RESUMO
PURPOSE: Bladder ischemia and oxidative stress contribute to the pathogenesis of bladder dysfunction caused by bladder outlet obstruction. H2 reportedly acts as an effective antioxidant. We investigated whether oral ingestion of H2 water would have a beneficial effect on bladder function in a rat model of bladder outlet obstruction. MATERIALS AND METHODS: H2 water was made by dissolving H2 gas in ordinary drinking water using a hydrogen water producing apparatus. The bladder outlet obstruction model was surgically induced in male rats. Rats with obstruction were fed H2 water or ordinary drinking water. On week 4 postoperatively cystometry was performed. Oxidative stress markers and the bladder nerve growth factor level were determined. Bladder tissues were processed for pharmacological studies and histological analysis. RESULTS: The micturition interval and micturition volume significantly decreased in obstructed rats given ordinary drinking water. These decreases were significantly suppressed by oral ingestion of H2 water. Increased post-void residual volume in obstructed rats was significantly reduced by H2 water. Obstruction led to a significant increase in bladder weight, oxidative stress markers and nerve growth factor. H2 water significantly suppressed these increases without affecting bladder weight. There was no significant difference in histological findings between rats with bladder obstruction given H2 water and ordinary drinking water. Decreased responses of detrusor muscle strips from obstructed bladders to KCl, carbachol and electrical field stimulation were reversed by H2 water ingestion. CONCLUSIONS: Results suggest that H2 water could ameliorate bladder dysfunction secondary to bladder outlet obstruction by attenuating oxidative stress.
Assuntos
Hidrogênio/uso terapêutico , Obstrução do Colo da Bexiga Urinária/complicações , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/prevenção & controle , Água , Animais , Modelos Animais de Doenças , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Obstrução do Colo da Bexiga Urinária/metabolismoRESUMO
INTRODUCTION: Arterial occlusive disease is the leading cause of erectile dysfunction (ED). Using an established rat model we wanted to characterize the changes caused by atherosclerosis-induced chronic ischemia on penile structures and erectile function. AIM: To investigate the effect of melatonin on these parameters. METHODS: Adult male Sprague-Dawley rats were divided into control, arterial injury (AI) and AI with melatonin treatment groups. AI and AI-melatonin groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI surgery for 8 weeks. AI-melatonin group rats received melatonin (20 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, erectile function was tested. Corpus cavernosum (CC) tissues were processed for pharmacological and immunohistochemical studies, histological examination, and Western blotting. MAIN OUTCOME MEASURES: Apomorphine test was performed to evaluate erectile function. Organ bath study was performed to measure the CC-contraction induced by KCl and phenylephrine, and relaxation induced by electrical field stimulation (EFS) and sodium nitroprusside (SNP). RESULTS: The number of erectile responses was significantly lower in the AI group (2.5 ± 0.5/hour) than in the control (5.0 ± 0.7/hour) and in the melatonin-treated groups (5.0 ± 0.3/hour). The responses to phenylephrine were lower in the AI-groups than in the controls, but there were no differences between control and AI-melatonin groups. SNP-induced relaxation in the AI-melatonin group was higher than in the AI, but lower than in control group. The EFS-elicited relaxation responses in the AI group were significantly lower than in the control and AI-melatonin groups. Compared to controls, CC tissues from the AI group showed significantly higher collagen content, and lower protein expression of eNOS and nNOS, and increased expression of iNOS. These changes were reduced or prevented by melatonin treatment. CONCLUSION: Treatment with melatonin reduced/prevented functional and morphological changes induced by chronic ischemia on penile structure and function.
Assuntos
Aterosclerose/complicações , Disfunção Erétil/tratamento farmacológico , Isquemia/complicações , Melatonina/farmacologia , Ereção Peniana/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Colesterol na Dieta , Doença Crônica , Modelos Animais de Doenças , Disfunção Erétil/fisiopatologia , Humanos , Isquemia/fisiopatologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND/AIMS: This study was performed to investigate the detailed mechanism underlying the effects of the selective α(1A)-adrenoceptor antagonist, silodosin, on bladder function in a rat model of atherosclerosis-induced chronic bladder ischemia (CBI). METHODS: The CBI model was prepared by balloon endothelial injury of the bilateral iliac arteries in male rats. Using an osmotic pump, the CBI rats received either silodosin or vehicle alone subcutaneously for 8 weeks. Rats received a 2% cholesterol diet throughout the experiment. Bladder blood flow (BBF) was measured. Immunohistochemical staining was performed to determine the nerve distribution and nerve growth factor expression in the bladder. Bladders were used for muscle strip contraction analysis. The expression levels of muscarinic M2 and M3 receptors were measured. RESULTS: Silodosin abrogated the decrease in BBF in CBI rats. Silodosin prevented the decrease in nerve distribution and increase in nerve growth factor expression in the CBI model. Bladder contractile response was reduced in the CBI group. Silodosin ameliorated the effect on the bladder contractile response. The level of muscarinic M3 receptor mRNA present in the bladder of CBI rats was increased by silodosin. CONCLUSION: The results of this study suggest that silodosin ameliorates the denervation of the bladder and effects on detrusor contractile function under ischemic conditions by restoring BBF.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Indóis/farmacologia , Isquemia , Músculo Liso , Fluxo Sanguíneo Regional/efeitos dos fármacos , Bexiga Urinária , Animais , Aterosclerose/complicações , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Isquemia/etiologia , Isquemia/metabolismo , Isquemia/patologia , Isquemia/fisiopatologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/irrigação sanguínea , Músculo Liso/inervação , Músculo Liso/patologia , Músculo Liso/fisiopatologia , Fator de Crescimento Neural/metabolismo , Ratos Sprague-Dawley , Receptor Muscarínico M2/genética , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Ubiquitina Tiolesterase/metabolismo , Bexiga Urinária/irrigação sanguínea , Bexiga Urinária/inervação , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologiaRESUMO
BACKGROUND: The 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. METHODS: Adult 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. RESULTS: Iliac 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. CONCLUSIONS: In 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).
Assuntos
Carbolinas/uso terapêutico , Isquemia/tratamento farmacológico , Próstata/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Animais , Carbolinas/farmacologia , Isquemia/patologia , Masculino , Próstata/irrigação sanguínea , Próstata/patologia , Ratos , Ratos Sprague-Dawley , Tadalafila , Vasodilatadores/farmacologiaRESUMO
PURPOSE: We investigated the effect of pelvic arterial occlusive disease on the RhoA/Rho-kinase pathway in a rat model of chronic bladder ischemia. MATERIALS AND METHODS: Male adult Sprague Dawley® rats at age 16 weeks were divided into arterial endothelial injury and control groups. The injury group underwent balloon endothelial injury of the bilateral iliac arteries and received a 2% cholesterol diet to induce pelvic arterial occlusive disease. The control group received a regular diet. At 8 weeks cystometrograms were performed. Bladder tissue was harvested for pharmacological studies and Western blot. RESULTS: Cystometrograms showed significantly lower bladder capacity in the arterial endothelial injury group than in controls. Organ bath studies revealed significantly decreased phasic contractions induced by carbachol in bladder strips from the injury group than from controls. In controls bladder strip tonic contractions induced by carbachol were significantly decreased compared with phasic contractions. However, no significant difference was observed between phasic and tonic contractions in the injury group. The Rho-kinase inhibitor Y-27632 produced a concentration dependent decrease in tonic contractions, which was more pronounced in the injury group. Western blot showed significantly increased RhoA and Rho-kinase ß expression in the injury group. CONCLUSIONS: Our results suggest that pelvic arterial occlusive disease can affect the RhoA/Rho-kinase pathway in the bladder. This pathway might possibly be involved in the maintenance of tonic contraction and contribute to the bladder hyperactivity caused by pelvic arterial occlusive disease.
Assuntos
Arteriopatias Oclusivas/enzimologia , Isquemia/enzimologia , Músculo Liso/irrigação sanguínea , Músculo Liso/enzimologia , Bexiga Urinária/irrigação sanguínea , Bexiga Urinária/enzimologia , Quinases Associadas a rho/fisiologia , Animais , Doença Crônica , Masculino , Pelve , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: The objectives of this study were to examine the expression of various cellular proteins within the urothelium (UT) and lamina propria (LP) following chronic bladder ischemia in the rat urinary bladder. MATERIALS AND METHODS: Urinary bladders were removed from adult Sprague-Dawley rats 8 weeks after creation of bladder ischemia and from sham controls. Immunocytochemistry was used to examine distribution of LP-vimentin-immunoreactive (IR) cells and connexins (Cx26; Cx43), and western immunoblotting or ELISA for proteins involved in UT barrier and sensory functions. RESULTS: Ischemia was associated with a significant increase in LP-vimentin-IR cells and increased expression of the gap junction proteins Cx26 and Cx43 within the bladder UT as compared to sham control. Ischemia also resulted in an increased (p < 0.05) expression level of the junctional marker (ZO-1) and non-significantly increased expressions of the trophic factor nerve growth factor as well as norepinephrine. CONCLUSIONS: Our findings reveal that chronic ischemia alters a number of proteins within the UT and underlying LP. These proteins are involved in barrier function, remodeling, repair as well as intercellular communication. The increased expression of LP-vimentin-IR cells suggests that changes in cell-cell interactions could play a role in ischemia-induced changes in bladder activity.
Assuntos
Isquemia/metabolismo , Bexiga Urinária/metabolismo , Urotélio/metabolismo , Vimentina/biossíntese , Animais , Doença Crônica , Conexina 26 , Conexina 43/biossíntese , Conexinas/biossíntese , Modelos Animais de Doenças , Masculino , Mucosa/irrigação sanguínea , Mucosa/metabolismo , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/irrigação sanguínea , Urotélio/irrigação sanguíneaRESUMO
Chronic bladder ischemia is potentially a common cause of lower urinary tract symptoms in the elderly. Epidemiological studies have shown a close association between lower urinary tract symptoms and vascular risk factors for atherosclerosis, and investigations using transrectal color Doppler ultrasonography have shown a negative correlation between decreased lower urinary tract perfusion and International Prostate Symptom Score in elderly patients with lower urinary tract symptoms. Bladder blood flow is also known to decrease in men with bladder outlet obstruction as a result of benign prostatic hyperplasia. Studies in animal models suggest that chronic bladder ischemia and repeated ischemia/reperfusion during a micturition cycle might produce oxidative stress, leading to denervation of the bladder and the expression of tissue-damaging molecules in the bladder wall, which could be responsible for the development of bladder hyperactivity progressing to bladder underactivity. The effects of drugs with different mechanisms of action; for example, α1-adrenoceptor antagonists, phosphodiesterase type 5 inhibitors, free radical scavengers and ß3-adrenoceptor agonist, have been studied in animal models of chronic bladder ischemia. The drugs, representing different treatment principles for increasing blood flow and decreasing oxidative stress, showed protective effects not only on urodynamic parameters, but also on negative effects on muscle contractility and on detrimental structural bladder wall changes. Improvement of lower urinary tract perfusion and control of oxidative stress can be considered new therapeutic strategies for treatment of bladder dysfunction induced by chronic ischemia.
Assuntos
Aterosclerose/tratamento farmacológico , Isquemia/fisiopatologia , Estresse Oxidativo/fisiologia , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/irrigação sanguínea , Idoso , Animais , Antioxidantes/uso terapêutico , Aterosclerose/fisiopatologia , Doença Crônica , Humanos , Isquemia/tratamento farmacológico , Sintomas do Trato Urinário Inferior , Masculino , Estresse Oxidativo/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/uso terapêutico , Receptores Adrenérgicos alfa 1/uso terapêutico , Obstrução do Colo da Bexiga Urinária/fisiopatologiaRESUMO
OBJECTIVES: To determine whether lysophosphatidic acid activates the mitogen-activated protein kinase and increases DNA synthesis in human bladder smooth muscle cells, and to examine the involvement of lysophosphatidic acid and lysophosphatidic acid receptor in mechanical stretch-induced mitogen-activated protein kinase activation in cultured human bladder smooth muscle cells. METHODS: TaqMan reverse transcription polymerase chain reaction was used to determine the mRNA expression levels of six lysophosphatidic acid receptor subtypes. Mitogen-activated protein kinase activity enhanced by either lysophosphatidic acid or mechanical stretch was measured by western blotting. The effect of lysophosphatidic acid on DNA synthesis was assessed by 5-bromo-2'-deoxy-uridine incorporation assay. RESULTS: Lysophosphatidic acid 1 subtype mRNA was predominantly expressed (96%). Lysophosphatidic acid activated the mitogen-activated protein kinase in a concentration-dependent manner. C-jun NH2 -terminal kinase showed the highest activity among the three subsets of the mitogen-activated protein kinase family members (c-jun NH2 -terminal kinase, extracellular signal-regulated kinases, p38). Lysophosphatidic acid also increased incorporation of 5-bromo-2'-deoxy-uridine. These responses were suppressed by Ki16425 (lysophosphatidic acid receptor antagonist). Mechanical stretch mainly induced c-jun NH2 -terminal kinase activation. This activation was partially inhibited by Ki16425. CONCLUSIONS: Lysophosphatidic acid might activate the c-jun NH2 -terminal kinase component of the mitogen-activated protein kinase family and DNA synthesis through lysophosphatidic acid receptors (presumably, through lysophosphatidic acid 1) in human bladder smooth muscle cells. The present study also implicates the involvement of lysophosphatidic acid and lysophosphatidic acid receptors in mechanical stretch-induced c-jun NH2 -terminal kinase activation. Lysophosphatidic acid receptor can be partially activated by mechanical stretching through lysophosphatidic acid-dependent or independent mechanism.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lisofosfolipídeos/química , Receptores de Ácidos Lisofosfatídicos/metabolismo , Proliferação de Células , Células Cultivadas , Humanos , Sistema de Sinalização das MAP Quinases , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Bexiga Urinária/citologiaRESUMO
PURPOSE: We assessed whether progressive vascular damage causes bladder underactivity in rats. MATERIALS AND METHODS: Adult male Sprague Dawley® rats were divided into 4 groups. Controls received a regular diet and tap water. The L-NAME group received a 2% cholesterol diet and L-NAME (3 mg/ml) dissolved in drinking water. The arterial injury group underwent balloon endothelial injury of the common iliac arteries and received a 2% cholesterol diet and tap water after injury. The arterial injury/L-NAME group also received L-NAME dissolved in drinking water. At 8 weeks urodynamics were performed, bladder tissue was harvested for pharmacological studies, and the iliac arteries and bladders were histologically examined. RESULTS: Iliac arteries from the injury and injury/L-NAME groups showed neointimal formation and luminal occlusion but arteries from the L-NAME group did not. In the L-NAME and injury groups bladder capacity and voided volume were less than in controls. Conversely, in the injury/L-NAME group these cystometric parameters were significantly greater than in the other groups. Post-void residual volume in the injury/L-NAME group tended to increase compared with the other groups. Contractile responses of bladder strips to various stimuli in the L-NAME, injury and injury/L-NAME groups were significantly less than in controls and the lowest in the injury/L-NAME group. The injury and injury/L-NAME groups showed a significantly increased percent of collagen compared to controls. CONCLUSIONS: Pelvic arterial occlusive disease plus vascular endothelial dysfunction may cause progressive vascular damage resulting in bladder dysfunction that develops from bladder hyperactivity to bladder underactivity.
Assuntos
Doenças da Bexiga Urinária/etiologia , Doenças Vasculares/complicações , Animais , Arteriopatias Oclusivas/complicações , Progressão da Doença , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: Cellular therapy induced transient urodynamic improvement in a rat model of Parkinson disease in which bladder dysfunction was noted after unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. We sought to prolong the effect by injecting allogeneic rat bone marrow mesenchymal stromal cells before and after microencapsulation into the substantia nigra pars compacta. MATERIALS AND METHODS: Female rats underwent unilateral stereotactic injection of 6-hydroxydopamine in the medial forebrain bundle. Injection was performed in the ipsilateral substantia nigra pars compacta using vehicle alone or vehicle with nonmicroencapsulated or microencapsulated rat bone marrow derived mesenchymal stromal cells. Rats were evaluated by cystometry 7, 14, 28 and 42 days after treatment. Brains were extracted for immunostaining. RESULTS: At 42 days the nonmicroencapsulated group had lower threshold and intermicturition pressure, spontaneous activity and AUC than vehicle treated animals. Rats that received microencapsulated cells had lower threshold pressure at 28 days and lower spontaneous activity at 42 days than vehicle treated rats. Microencapsulated and nonmicroencapsulated rat bone marrow derived mesenchymal stromal cells were noted in the substantia nigra pars compacta up to 42 days after transplantation. At 42 days tyrosine hydroxylase positive neurons were more numerous in the substantia nigra pars compacta of the nonmicroencapsulated group, followed by the microencapsulated and vehicle treated groups. CONCLUSIONS: Urodynamic effects of the 6-hydroxydopamine lesion persisted up to 42 days after vehicle injection. Transplantation of nonmicroencapsulated rat bone marrow derived mesenchymal stromal cells improved urodynamic pressure by 42 days after treatment more markedly than microencapsulated cells. This was associated with more tyrosine hydroxylase positive neurons in the treated substantia nigra pars compacta of the nonmicroencapsulated group, suggesting that functional improvement requires a juxtacrine effect.
Assuntos
Medula Óssea/fisiopatologia , Terapia Baseada em Transplante de Células e Tecidos , Transplante de Células-Tronco Mesenquimais , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Urodinâmica , Animais , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Microscopia Confocal , Oxidopamina , Ratos , Ratos Sprague-Dawley , Substância Negra/fisiopatologiaRESUMO
The aim of this study was to evaluate the association between antibodies against cytomegalovirus (CMV) glycoprotein B (gB) and acute rejection after transplantation. Seventy-seven consecutive renal transplant recipients in a D + /R+ setting were studied. Biopsy-proven rejection occurred in 35% of the recipients. Among these recipients, 85% had antibodies against CMV gB. The rate of acute rejection was significantly higher in recipients with antibodies against gB than in those without them. Antibodies against gB can be a useful predictor of acute rejection in renal transplant recipients in a D + /R+ setting.
Assuntos
Anticorpos Antivirais/imunologia , Epitopos/imunologia , Rejeição de Enxerto/etiologia , Transplante de Rim/efeitos adversos , Proteínas do Envelope Viral/imunologia , Adulto , Anticorpos Antivirais/sangue , Humanos , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Proteínas do Envelope Viral/químicaRESUMO
The pathophysiology of lower urinary tract symptoms (LUTS), particularly in the elderly, seems to be multifactorial. One of the factors involved may be chronic ischemia of the bladder caused by bladder outflow obstruction (male) or atherosclerosis (male/female). The mechanisms by which chronic ischemia initiates and causes LUTS and progressive bladder dysfunction, and the time course of the effects, are incompletely known. Bladder ischemia and repeated ischemia/reperfusion during a micturition cycle may produce oxidative stress, leading to denervation of the bladder and the expression of tissue damaging molecules in the bladder wall. This may be responsible for the development of detrusor overactivity progressing to detrusor underactivity and inability to empty the bladder. The extent of bladder dysfunction in chronic bladder ischemia may depend on the degree and duration of ischemia. To prevent chronic bladder ischemia caused by atherosclerosis and to treat its consequences, more pathophysiological knowledge is needed. Several animal models of atherosclerosis-induced chronic bladder ischemia are available and should be useful tools for further research.
Assuntos
Isquemia/fisiopatologia , Sintomas do Trato Urinário Inferior/fisiopatologia , Bexiga Urinária/irrigação sanguínea , Bexiga Urinária/fisiopatologia , Animais , Aterosclerose/complicações , Doença Crônica , Modelos Animais de Doenças , Feminino , Humanos , Isquemia/etiologia , Isquemia/metabolismo , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/metabolismo , Masculino , Estresse Oxidativo , Fluxo Sanguíneo Regional , Bexiga Urinária/metabolismo , Obstrução do Colo da Bexiga Urinária/complicações , MicçãoRESUMO
AIMS: In human urinary bladder, beta3-ARs play an important role in promoting detrusor relaxation during the storage phase of the micturition cycle. The present study investigated whether a Trp64Arg polymorphism of the gene encoding the beta3-AR is associated with overactive bladder (OAB) syndrome. METHODS: This study involved 100 women with OAB and 101 healthy control women without OAB. Hair root samples were obtained from all subjects and used for beta3-AR gene analysis. Polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis was performed to analyze a polymorphism in the gene of Trp64Arg. RESULTS: The overall frequency of the 64Arg variant (heterozygous plus homozygous) in OAB patients was 47% and significantly higher than the frequency of 22.8% found in non-OAB control women. Within OAB patients, numbers of micturitions per day, urgency episodes per day, and urgency incontinence episodes per day in the 64Arg variant carriers were not significantly different from those in the normal gene carriers. CONCLUSIONS: This study shows that the Trp64Arg polymorphism in the beta3-AR gene is weakly but significantly associated with OAB syndrome.
Assuntos
Receptores Adrenérgicos beta 3/genética , Bexiga Urinária Hiperativa/genética , Adulto , Idoso , DNA/genética , Feminino , Frequência do Gene , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Fragmento de RestriçãoRESUMO
PURPOSE: We investigated the effects of the selective α1A-adrenoceptor antagonist silodosin on bladder blood flow and bladder function in a rat model of atherosclerosis induced chronic bladder ischemia without bladder outlet obstruction. MATERIALS AND METHODS: The chronic bladder ischemia model was prepared by creating balloon endothelial injury of the bilateral iliac arteries in male rats. Using an osmotic pump, chronic bladder ischemia rats received silodosin subcutaneously at a rate of 0.1 or 0.3 mg/kg per day, or vehicle for 8 weeks. All groups received a 2% cholesterol diet throughout the experiment. For each α1-adrenoceptor subtype mRNA expression in bladder microvessels was examined by in situ hybridization. Bladder blood flow was measured using a laser speckle blood flow imager. Malondialdehyde in bladder tissue and 8-hydroxy-2'-deoxyguanosine in urine were measured as markers of oxidative stress. A metabolic cage study and cystometry were performed in conscious rats. RESULTS: The expression of all α1-adrenoceptor subtype mRNA was observed in rat bladder microvessels. Silodosin abrogated the decreased bladder blood flow in the empty bladder and during bladder distention that were evident in rats with chronic bladder ischemia. Levels of oxidative stress markers in these rats were significantly decreased by silodosin administration. Silodosin ameliorated bladder dysfunction in rats with chronic bladder ischemia in the metabolic cage study and on cystometry. CONCLUSIONS: Results suggest that in ischemic conditions α1-adrenoceptor antagonists such as silodosin may improve bladder function by restoring bladder blood flow.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Indóis/farmacologia , Isquemia/tratamento farmacológico , Isquemia/fisiopatologia , Bexiga Urinária/irrigação sanguínea , Bexiga Urinária/efeitos dos fármacos , Animais , Aterosclerose/fisiopatologia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Modelos Animais de Doenças , Taxa de Filtração Glomerular , Imuno-Histoquímica , Hibridização In Situ , Isquemia/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Obstrução do Colo da Bexiga UrináriaRESUMO
PURPOSE: We investigated the effect of tadalafil on chronic ischemia related bladder dysfunction. MATERIALS AND METHODS: Adult male Sprague-Dawley® rats were divided into control, arterial endothelial injury and arterial endothelial injury with tadalafil treatment groups. The arterial injury and arterial injury-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet after injury. Arterial injury-tadalafil rats received tadalafil (2 mg/kg per day) orally for 8 weeks after injury. The control group received a regular diet. At 8 weeks urodynamic investigation was performed. Bladder tissue was harvested for pharmacological studies, and histological examination of the iliac arteries and bladders was performed. RESULTS: Iliac arteries from arterial injury and arterial injury-tadalafil rats showed neointimal formation and luminal occlusion. In the arterial injury group the micturition interval was significantly shorter (mean ± SEM 5.4 ± 0.5 vs 11.1 ± 1.1 minutes), and bladder capacity and voided volume were less than in controls. Contractile responses of bladder strips to KCl, electrical field stimulation and carbachol were significantly less after arterial injury than in controls. The arterial injury group showed a significantly increased percent of collagen compared with controls (mean 37.4% ± 1.8% vs 21.5% ± 1.8%). In the arterial injury-tadalafil group intimal formation and luminal occlusion were not prevented. However, there were significant improvements in all functional and morphological parameters compared with the arterial injury group. CONCLUSIONS: Arterial occlusive disease may lead to chronic bladder ischemia and bladder hyperactivity. Chronic treatment with tadalafil protects bladder function and morphology, resulting in decreased bladder hyperactivity. If valid for humans, the data support phosphodiesterase 5 inhibition as treatment for chronic ischemia related bladder dysfunction.
Assuntos
Carbolinas/uso terapêutico , Isquemia/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Bexiga Urinária/irrigação sanguínea , Bexiga Urinária/fisiopatologia , Animais , Carbolinas/farmacologia , Doença Crônica , Modelos Animais de Doenças , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Ratos , Ratos Sprague-Dawley , Tadalafila , Bexiga Urinária/efeitos dos fármacosRESUMO
UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There are many studies showing melatonin's potent endogenous free radical scavenging and antioxidative properties, which protect against oxidative insult, but there is no information about the effect of chronic treatment with melatonin on oxidative-stress-related bladder dysfunction caused by chronic ischaemia. The model used in this study shows that functional and morphological changes caused by chronic bladder ischaemia and oxidative stress were protected by chronic treatment with melatonin, resulting in improvement of bladder hyperactivity. OBJECTIVE: To investigate the potential therapeutic benefit of melatonin for chronic ischaemia-related bladder dysfunction. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into control, arterial injury (AI), AI with low-dose melatonin treatment (AI-ML) and AI with high-dose melatonin treatment (AI-MH) groups. The AI, AI-ML and AI-MH groups underwent a procedure to induce endothelial injury of the iliac arteries and received a 2% cholesterol diet after AI. The rats in the AI-ML and AI-MH groups were treated with melatonin 2.5 or 20 mg/kg/day orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, urodynamic investigations were performed. Bladder tissues and iliac arteries were processed for pharmacological studies, and for immunohistochemical and histological examination. RESULTS: Iliac arteries from AI, AI-ML and AI-MH rats displayed neo-intimal formation and luminal occlusion. In the AI group, the micturition interval was significantly shorter, and bladder capacity and voided volume were lower than in the controls. Contractile responses of bladder strips to KCl, electrical field stimulation and carbachol were significantly lower after AI than in the controls. The AI bladders were found to have a significantly increased collagen ratio, oxidative stress and inducible nitric oxide synthase (NOS) expression, and decreased constitutive NOS expression compared with the controls. In the AI-ML and AI-MH groups, neo-intimal formation was not prevented, but there were beneficial effects on bladder function and morphology. In the AI-ML group, the beneficial effects failed to reach statistical significance. In the AI-MH group, melatonin significantly improved oxidative stress and NOS expression, and there were significant improvements in all the functional and morphological variables compared with the AI group. CONCLUSIONS: Arterial occlusive disease may lead to chronic bladder ischaemia and bladder hyperactivity associated with oxidative stress. In the model used, chronic treatment with melatonin protected bladder function and morphology, probably through its free radical scavenging and antioxidative properties. Melatonin may prevent oxidative damage and improve ischaemia-related bladder dysfunction.
Assuntos
Isquemia/tratamento farmacológico , Melatonina/uso terapêutico , Bexiga Urinária/irrigação sanguínea , Bexiga Urinária/fisiopatologia , Animais , Doença Crônica , Isquemia/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologiaRESUMO
AIMS: The present study investigated the role of the Rho-kinase (ROK) pathway in the maintenance of bladder tone during the storage phase, and its effects on bladder compliance. METHODS: Muscle strips from isolated rat bladder (detrusor strips) were used to evaluate the effects of the ROK inhibitors Y-27632 and HA-1077 on resting tension, which is independent of G-protein coupled pathways. Stretch-induced ROK activation was assessed by measuring phosphorylation of MYPT1 (myosin phosphatase targeting subunit) using Western blotting. The effect of ROK inhibitors on bladder compliance during bladder filling was assessed in an in vitro whole bladder model. RESULTS: Y-27632 and HA-1077 caused concentration-dependent relaxation of detrusor strips. Stretch increased MYPT1-p[Thr853] levels by approximately 1.5-fold in normal Krebs buffer. The ROK inhibitor Y-27632 abolished the stretch-induced increase and reduced the level of MYPT1-p[Thr853] to <50% of the basal values in normal Krebs buffer. Stretch-induced phosphorylation of MYPT1 was independent of Ca(2+) originating from either extracellular or intracellular stores. When tested in the isolated whole rat bladder model, HA-1077 significantly increased bladder compliance at both 3 and 10 µM. CONCLUSIONS: This study demonstrates that the ROK pathway is constitutively active and stretch further activates the ROK pathway, which contributes to the generation of bladder tone, thereby affecting bladder compliance.
Assuntos
Ativação Enzimática , Mecanotransdução Celular , Contração Muscular , Músculo Esquelético/enzimologia , Músculo Esquelético/inervação , Reflexo de Estiramento , Bexiga Urinária/enzimologia , Bexiga Urinária/inervação , Quinases Associadas a rho/metabolismo , Animais , Cálcio/metabolismo , Complacência (Medida de Distensibilidade) , Relação Dose-Resposta a Droga , Humanos , Masculino , Mecanotransdução Celular/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteína Fosfatase 1/metabolismo , Ratos , Ratos Sprague-Dawley , Reflexo de Estiramento/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
Robot-assisted radical prostatectomy has been shown to have comparable and possibly improved postoperative continent rates compared with retropubic and laparoscopic radical prostatectomy. However, postoperative urinary incontinence has remained one of the most bothersome postoperative complications. The basic concept of the intraoperative technique to improve postoperative urinary continence is to maintain as normal anatomical and functional structure in the pelvis as possible. Therefore, improved knowledge of the normal structure in the pelvis should lead to a greater understanding of the pathophysiology of urinary incontinence, and further development of intraoperative techniques to improve the outcomes of urinary continence. It might be necessary to carry out three steps to realize improvement of the early return of urinary continence after robot-assisted radical prostatectomy: (i) preservation (bladder neck, neurovascular bundle, puboprostatic ligament, pubovesical complex, and/or urethral length, etc.); (ii) reconstruction (posterior and/or anterior reconstruction, and/or reattachment of the arcus tendineus to the bladder neck, etc.); and (iii) reinforcement (bladder neck plication and/or sling suspension, etc.). On the basis of these steps, further modifications during robot-assisted radical prostatectomy should be developed to improve urinary continence and quality of life after robot-assisted radical prostatectomy.
Assuntos
Prostatectomia/efeitos adversos , Prostatectomia/métodos , Incontinência Urinária/etiologia , Humanos , Incontinência Urinária/fisiopatologia , Incontinência Urinária/prevenção & controleRESUMO
SUBJECTS AND METHODS: ⢠Secondary analysis of anonymous data from 10,434 patients enrolled in a postmarketing surveillance study of tamsulosin in Japan was performed. Data were prospectively collected through the central register from men diagnosed with LUTS in 1100 medical institutions between October 2004 and March 2005. ⢠Those who had received an α1-adrenoceptor antagonist within 1 week before the initial visit were excluded. ⢠The survey items were International Prostate Symptom Score (IPSS), quality of life (QOL) score, and patient characteristics including age, bodyweight, body mass index, and LUTS-related comorbid conditions. ⢠Data on IPSS items were used in a hierarchical cluster analysis (Ward's method). RESULTS: ⢠Of 10,434 men with LUTS, 9910 were included in the analysis after 5% data trimming (524 patients). Five symptom clusters were identified and the symptom types of each cluster were examined. ⢠The largest cluster (27%) consisted of patients with multiple severe symptoms, i.e. complaining of six or more symptoms with a mean score ≥2.8. In contrast, the second smallest cluster (13%) consisted of patients with minimal symptoms, i.e. complaining of essentially one or two symptom with a mean score ≤2.1. ⢠The other three clusters were labelled based on their dominant symptoms. The clusters were weak stream (27%), storage symptoms (21%) and voiding symptoms (12%). ⢠The storage symptoms group was older, and had more comorbidities. ⢠The distribution of the QOL score was different among the clusters, and the percentage of patients who were very dissatisfied was highest in the multiple severe symptoms group and lowest in the minimal symptoms group. CONCLUSIONS: ⢠Cluster analysis using the IPSS showed that men with LUTS can be classified into five characteristic symptom groups. ⢠A new approach to symptom-based classification may be useful to elucidate the pathology of male LUTS and individualize the therapeutic strategy for affected patients, but further studies are needed.
Assuntos
Sintomas do Trato Urinário Inferior/classificação , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Pessoa de Meia-Idade , Noctúria/etiologia , Estudos Prospectivos , Hiperplasia Prostática/complicações , Qualidade de Vida , Bexiga Urinária Hiperativa/etiologia , Incontinência Urinária de Urgência/etiologiaRESUMO
AIMS: To develop a rat model of atherosclerosis-induced chronic bladder ischemia and investigate the effect of chronic bladder ischemia on voiding behavior and bladder function. METHODS: Adult male rats were divided into three groups. The arterial injury (AI) group underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet. The sham group underwent sham operation and received a 2% cholesterol diet. The control group received a regular diet. After 8 weeks, a metabolic cage study and cystometry were performed without anesthesia. Bladder blood flow was measured using a laser Doppler blood flowmeter. Histological examination of the iliac arteries and the bladder was performed. The bladder was also processed for immunohistochemical staining of oxidative stress markers. RESULTS: The metabolic cage study showed that in the AI group, voiding frequency significantly increased while voided volume significantly decreased. Cystometry showed that the frequency of reflex bladder contractions was significantly higher in the AI group. Filling-induced decrease in bladder blood flow was the greatest in the AI group. Histological study showed that in the AI group alone, atherosclerotic occlusion occurred in the iliac arteries as well as in the downstream bladder microvessels. Oxidative stress marker positive cells were more prevalent in the AI bladder than in the other bladders. CONCLUSIONS: Combined with a high-cholesterol diet, endothelial injury of iliac arteries induced arterial occlusive disease in the downstream vessels and consequent bladder ischemia in rats. This model of chronic bladder ischemia showed detrusor overactivity manifested as an increase in voiding frequency.