patients with benign prostate hyperplasia and requires stable anchorage of the cytoskeleton to the cell membrane. These connections are regulated by focal adhesion kinase (FAK). Here, we addressed the involvement of FAK in the regulation of smooth muscle contraction in hyperplastic human prostate tissues. Prostate tissues were obtained from radical prostatectomy. Expression of FAK and focal adhesion proteins was assessed by Western blot analysis and immunohistochemical stainings. Effects of the FAK inhibitors PF-573228 and Y-11 on contraction of prostate strips were examined in the organ bath. Expression of FAK and focal adhesion proteins (integrin-5α, paxilin, and c-Src) was detected by Western blot analysis in prostate samples. By double immunofluorescence staining with calponin and pan-cytokeratin, expression of FAK was observed in stromal and epithelial cells. Immunoreactivity for FAK colocalized with integrin-5α, paxilin, talin, and c-Src. Stimulation of prostate tissues with the α1-adrenergic agonist phenylephrine increased the phosphorylation state of FAK at Tyr³⁹⁷ and Tyr⁹²⁵ with different kinetics, which was blocked by the α1-adrenoceptor antagonist tamsulosin. Norepinephrine and phenylephrine induced concentration-dependent contractions of prostate strips. Both FAK inhibitors PF-573228 and Y-11 significantly inhibited norepinephrine- and phenylephrine-induced contractions. Finally, PF-573228 and Y-11 inhibited contractions induced by electric field stimulation, which was significant at the highest frequency. In conclusion, α1-adrenergic smooth muscle contraction or its regulation involves FAK in the human prostate. Consequently, FAK may be involved in the pathophysiology of LUTS and in current or future LUTS therapies.

MP19-09 NSC23766, A RAC GTPASE INHIBITOR, INHIBITS SMOOTH MUSCLE CONTRACTION IN THE HYPERPLASTIC HUMAN PROSTATE

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research1 Apr 2014MP19-09 NSC23766, A RAC GTPASE INHIBITOR, INHIBITS SMOOTH MUSCLE CONTRACTION IN THE HYPERPLASTIC HUMAN PROSTATE Thomas Kunit, Andrea Schreiber, Christian Gratzke, Beata Rutz, Raphaela Waidelich, Frank Strittmatter, Christian G. Stief, and Martin Hennenberg Thomas KunitThomas Kunit More articles by this author , Andrea SchreiberAndrea Schreiber More articles by this author , Christian GratzkeChristian Gratzke More articles by this author , Beata RutzBeata Rutz More articles by this author , Raphaela WaidelichRaphaela Waidelich More articles by this author , Frank StrittmatterFrank Strittmatter More articles by this author , Christian G. StiefChristian G. Stief More articles by this author , and Martin HennenbergMartin Hennenberg More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.710AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate smooth muscle contraction may be critical for pathophysiology and therapy of lower urinary tract symptoms (LUTS) in patients with benign prostate hyperplasia (BPH). Although several options are available, medical therapy still remains a challenge, in particular with respect to the imminent demographic transition. Consequently, new strategies for inhibition of smooth muscle contraction in the lower urinary tract are of interest. Rac, a small monomeric GTPase, is an important regulator of smooth muscle tone outside the lower urinary tract. Here, we studied Rac inhibition and expression in the human prostate. METHODS Periurethral prostate tissues were obtained from patients undergoing radical prostatectomy (n=27). Effects of the Rac inhibitor, NSC23766 on adrenergic contraction were studied in the organ bath. Rac expression was examined by Western blot analysis, and immunofluorescence staining. RESULTS The α1-adrenoceptor agonist, phenylephrine (0.1-100 μM), induced concentration-dependent contractions of human prostate strips. NSC23766 (50 μM) inhibited phenylephrine-induced contractions (Fig.). This was significant at 0.3 μM phenylephrine (p<0.05 for NSC23766 vs. control), 1 μM (p<0.003), 3 μM (p<0.002), 10 μM (p<0.0002), and 30 μM (p<0.03). Similarly, NSC23766 (50 μM) inhibited noradrenaline-induced contractions (Fig.). This was significant at 0.3 μM (p<0.05) noreadrenaline, 1 μM (p<0.02), 3 μM (p<0.03), 10 μM (p<0.02), 30 μM (p<0.02), and 100 μM (p<0.03). In Western blot analysis revealed bands with the expected size for Rac1 in prostate tissue from each patient being included in this analysis. After immunofluorescence staining, immunoreactivity for Rac1 was observed in the prostate stroma, and in glands. Double labeling with calponin and pan-cytokeratin indicated localization in smooth muscle cells and in epithelial cells. CONCLUSIONS Rac is critical for prostate smooth muscle contraction. Regulation of smooth muscle tone in the lower urinary tract by Rac may be involved in pathophysiology of LUTS, and may represent a putative new target for therapy. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e192 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Thomas Kunit More articles by this author Andrea Schreiber More articles by this author Christian Gratzke More articles by this author Beata Rutz More articles by this author Raphaela Waidelich More articles by this author Frank Strittmatter More articles by this author Christian G. Stief More articles by this author Martin Hennenberg More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Future Pharmacotherapies for Male Lower Urinary Tract Symptoms

Lower urinary tract symptoms (LUTS) in men are a prevalent condition with complex and multifactorial etiology. Different types of symptoms overlap among them and treatment has evolved to a more holistic and individualized approach. Advances in the understanding of LUTS pathophysiology has led to the development of new drugs and compounds to treat male LUTS. Recently, new drugs, such as phosphodiesterase type 5 inhibitors and beta3 adrenergic agonists, have been approved for the treatment of LUTS and have just made it to clinical practice. New agents for intraprostatic injection, for instance PRX302 and NX-1207, are currently under evaluation in clinical trials with promising results. Rho-kinase inhibitors, transient receptor potential channel blockers and activators of soluble guanylyl cyclase are examples of compounds targeting different pathways involved in the pathophysiology of male LUTS, which have been tested in experimental studies. New advances in pharmacotherapy may also allow combination of drugs to achieve synergistic effect.

Current Understanding of the Interplay between Oab &amp; Bph

Lower urinary tract symptoms (LUTS) are very common and bothersome to men. For many years all male LUTS, even the storage ones, were attributed to the prostate, which was the target of therapeutic approaches. Increasing knowledge of the contribution of bladder dysfunction to LUTS pathophysiology has brought into focus detrusor overactivity (DO) and its treatments. Available data indicate that in many cases DO and overactive bladder (OAB) symptoms are secondary to bladder outlet obstruction (BOO), due to prostatic disease. Accumulating evidence also suggests that the two pathologies may coexist because they share etiologic factors. Despite the prevalence of storage symptoms in men with benign prostatic hyperplasia (BPH), antimuscarinics, the main treatment for OAB, were infrequently used because of fear of urinary retention. Available clinical trials indicate that the addition of an antimuscarinic to prostate-targeted treatments, or treatment initiation with a combination regimen, is safe in terms of urinary retention and offers improvements in storage symptoms. Nevertheless, the improvement in overall quality of life is modest. Criteria for the selection of patients likely to benefit most from the addition of antimuscarinics to common BPH treatments are lacking.

Late Onset Hypogonadism and Lower Urinary Tract Symptoms: New Insights

Late onset hypogonadism was originally perceived as an academic topic. In the course of two decades it has become an issue impacting on everyday urology. For long time clinical conditions, such as cardiovascular disease, diabetes mellitus type 2, sexual dysfunction and urological complaints affecting the aging male, were regarded as independent clinical entities, treated by a number of medical specialists. Over the last decade their close interrelationship could be convincingly demonstrated. Declining testosterone levels in elderly appear to be central to the above pathologies. Epidemiological studies show that prostate disease occurs at an age when serum testosterone levels decline. It is now clear that erectile dysfunction is a local expression of endothelial dysfunction of the cardiovascular system. Testosterone deficiency is associated with an increased incidence of cardiovascular disease and diabetes mellitus, sequels of the metabolic syndrome. There is a relationship between the metabolic syndrome and lower urinary tract symptoms (LUTS). The pathophysiology of LUTS has much in common with the pathological substrate of erectile dysfunction with regard to vascular factors and the role of nitric oxide, explaining why phosphodiesterase type 5 inhibitors have often a beneficial effect on LUTS. It must be regarded an omission not to include testosterone measurements in the work-up of the LUTS, erectile dysfunction, cardiovascular disease and diabetes mellitus type 2. These conditions hinge on testosterone deficiency, and if testosterone deficiency can be proven, testosterone treatment can improve these conditions. There are many sites in the lower urinary tract where testosterone exerts effects.

The effects of chronic hyperlipidemia on bladder function in myocardial infarction‐prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits

Lower urinary tract symptoms (LUTS) are common in the aging population. LUTS cause profoundly negative impacts on their quality of life. Pathophysiology of LUTS is multifactorial, and recently, bladder ischemia and metabolic syndrome have been suggested as etiological factors. To evaluate chronic hyperlipidemia on bladder function, we examined the functional and histological changes of the bladder in myocardial infarction-prone Watanabe Heritable Hyperlipidemic (WHHLMI) rabbits. 20- to 24-month-old WHHLMI rabbits and age- and sex-matched control rabbits were prepared. Bladder functions were evaluated using cystometrograms and functional experiments with isolated bladder specimens. Histological studies of bladder and internal iliac arteries were performed with hematoxylin and eosin staining. The bladder was also stained immunohistochemically with mouse monoclonal S-100 antibodies and sheep polyclonal calcitonin gene-related peptide (CGRP) antibodies. In cystometric examination, WHHLMI rabbits showed significantly shorter micturition interval, smaller voided volume with non-voiding contractions, and lower micturition pressure, as compared to control. The functional experiments showed that carbachol- and electrical field stimulation-induced contractions were significantly decreased in WHHLMI rabbits than those in control. In WHHLMI rabbits, cross-sections of internal iliac arteries showed significant atherosclerosis and thickening of media. Bladder showed thinner urothelium and decreased smooth muscle area in WHHLMI rabbits, as compared to control. WHHLMI rabbits showed a significant decrease in S-100 protein positive neurons, and an increased number of CGRP positive neurons. This study demonstrated that WHHLMI rabbits showed detrusor overactivity with decreased detrusor contraction. It is suggested that chronic hyperlipidemia contributes to the bladder dysfunction.

New Concepts in Epidemiology of Lower Urinary Tract Symptoms in Men

Context Recent insights into the pathophysiology of lower urinary tract symptoms (LUTS) have led to the introduction of new concepts, such as postmicturition LUTS as a third category alongside voiding and storage LUTS; the consideration of the lower urinary tract as a functional unit, in view of the importance of the role of the bladder in LUTS; and the realization that the prevalence of LUTS is similar in the two genders. Objective Verify whether epidemiologic information supports these concepts. Evidence acquisition Four important epidemiologic studies—the International Continence Society “Benign Prostatic Hyperplasia” (ICS-BPH) study, the EPIC survey, the Boston Area Community Health (BACH) survey, and the Epidemiology of LUTS (EpiLUTS) survey—were identified and reviewed. Evidence synthesis The epidemiologic findings not only support these concepts but also have provided additional information that should be borne in mind for the management of LUTS. Findings include the facts that voiding symptoms are more common in men and storage symptoms are more common in women, that the prevalence of LUTS does not differ by race, and that treatment seeking by patients with LUTS is very low. In addition, LUTS have been found to be associated with chronic diseases. This observation may lead to insights into the pathophysiology of LUTS. Conclusion Epidemiologic studies support the new concepts.

An investigation of the relationship between sex‐steroid levels and urological symptoms: results from the Boston Area Community Health survey

To investigate whether circulating levels of sex hormones are associated with urological symptoms, using data from the Boston Area Community Health (BACH) Survey. BACH used a multistage stratified-cluster approach to randomly sample 5506 adults aged 30-79 years in Boston, MA, USA. Anthropometric measures, lifestyle and psychosocial factors, comorbidities and urological symptoms were obtained using a questionnaire administered by an interviewer. Serum testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS), dihydrotestosterone (DHT) and oestradiol (E2) levels were measured, and bioavailable testosterone (BT) was calculated in 1899 men (538 Black, 651 Hispanic and 710 White). Regression analysis was used to investigate the relationships between androgen levels and American Urological Association symptom index (AUA-SI), lower urinary tract symptoms (LUTS) (> or = 8 on the AUA-SI), urinary incontinence (UI), dribble and hesitancy. Of all subjects, 19% reported LUTS, 6% UI, 9% dribble and 4% hesitancy. Testosterone, BT and DHEAS levels were inversely related to the AUA-SI (P = 0.009, <0.001 and <0.001, respectively); SHBG values and the AUA-SI were positively correlated (P < 0.001). Adjusting for age, BT and DHEAS levels had negative relationships with the AUA-SI; BT and DHEAS levels were negatively related to LUTS and SHBG was positively related to LUTS (both P < 0.001); after age adjustment, only LUTS and DHEAS remained related, and only the relationship between dribble and E2 remained significant; no hormone levels were related to hesitancy. Circulating levels of sex hormones are generally not significant predictors of urological symptoms in men after adjusting for age. The pathophysiology of LUTS is complex and probably includes factors other than circulating sex steroid levels.

Overactive bladder in the male patient: bladder, outlet, or both?

Generations of urologists have presumed that the cause of lower urinary tract symptoms (LUTS) in men is infravesical (prostatic) obstruction. When symptoms such as urinary urgency and frequency can't easily be explained directly by obstruction, secondary effects of obstruction on the bladder are identified as causative factors. Although to some extent this explanation may still be accurate, emerging concepts in the pathophysiology of LUTS in men may be at odds with these traditional explanations. The idea that primary bladder pathology may explain the symptom complex in at least one subset of men with LUTS has both experimental and clinical support. This review discusses the physiologic and clinical observations used to explain the mechanisms underlying LUTS. Specifically, this review focuses on two data sets: one supporting infravesical obstruction as the causative factor for LUTS, and another positing that a primary bladder abnormality is responsible.