Chronic Pelvic Ischemia Research Articles

Statin administration ameliorates ischemia-induced overactive bladder with improvement of blood flow and anti-inflammatory effects in rats.

Statins are widely used to treat dyslipidemia and have been shown to reduce the risk of ischemic heart disease and cerebrovascular disease. The effects of statins on ischemia-induced overactive bladder (OAB) and the associated mechanisms were investigated in a rat model of chronic pelvic ischemia. A pelvic ischemia model was created by iliac arterial injury (AI) and a high-fat diet using male Sprague-Dawley rats. Rats were assigned to 3 groups: control group, AI group, and AI + statin group. The control group underwent sham operation and was fed a normal diet. The AI group underwent AI surgery and was fed a high-cholesterol diet. The AI + statin group was administered a statin for 4 weeks. Cystometry was performed for 8 weeks after surgery. Blood flow was evaluated by laser meter. Thickness of the iliac arteries was measured, and microvascular density in the lamina propria was evaluated by immunostaining for CD31. Expressions of inflammatory cytokines in the bladder were measured by real-time PCR. Cystometry showed a significantly shorter voiding interval and lower bladder capacity in the AI group than in the control group. The AI + statin group showed improvement of these findings. The AI group showed decreased bladder blood flow, increased iliac arterial wall thickening, and decreased microvascular density compared to the control group. Statin administration improved blood flow. Iliac arterial wall thickening was suppressed, and microvascular density was increased by statin administration, though not significantly. Real-time PCR showed significantly higher expressions of inflammatory cytokines (IL-6, IL-8, and TNF-α) in the AI group than in the control group, and IL-6 and IL-8 expressions were lower in the AI + statin group than in the AI group. The present results suggest that statins are effective in OAB caused by arteriosclerosis and ischemia. The mechanism of their effects involves improved bladder blood flow and decreased bladder inflammation.

Molecular Regulation of Concomitant Lower Urinary Tract Symptoms and Erectile Dysfunction in Pelvic Ischemia.

Aging correlates with greater incidence of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in the male population where the pathophysiological link remains elusive. The incidence of LUTS and ED correlates with the prevalence of vascular risk factors, implying potential role of arterial disorders in concomitant development of the two conditions. Human studies have revealed lower bladder and prostate blood flow in patients with LUTS suggesting that the severity of LUTS and ED correlates with the severity of vascular disorders. A close link between increased prostatic vascular resistance and greater incidence of LUTS and ED has been documented. Experimental models of atherosclerosis-induced chronic pelvic ischemia (CPI) showed increased contractile reactivity of prostatic and bladder tissues, impairment of penile erectile tissue relaxation, and simultaneous development of detrusor overactivity and ED. In the bladder, short-term ischemia caused overactive contractions while prolonged ischemia provoked degenerative responses and led to underactivity. CPI compromised structural integrity of the bladder, prostatic, and penile erectile tissues. Downstream molecular mechanisms appear to involve cellular stress and survival signaling, receptor modifications, upregulation of cytokines, and impairment of the nitric oxide pathway in cavernosal tissue. These observations may suggest pelvic ischemia as an important contributing factor in LUTS-associated ED. The aim of this narrative review is to discuss the current evidence on CPI as a possible etiologic mechanism underlying LUTS-associated ED.

Vibegron inhibits enhanced spontaneous contractions induced by anoxia/reoxygenation in isolated whole bladder from rats

It has been recently proposed that repeated bladder ischemia/reperfusion induced by chronic pelvic ischemia may lead to detrusor overactivity, followed by lower urinary tract symptoms. Vibegron is a selective β3-adrenoceptor agonist approved for the treatment of overactive bladder. Several studies have tested β3-adrenoceptor agonists using animal models with detrusor overactivity related to bladder ischemia/reperfusion. However, whether β3-adrenoceptor agonists directly affect ischemia/reperfusion-evoked detrusor overactivity is unclear. Therefore, we examined whether bladder anoxia/reoxygenation could enhance spontaneous bladder contractions (SBCs) and investigated the effect of vibegron on enhanced SBCs. Isolated whole bladders from rats were incubated with Krebs solution aerated with 95% N2 + 5% CO2 for 5 h (anoxia). Subsequently, the bathing solution was replaced with an oxygen-saturated solution (reoxygenation). Anoxia/reoxygenation caused enhancement of the amplitude but not the frequency of SBC compared with that before reoxygenation. Vibegron (0.3–30 μM) inhibited this increase in SBC amplitude, but not the frequency, in a dose-dependent manner. The inhibitory effect of vibegron was not affected by pretreatment with the adenylyl cyclase inhibitor SQ22536 (100 μM) or protein kinase A inhibitor KT5720 (1 μM) and was not accompanied by considerable changes in cyclic adenosine monophosphate (cAMP) content in the bladder. In contrast, the large conductance potassium channel inhibitor iberiotoxin (100 nM) suppressed the inhibitory effect of vibegron. These results suggest that bladder ischemia/reperfusion induces SBC enhancement and vibegron directly inhibits detrusor overactivity via the large conductance potassium channel, which involves β3-adrenoceptor, rather than the cAMP signaling pathway.

The concentration of androgens and estrogens in benign prostatic hyperplasia

Background. The etiology of benign prostatic hyperplasia (BPH) has not been fully studied. The main role in the induction of prostate tissue proliferation is assigned to the metabolism of testosterone. Recently, it has been reported that one of the risk factors for BPH is a chronic violation of the blood supply to the prostate.The study objective is to determine the level of reproductive hormones in blood serum and prostate tissue when creating a model of chronic ischemia.Materials and methods. The model of chronic pelvic ischemia was created in 10 white non-linear mature rats by partial ligation of the inferior vena cava. The control group of the study consisted of 10 male rats of the same age. After 1.5 months, we performed a hormonal study in all rats (n = 20) determining the concentration of testosterone, dihydrotestosterone and estradiol in the blood and prostate tissue. Also, in all animals (n = 20), a morphological study of the prostate was performed.Results. We’ve found a significant increase in prostate mass in the main group of rats by 16.4 % (p <0.05). Animals with BPH and impaired blood supply to the prostate had changes in their hormonal status: increased levels of testosterone (p <0.05) and dihydrotestosterone (p >0.05) in the prostate tissue.Conclusion. Long-term ischemic disorders in the prostate may be a trigger factor for the development of BPH due to an increase in the concentration of testosterone.

Re: The Impact of Chronic Pelvic Ischemia on LUTS and Urinary Levels of Neuroinflammatory, Inflammatory, and Oxidative Stress Markers in Elderly Men: A Case-Control Study.

Re: The Impact of Chronic Pelvic Ischemia on LUTS and Urinary Levels of Neuroinflammatory, Inflammatory, and Oxidative Stress Markers in Elderly Men: A Case-Control Study.

Molecular and Histologic Evidence of Novel Erectile Dysfunction Rat Model as an Aging Atherosclerosis Model: A Preliminary Study.

PurposeTo validate a novel arteriogenic erectile dysfunction (ED) model with atherosclerosis (AS) based on molecular and histologic evidence induced by chronic pelvic ischemia (CPI) and determine effect of phosphodiesterase-5 inhibitor treatment.Materials and MethodsTwenty 16-week-old male Sprague–Dawley rats were divided into three experimental groups (Group I, untreated sham-operated rats with regular diet; Group II, CPI with cholesterol diet; Group III, CPI model with cholesterol diet and mirodenafil). Erectile function was accessed using maximum intracavernous pressure (ICP) and ICP/mean arterial pressure (MAP). Molecular changes were examined by western blot analysis using hypoxia inducible factor 1-alpha (HIF-1α), endothelial nitric oxide synthase (eNOS), and transforming growth factor beta-1 (TGF-β1) antibodies. Collagen change was evaluated by Masson's trichrome staining.ResultsIn vivo measurements of ICP and ICP/MAP in Group II were significantly lower than those in Group I (p<0.01). Smooth muscle/collagen ratio in Group II was significantly lower than that in Group I (p<0.05). After treatment with mirodenafil for four weeks, Group III showed significantly higher levels of ICP and ICP/MAP than Group II (p<0.05). Western blot analysis showed that HIF-1α and TGF-β1 levels were significantly higher in Group II whereas eNOS levels were significantly lower in Group II than those in Group I or III.ConclusionsA novel arteriogenic ED with AS model is successfully induced by CPI and validated based on molecular and histologic evidences.

The Impact of Chronic Pelvic Ischemia on LUTS and Urinary Levels of Neuroinflammatory, Inflammatory, and Oxidative Stress Markers in Elderly Men: A Case-control Study

ObjectiveTo investigate lower urinary tract symptoms (LUTS) and urinary levels of neuroinflammatory, inflammatory, and oxidative stress markers in elderly men with chronic pelvic ischemia (CPI) caused by significant aortoiliac disease. Materials and MethodsThirteen men aged over 60 years, with aorta, unilateral or bilateral common/internal iliac artery occlusion documented by computed tomography angiography or angiography, were enrolled from the vascular surgery department. Twelve sex- and age-matched controls without significant aortoiliac disease were used for comparison. Exclusion criteria included neurogenic bladder dysfunction, bladder or prostate cancer, prostatic surgery, pelvic radiotherapy, or chronic treatment for LUTS. Participants underwent urological examination, including assessment of International Prostate Symptom Score (IPSS), uroflowmetry, postvoid residual (PVR), and prostate volume. Urine samples were collected, and levels of neuroinflammatory (nerve growth factor, NGF), inflammatory (cytokines), and oxidative stress markers (8-hydroxy-2′-deoxyguanosine) were determined by enzyme-linked immunosorbent assay. ResultsGroups were similar for age, PVR, prostate volume, and most cardiovascular risk factors. IPSS was higher in patients with CPI (11 ± 3 vs 8 ± 2, P = .02), with a significant mean difference between groups of three points. Urinary NGF was significantly higher in men with CPI (3.7 ± 0.8 vs 2.9 ± 0.7, P = .02), but no differences were found in inflammatory and oxidative biomarkers among groups. ConclusionSevere CPI in elderly men is associated with a significant increase in LUTS and bladder neurogenic inflammation, as suggested by the increase of NGF release in urine, sensitizing bladder afferents. These findings confirm the relevance of ischemia in bladder function and appear to validate animal models of bilateral iliac artery occlusion.

Морфологические доказательства ишемической природы фиброза предстательной железы при классическом синдроме хронической тазовой боли/хроническом простатите IIIБ

To examine the structure of the prostate tissue in patients with III B chronic prostatitis (CP) and chronic pelvic pain syndrome (CPPS). The study analyzed transrectal fine-needle biopsy specimens of 10 patients with the verified diagnosis of chronic pelvic pain syndrome/category III B chronic prostatitis (CPPS/IIIB CP) according to the National Institutes of Health classification. Tissues were examined using light and electron microscopy, and immunohistochemical study of the expression of CD31, CD34, NSE and S-100 markers. All biopsy specimens of all patients showed fibroplastic changes of the prostate tissue most markedly pronounced in the stroma and muscle fibers in the form of total fibrosis, myofibril atrophy, and extracellular lipofuscin deposition. The examination revealed a significant reduction in the density of microcirculatory bed vessels and arteriolar luminal stenosis, a reduction in the number of nerve fibers, and compression of their fibrous tissue. No inflammatory changes were found in the prostate. In patients with CPPS/IIIB CP, the changes in the prostate at the microscopic and ultrastructural levels are characteristic of severe chronic tissue hypoxia, which leads to the development of fibrosis resulting in stenosis of microcirculatory bed vessels and degenerative changes in nerve fibers and cells. No signs of an inflammatory reaction in the examined tissue were established. Changes in the prostate tissue in CPPS/IIIB CP suggest the presence of chronic pelvic ischemia and exclude its association with inflammation as the main pathological process.

MP82-15 THE AMELIORATIVE POTENTIAL OF TAMSULOSIN ON BLADDER FUNCTION IN A RAT MODEL OF CHRONIC PELVIC ISCHEMIA

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology II1 Apr 2017MP82-15 THE AMELIORATIVE POTENTIAL OF TAMSULOSIN ON BLADDER FUNCTION IN A RAT MODEL OF CHRONIC PELVIC ISCHEMIA Norifumi Sawada, Satoru Kira, Tatsuya Ihara, Takanori Mochizuki, Yuki Imai, Hiroshi Nakagomi, Takahiko Mitsui, Karl-Erik Andersson, and Masayuki Takeda Norifumi SawadaNorifumi Sawada More articles by this author , Satoru KiraSatoru Kira More articles by this author , Tatsuya IharaTatsuya Ihara More articles by this author , Takanori MochizukiTakanori Mochizuki More articles by this author , Yuki ImaiYuki Imai More articles by this author , Hiroshi NakagomiHiroshi Nakagomi More articles by this author , Takahiko MitsuiTakahiko Mitsui More articles by this author , Karl-Erik AnderssonKarl-Erik Andersson More articles by this author , and Masayuki TakedaMasayuki Takeda More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2562AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The exact etiology of LUTS in human is still poorly understood. Alpha1-blockers are widely used in the treatment of LUTS associated with BPH. Tamsulosin has been reported to possess a potential of increasing blood flow in bladder microcirculation. Using a characterized rat model of chronic pelvic ischemia, we have studied the ameliorating potential of tamsulosin on the changes in bladder function caused by chronic ischemia. METHODS Chronic pelvic ischemia (CPI) was induced by causing bilateral endothelial injury of both iliac arteries and feeding a 2% cholesterol diet. A total of 60 male Sprague Dawley rats (18 weeks old) were divided into three groups: Control, CPI, and CPI-tamsulosin. The Control group received a regular diet and the CPI-tamsulosin group received tamsulosin (10 mg/kg/day) for 8 weeks. Eight weeks after surgery, half of the rats in the Control, CPI and CPI-tamsulosin groups were examined by cystometry and sacrificed for organ bath study. The other half of the rats from each group was examined 16 weeks after surgery (the CPI-tamsulosin group were continued treatment in the latter half of 8 weeks). RESULTS The iliac arteries from the AI showed neo-intimal proliferation and vascular occlusion. This was not prevented by tamsulosin treatment. After 8 weeks, there was no difference between CPI and CPI-tamsulosin groups in micturition interval (MI), bladder capacity (Bcap), and voiding volume (VV). Those parameters in both groups were significantly less than in the Control group (P<0.05). After 16 weeks, those parameters were improved in CPI-tamsulosin group without changing other parameters. CONCLUSIONS Tamsulosin treatment improved voiding function in rats with established chronic pelvic ischemia. The translational impact of this finding would be worth further study for improving the bladder function. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1102-e1103 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Norifumi Sawada More articles by this author Satoru Kira More articles by this author Tatsuya Ihara More articles by this author Takanori Mochizuki More articles by this author Yuki Imai More articles by this author Hiroshi Nakagomi More articles by this author Takahiko Mitsui More articles by this author Karl-Erik Andersson More articles by this author Masayuki Takeda More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD26-05 THE IMPACT OF ATHEROSCLEROSIS-INDUCED PELVIC ISCHEMIA ON LUTS IN ELDERLY MEN

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Non-neurogenic Voiding Dysfunction II1 Apr 2017PD26-05 THE IMPACT OF ATHEROSCLEROSIS-INDUCED PELVIC ISCHEMIA ON LUTS IN ELDERLY MEN Daniel Costa, Alice Porto, Ana Coelho, João Neves, Luís Vale, Carlos Silva, Tiago Antunes-Lopes, and Francisco Cruz Daniel CostaDaniel Costa More articles by this author , Alice PortoAlice Porto More articles by this author , Ana CoelhoAna Coelho More articles by this author , João NevesJoão Neves More articles by this author , Luís ValeLuís Vale More articles by this author , Carlos SilvaCarlos Silva More articles by this author , Tiago Antunes-LopesTiago Antunes-Lopes More articles by this author , and Francisco CruzFrancisco Cruz More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1213AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Several studies demonstrated the association between LUTS and atherosclerosis risk factors and metabolic syndrome. However, a direct impact of chronic pelvic ischemia on LUTS in elderly men was never fully determined. The only evidence is coming from animal models of iliac obstruction which show significant bladder dysfunction after ischemia. Herewith, we investigated LUTS and urinary levels of nerve growth factor (NGF) in elderly men with chronic pelvic ischemia caused by documented aorta, unilateral or bilateral common/internal iliac obstruction. METHODS Thirteen men >60y, with aorta, unilateral or bilateral common/internal iliac artery occlusion documented by angio-CT scan or angiography, were enrolled from the vascular surgery department. Twelve men >60y without significant aorto-iliac disease, as confirmed by image studies, were used as controls. Exclusion criteria included neurogenic bladder dysfunction, bladder or prostate cancer, prostate surgery, pelvic radiotherapy or chronic treatment for LUTS. Participants underwent urological examination, including IPSS score to assess LUTS, uroflowmetry, postvoid residual (PVR) and prostate volume determination. Urine samples were collected from all participants and urinary NGF was measured by ELISA to explore the presence of chronic neurogenic inflammation. RESULTS Data are summarized in the table. Both groups were identical for age and prostate volume. BMI was slightly higher in the control group. IPSS score was statistically significant higher in the pelvic ischemia group than in controls. The IPSS difference between the two groups was 3 points. Urinary NGF/creatinine was significantly higher in the ischemic patients. CONCLUSIONS Severe pelvic ischemia in elderly men is associated with a significant increase in LUTS and chronic bladder neurogenic inflammation, as suggested by the increase of NGF release, a neurotrophin that may sensitize bladder primary afferents. These findings confirm the relevance of pelvic ischemia in bladder function and validate animal models of bilateral iliac artery occlusion currently under use to investigate the pathophysiologic mechanisms at stake. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e507-e508 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Daniel Costa More articles by this author Alice Porto More articles by this author Ana Coelho More articles by this author João Neves More articles by this author Luís Vale More articles by this author Carlos Silva More articles by this author Tiago Antunes-Lopes More articles by this author Francisco Cruz More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

ANDROGEN DEFICIENCY AND PROGRESSION OF BENIGN PROSTATIC HYPERPLASIA IN PATIENTS WITH METABOLIC SYNDROME: IS THERE ANY CONTROVERSY? (A LITERATURE REVIEW)

The present review describes the mechanisms of benign prostatic hyperplasia (BPH) development in patients with metabolic syndrome (MS) and its association with androgen deficiency, which is frequently observed in these patients. We cover the data indicating that despite a reduced serum level of testosterone in patients with MS, they are more likely to be diagnosed with BPH, have more significant prostate enlargement, more rapid BPH progression, as well as deterioration of urination problems compared to patients of similar age without MS. The following factors are considered to trigger BPH in patients with MS: changes in the tissue metabolism of sex hormones with increased androgens and estrogens concentrations in the prostate gland despite the reduced serum androgen levels, relative prevalence of the estrogenic effects, chronic pelvic ischemia, stimulation of prostate cells proliferation due to the elevated insulin level and the increased secretion of growth factors, and developing chronic low-intensity inflammation. Specific features of BPH pathogenesis in individuals with MS suggest a correction of therapeutic approaches to BPH in such cases, because conventional therapy in patients with BPH and MS is less effective than in patients with BPH only.

Drug Concentration in Rat Plasma, Bladder, and Prostate After Mirodenafil Administration in a Chronic Pelvic Ischemia Model

To evaluate the distribution of a daily phosphodiesterase type 5 inhibitor dose (mirodenafil) in rat plasma and bladder and prostate tissue in a model of atherosclerosis-induced chronic pelvic ischemia. Thirty-two 18-week-old male Sprague Dawley rats were divided into two groups. Group I (n = 16) comprised a chronic pelvic ischemia model treated with mirodenafil and group II (n = 16) comprised a sham-operated model also treated with mirodenafil. The mirodenafil concentrations in each organ were measured at specific time points after 14 days of daily mirodenafil administration. The drug distribution ratio of group I to group II of each organ was measured, and the bladder tissue-to-plasma and prostate tissue-to-plasma ratios were calculated. The mean drug concentration in the bladder of the rats in group I did not differ significantly from that of group II after mirodenafil administration. In the prostate, the mean drug concentration of group I was significantly higher than that of group II at 1 and 4 hours after drug administration. The drug concentration was higher in the bladder tissue than in the prostate tissue and the bladder tissue-to-plasma ratio was significantly higher than the prostate tissue-to-plasma ratio. Our results suggest that mirodenafil levels might be sufficient in the target tissue after daily treatment in an ischemia-induced aging model. Considering the difficulties of tissue distribution study in human subjects, the results of this investigation provided meaningful evidence of the application of daily doses of mirodenafil for treating lower urinary tract symptoms in an aging population.

Effects of Omega-3 Fatty Acids on Erectile Dysfunction in a Rat Model of Atherosclerosis-induced Chronic Pelvic Ischemia.

The aim of this study was to investigate whether the omega-3 fatty acids help to improve erectile function in an atherosclerosis-induced erectile dysfunction rat model. A total of 20 male Sprague-Dawley rats at age 8 weeks were divided into three groups: Control group (n = 6, untreated sham operated rats), Pathologic group (n = 7, untreated rats with chronic pelvic ischemia [CPI]), and Treatment group (n = 7, CPI rats treated with omega-3 fatty acids). For the in vivo study, electrical stimulation of the cavernosal nerve was performed and erectile function was measured in all groups. Immunohistochemical antibody staining was performed for transforming growth factor beta-1 (TGF-β1), endothelial nitric oxide synthase (eNOS), and hypoxia inducible factor 1-alpha (HIF-1α). In vivo measurement of erectile function in the Pathologic group showed significantly lower values than those in the Control group, whereas the Treatment group showed significantly improved values in comparison with those in the Pathologic group. The results of western blot analysis revealed that systemically administered omega-3 fatty acids ameliorated the cavernosal molecular environment. Our study suggests that omega-3 fatty acids improve intracavernosal pressure and have a beneficial role against pathophysiological consequences such as fibrosis or hypoxic damage on a CPI rat model, which represents a structural erectile dysfunction model.

Chronic Pelvic Ischemia: Contribution to the Pathogenesis of Lower Urinary Tract Symptoms (LUTS): A New Target for Pharmacological Treatment?

The incidence of lower urinary tract symptoms, including overactive bladder (OAB), is continuing to rise, and is associated with a negative impact on quality of life and a heavy economic burden. A major risk factor for OAB is advancing age. The etiology of OAB is multifactorial and appears to involve myogenic, neurogenic, and urotheliogenic factors. In this article, we review the strengthening preclinical evidence supporting the contribution of chronic pelvic ischemia to the pathogenesis of OAB. In animal models, chronic ischemia induced by arterial injury and a high-fat diet upregulates markers of oxidative stress and proinflammatory cytokines in the urothelium and lamina propria, and leads to increased expression of nerve growth factor. These processes result in increased afferent activity and an increased frequency of micturition, reflecting a state of bladder hyperactivity. In severe, prolonged cases, bladder overactivity may develop into underactivity. Antimuscarinic therapies are the mainstay of OAB treatment, but their usefulness is limited by modest efficacy and troublesome side-effects. Our increasing understanding of the contribution of chronic ischemia to OAB is leading toward novel therapeutic options targeting chronic pelvic ischemia and its morphological, functional, and oxidative consequences. Preclinical trials have demonstrated encouraging results with α1 -adrenoreceptor blockade, phosphodiesterase type 5 inhibition, β3 -adrenoreceptor agonism, free radical scavenging, and stem cell therapy, in preventing morphological, biochemical and functional changes induced by chronic bladder ischemia.

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia.

BackgroundThe etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action.MethodsAdult male Sprague-Dawley rats were divided into control, arterial endothelial injury (AI), and AI with tadalafil treatment (AI-tadalafil) groups. AI and AI-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-tadalafil rats were treated with tadalafil (2 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, animals were sacrificed, and pharmacological and morphological studies on prostate tissues were performed.ResultsIliac arteries from AI rats displayed neo-intimal formation and luminal occlusion, an effect that was not prevented by tadalafil treatment. In the AI group, there was an obvious epithelial atrophy and a statistically significant increase in collagen fibers compared with the controls. Immunohistochemically, there was an up-regulation of smooth muscle α-actin (SMA). Contractile responses of prostate strips to KCl, electrical field stimulation (EFS), and phenylephrine (PE) were significantly higher after AI than in controls. Chronic treatment with tadalafil prevented the increase in contractile responses in ischemic tissue, and decreased the collagen deposition compared with the AI group.ConclusionsIn this rat model, chronic pelvic ischemia caused distinct functional and morphological changes in the prostate. Prostatic tissue from ischemic animals showed an increased contractile response to electrical and pharmacological stimulation, an increase in SMA, and an increased deposition of collagen. All these changes could be prevented by treatment with the PDE5 inhibitor, tadalafil, suggesting an involvement of cyclic guanosine monophosphate (cGMP). Prostate 75:233–241, 2015. © 2014 The Authors. The Prostate Published by Wiley Periodicals, Inc.

The role of phosphodiesterase type-5 inhibitors in treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia.

Phosphodiesterase type-5 (PDE-5) inhibitors are approved as the first line of therapy for the treatment of erectile dysfunction. However, different studies have been performed to study the use of these agents in other areas of urology. There are many studies related to the use of PDE-5 inhibitors as a monotherapy or combination therapy with alpha-blockers for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). It has been shown that contractions induced by various agents or electrical field stimulation in organ bath models of prostatic tissue can be reversed by PDE-5 inhibitors. Age, body mass index and the severity of LUTS are important factors for the selection of patients suitable for this treatment. It has also been reported that the use of PDE-5 inhibitors can relieve the chronic pelvic ischemia and endothelial dysfunction associated with metabolic syndrome. Most of the side effects observed with PDE-5 inhibitors are minimal and tolerable. The use of PDE-5 inhibitors is absolutely contraindicated in patients taking nitrate preparations. A significant interaction has not been observed even when a patient is taking several antihypertensive agents concurrently. Co-administration of alpha-blockers and PDE-5 inhibitors may result in orthostatic hypotension; therefore, patients should be stable on α-blocker therapy before the initiation of the combination therapy, and the initial PDE-5 inhibitor dose should be the lowest possible. In this review, our aim was to evaluate the role of PDE-5 inhibitors in the treatment of LUTS associated with BPH by analyzing the current literature.

Molecular Reactions and Ultrastructural Damage in the Chronically Ischemic Bladder

Clinical and basic research data suggest that pelvic ischemia may contribute to bladder overactivity. We characterized the molecular and ultrastructural reactions of the chronically ischemic bladder. A model of pelvic ischemia was developed by creating iliohypogastric/pudendal arterial atherosclerosis in rabbits. At 12 weeks conscious urinary frequency was examined, bladder blood flow was recorded and cystometrograms were done using general anesthesia. Bladder tissue was processed for molecular and ultrastructural analysis using quantitative real-time polymerase chain reaction, Western blot and transmission electron microscopy. Conscious urinary frequency and the frequency of spontaneous bladder contractions significantly increased in animals with pelvic ischemia. Bladder ischemia up-regulated the gene and protein expression of hypoxia inducible factor-1α, transforming growth factor-β and nerve growth factor B. Vascular endothelial growth factor gene expression also increased but protein levels were unchanged. Transmission electron microscopy of ischemic bladder samples showed swollen mitochondria with degraded granules, thickened epithelium, deformed muscle fascicles, collagen deposition and impaired microvasculature with thickened intima and disrupted endothelial cell junctions. Degenerating axonal and Schwann cell profiles, and myelin sheath splitting around axons and Schwann cells were evident in ischemic bladders. Interrupting pelvic blood flow resulted in an ischemic overactive bladder and significant increase in conscious urinary frequency. Molecular responses involving hypoxia inducible factor, transforming growth factor-β, vascular endothelial growth factor and nerve growth factor were associated with mitochondrial injury, fibrosis, microvasculature damage and neurodegeneration. Ischemia may have a key role in bladder overactivity and lower urinary tract symptoms.

Do atherosclerosis and chronic bladder ischemia really play a role in detrusor dysfunction of old age?

To determine whether atherosclerosis-induced chronic pelvic ischemia plays a role in the pathogenesis of aging bladder dysfunction. Old (70 weeks of age), apolipoprotein E gene knockout (APOEKO) mice, known to develop atherosclerosis spontaneously were used. A group of 70-week-old C57B mice were used as controls. The mice were killed and bladder smooth muscle strips obtained for in vitro contractile force determinations. The maximal contractions in response to 110 mM KCl, 10(-5) M bethanechol, and resting muscle tone were compared. The abdominal aortas and iliac arteries were harvested from the mice, and computerized image analysis was used to determine the percentage of surface area of atherosclerosis in each mouse. Although the APOEKO mice had massive atherosclerosis of the abdominal aortas and iliac arteries (lesion surface area +/- SEM 15.93% +/- 3.02%, n = 4), the control mice (n = 5) had no atherosclerosis at all. No statistically significant difference was found in detrusor function (KCl 0.48 +/- 0.11 versus 0.49 +/- 0.05, bethanechol 0.11 +/- 0.02 versus 0.13 +/- 0.04, tone 0.063 +/- 0.019 versus 0.07 +/- 0.004, respectively) between the APOEKO mice (n = 6) and the control mice (n = 6). Pelvic atherosclerosis caused no statistically significant changes in bladder smooth muscle contractile responses to bethanechol, KCl, or resting tone. The difference between these and previously reported results may have been a result of the more gradual onset of atherosclerosis in our model, which better mimics pelvic organ ischemia in the elderly.