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1.
Eur Urol ; 78(4): 624-628, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32475747

RESUMO

The current coronavirus disease 2019 (COVID-19) pandemic is a challenge for physicians in triaging patients in emergency rooms. We found a potentially dangerous overlap of classical urinary symptoms and the as yet not fully described symptoms of COVID-19. After a patient was primarily triaged as a urosepsis case and then subsequently diagnosed with COVID-19, we focused on an increase in urinary frequency as a symptom of COVID-19 and identified this in seven males out of 57 patients currently being treated in our COVID-19 wards. In the absence of any other causes, urinary frequency may be secondary to viral cystitis due to underlying COVID-19 disease. We propose consideration of urinary frequency as an anamnestic tool in patients with infective symptoms to increase awareness among urologists during the current COVID-19 pandemic to prevent fatal implications of misinterpreting urological symptoms.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Cistite/virologia , Pneumonia Viral/virologia , Incontinência Urinária de Urgência/virologia , Infecções Urinárias/virologia , Micção , Urodinâmica , Idoso , Técnicas de Laboratório Clínico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Cistite/diagnóstico , Cistite/fisiopatologia , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Incontinência Urinária de Urgência/diagnóstico , Incontinência Urinária de Urgência/fisiopatologia , Infecções Urinárias/diagnóstico , Infecções Urinárias/fisiopatologia
2.
Medicine (Baltimore) ; 99(26): e20852, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590783

RESUMO

RATIONALE: Either malacoplakia or xanthogranulomatous cystitis (XC) is a rare chronic infection disease of urinary bladder, which often mimics bladder masses undifferentiated from malignance and results in severe lower urinary tract symptoms. The malacoplakia combined with XC is even rarer in the literature. PATIENT CONCERNS: A 64-year-old female, who presented with nocturia, frequency of micturition, severe urgency with occasional urinary incontinence, and recurrent hematuria for >2 years, was diagnosed with azotemia and anemia. In addition, two 1.0 × 1.0 cm masses of bladder were detected by computer tomography. DIAGNOSES: Malacoplakia combined with xanthogranulomas cystitis was diagnosed histologically. Video urodynamic test showed poor bladder compliance (9 mL/comH2O), markedly decreased maximum bladder capacity (120 mL), and right vesicoureteral reflux at a low intravesical pressure level (25 cmH2O). INTERVENTIONS: Transurethral resection of bladder masses was carried out after treatment of urinary infection by intravenous piperacillin-tazobactam. Oral Ciprofloxacin and Tolterodine were postoperatively used to prevent recurrent lower urinary tract infections and alleviate detrusor overactivity. OUTCOMES: The treatment did not alleviate azotemia, frequency, urgency with incontinence, and bilateral hydroureteronephrosis, but the patient refused to undergo bladder augmentation on account of her poor economic status. LESSONS: Malacoplakia or/and xanthogranulomas cystitis may lead to poor bladder compliance and video urodynamic study should be considered in patients with refractory chronic lower urinary tract symptoms.


Assuntos
Cistite/complicações , Malacoplasia/complicações , Bexiga Urinária/anormalidades , Cistite/fisiopatologia , Feminino , Humanos , Malacoplasia/fisiopatologia , Pessoa de Meia-Idade , Noctúria/etiologia , Tomografia Computadorizada por Raios X/métodos , Bexiga Urinária/fisiopatologia , Incontinência Urinária/etiologia , Infecções Urinárias/etiologia , Infecções Urinárias/fisiopatologia
3.
Urology ; 137: 79-83, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31705946

RESUMO

OBJECTIVE: To investigate severe infectious complications after intravesical treatment with bacillus Calmette-Guérin (BCG). We examine a retrospective case series of 10 patients between 2006 and 2018 with severe cystitis or systemic infection after BCG. METHODS: Patients with BCG cystitis or disseminated infection were retrospectively identified between 2006 and 2018 at our institution. Cases were reviewed for bladder cancer treatments, demographics, treatment of infection, and outcomes. RESULTS: There was a 0.8% rate of severe BCG cystitis or disseminated infection. Seven patients experienced delayed-onset infections >3 months after last BCG instillation. Four had isolated bladder symptoms, and 5 had diverse systemic manifestations. One patient was asymptomatic and diagnosed on cystoscopic findings. All were treated with varied antibiotic regimens; 9 included antituberculous therapy, and 1 was treated with levofloxacin alone. Two underwent cystectomy for end-stage bladder. The remaining patients are asymptomatic with no residual effects. All are in remission for bladder cancer. CONCLUSION: Severe infectious complications after BCG are rare and thus difficult to study. Treatment regimens can vary widely. Thorough reporting of patient outcomes is essential to expand the limited body of knowledge.


Assuntos
Antibacterianos , Vacina BCG , Cistectomia/métodos , Cistite , Sepse , Neoplasias da Bexiga Urinária/terapia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Administração Intravesical , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/classificação , Vacina BCG/administração & dosagem , Vacina BCG/efeitos adversos , Cistite/diagnóstico , Cistite/etiologia , Cistite/fisiopatologia , Cistite/terapia , Feminino , Humanos , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Estudos Retrospectivos , Sepse/diagnóstico , Sepse/etiologia , Sepse/fisiopatologia , Sepse/terapia , Índice de Gravidade de Doença
4.
Neurourol Urodyn ; 39(2): 565-575, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31782979

RESUMO

AIMS: To investigate bladder function patterns following cystostomy and determine the best time window for cystometric evaluation of bladder function in conscious rats. MATERIALS AND METHODS: Cystostomy was performed in rats of the first seven groups; thereafter, cystometry was performed in the designed time interval. Noncystostomy rats of group 8 voided freely as control. Basal bladder pressure (Pves.basal ), maximum bladder pressure (Pves.max ), bladder threshold pressure (Pves.thre ), voiding interval (VI), bladder contraction duration (CD), bladder compliance (ΔC), voided volume (VV), postvoiding residual urine (PVR), and bladder capacity (BC) were recorded and compared with cystostomy groups, with VV, PVR, BC compared with the control values. Bladders were collected after the urodynamic study for weighing, hematoxylin-eosin, and Masson staining to investigate pathological changes. RESULTS: Pves.basal , Pves.max , and Pves.thre trended downward, while BC, VI, VV, and ΔC trended upward on days 1 to 5 postcystostomy. BC and VV significantly decreased on days 1 to 3 postcystostomy compared with control values; on days 5 to 15 postcystostomy, Pves.basal , Pves.max , Pves.thre , VI, VV, BC, and PVR were stable, and BC, VV, and PVR showed no significant differences from the control values. However, on day 21 postcystostomy, BC increased significantly compared with the controls. Bladder weight increased in the cystostomy groups compared with the controls. Pathological analysis showed severe acute bladder inflammation on days 1 to 3, mild inflammation on days 5 to 15, and increased collagen deposition in bladder tissue on day 21 postcystostomy. CONCLUSION: Cystometric evaluation of bladder function in conscious rats is best performed on days 5 to 15 postcystostomy.


Assuntos
Cistostomia , Bexiga Urinária/fisiologia , Animais , Complacência (Medida de Distensibilidade) , Cistite/fisiopatologia , Feminino , Contração Muscular/fisiologia , Tamanho do Órgão , Pressão , Ratos , Ratos Sprague-Dawley , Micção , Urodinâmica
5.
Am J Physiol Renal Physiol ; 318(2): F354-F362, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31869244

RESUMO

Recent breakthroughs demonstrate that peripheral diseases can trigger inflammation in the brain, causing psychosocial maladies, including depression. While few direct studies have been made, anecdotal reports associate urological disorders with mental dysfunction. Thus, we investigated if insults targeted at the bladder might elicit behavioral alterations. Moreover, the mechanism of neuroinflammation elicited by other peripheral diseases involves the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is present in microglia in the brain and cleaves and activates proinflammatory cytokines such as IL-1ß. Thus, we further explored the importance of NLRP3 in behavioral and neuroinflammatory changes. Here, we used the well-studied cyclophosphamide (CP)-treated rat model. Importantly, CP and its metabolites do not cross the blood-brain barrier or trigger inflammation in the gut, so that any neuroinflammation is likely secondary to bladder injury. We found that CP triggered an increase in inflammasome activity (caspase-1 activity) in the hippocampus but not in the pons. Evans blue extravasation demonstrated breakdown of the blood-brain barrier in the hippocampal region and activated microglia were present in the fascia dentata. Both changes were dependent on NLRP3 activation and prevented with 2-mercaptoethane sulfonate sodium (Mesna), which masks the effects of the CP metabolite acrolein in the urine. Finally, CP-treated rats displayed depressive symptoms that were prevented by NLRP3 inhibition or treatment with Mesna or an antidepressant. Thus, we conclude that CP-induced cystitis causes NLRP3-dependent hippocampal inflammation leading to depression symptoms in rats. This study proposes the first-ever causative explanation of the previously anecdotal link between benign bladder disorders and mood disorders.


Assuntos
Afeto , Comportamento Animal , Ciclofosfamida , Cistite/induzido quimicamente , Depressão/etiologia , Encefalite/etiologia , Hipocampo/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Afeto/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Caspase 1/metabolismo , Cistite/metabolismo , Cistite/fisiopatologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Encefalite/metabolismo , Encefalite/fisiopatologia , Feminino , Fluoxetina/farmacologia , Glibureto/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Mesna/farmacologia , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ratos Sprague-Dawley , Transdução de Sinais
6.
Neurourol Urodyn ; 38(8): 2159-2169, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31541501

RESUMO

AIM: We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model. METHODS: Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out. RESULTS: Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2 - and M3 -muscarinic receptors) and detrusor (M2 - and M3 -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1ß [IL-1ß], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-ß1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups. CONCLUSION: BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.


Assuntos
Cistite/induzido quimicamente , Medicamentos de Ervas Chinesas/farmacologia , Ketamina/efeitos adversos , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Animais , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Cistite/metabolismo , Cistite/patologia , Cistite/fisiopatologia , Feminino , Fibronectinas/efeitos dos fármacos , Fibronectinas/metabolismo , Neuroimagem Funcional , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Imagem por Ressonância Magnética , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Substância Cinzenta Periaquedutal/diagnóstico por imagem , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Células Receptoras Sensoriais , Substância P/efeitos dos fármacos , Substância P/metabolismo , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária Hiperativa/patologia , Bexiga Urinária Hiperativa/fisiopatologia , Urotélio/metabolismo
7.
Sci Rep ; 9(1): 5509, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940909

RESUMO

The internal surface of the bladder is lined by the urothelium, a stratified epithelium that forms an impermeable barrier to water and urine constituents. Abnormalities in the urothelial barrier have been described in certain forms of cystitis and were hypothesized to contribute to irritative voiding symptoms and pain by allowing the permeation of urinary K+ into suburothelial tissues, which then alters afferent signaling and smooth muscle function. Here, we examined the mechanisms underlying organ hyperactivity and pain in a model of cystitis caused by adenoviral-mediated expression of claudin-2 (Cldn2), a tight junction protein that forms paracellular pores and increases urothelial permeability. We found that in the presence of a leaky urothelium, intravesical K+ sensitizes bladder afferents and enhances their response to distension. Notably, dietary K+ restriction, a maneuver that reduces urinary K+, prevented the development of pelvic allodynia and inflammation seen in rats expressing Cldn2. Most importantly, intravesical K+ causes and is required to maintain bladder hyperactivity in rats with increased urothelial permeability. Our study demonstrates that in the face of a leaky urothelium, urinary K+ is the main determinant of afferent hyperexcitability, organ hyperactivity and pain. These findings support the notion that voiding symptoms and pain seen in forms of cystitis that coexist with urothelial barrier dysfunction could be alleviated by cutting urinary K+ levels.


Assuntos
Cistite/urina , Dor/etiologia , Potássio/urina , Urotélio/fisiopatologia , Animais , Claudinas/metabolismo , Cistite/dietoterapia , Cistite/metabolismo , Cistite/fisiopatologia , Modelos Animais de Doenças , Feminino , Dor/metabolismo , Permeabilidade , Ratos , Urotélio/metabolismo
8.
Am J Physiol Renal Physiol ; 317(7): F43-F51, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30995112

RESUMO

High expression of VEGF is associated with immature angiogenesis within the urinary bladder wall and bladder afferent nerve sensitization, leading to visceral hyperalgesia and pelvic pain. Research suggests a shift in VEGF alternative splice variant (VEGF-Axxxa and VEGF-Axxxb) expression with several pathologies (e.g., neuropathic pain and inflammation) as well as differing effects on pain. Translational studies have also demonstrated increased total VEGF expression in the bladders of women with interstitial cystitis/bladder pain syndrome. In the present study, we quantified VEGF alternative splice variant expression in lower urinary tract tissues under control conditions and with cyclophosphamide (CYP)-induced cystitis. Using conscious cystometry and intravesical instillation of a potent and selective VEGF receptor 2 (VEGFR2) tyrosine kinase inhibitor (Ki-8751, 1 mg/kg) in Wistar rats (male and female) with acute and chronic CYP-induced cystitis and control (no CYP) rats, we further determined the functional effects of VEGFR2 blockade on bladder function. With VEGFR2 blockade, bladder capacity increased (P ≤ 0.01) in male and female control rats as well as in male and female rats with acute (P ≤ 0.05) or chronic (P ≤ 0.01 or P ≤ 0.05, respectively) CYP-induced cystitis. Void volume also increased in female control rats (P ≤ 0.01) and female rats with acute (P ≤ 0.05) or chronic (P ≤ 0.05) CYP-induced cystitis as well as in male control rats (P ≤ 0.05) and male rats with chronic CYP-induced cystitis (P ≤ 0.01). These data suggest that VEGF may be a biomarker for interstitial cystitis/bladder pain syndrome and that targeting VEGF/VEGFR2 signaling may be an effective treatment.


Assuntos
Ciclofosfamida/farmacologia , Cistite/fisiopatologia , Bexiga Urinária/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Processamento Alternativo , Animais , Cistite/induzido quimicamente , Cistite Intersticial/fisiopatologia , Feminino , Masculino , Compostos de Fenilureia/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinolinas/farmacologia , RNA Mensageiro/análise , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Bexiga Urinária/química , Bexiga Urinária/metabolismo , Micção/efeitos dos fármacos , Urina , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
Neurourol Urodyn ; 38(4): 1044-1052, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30869827

RESUMO

AIMS: The main goal of our study was to investigate whether blebbistatin would prevent the cyclophosphamide (CYP)-induced changes in cystometric and inflammatory parameters indicating the development of bladder inflammation and bladder overactivity. As the nature of CYP-induced urotoxicity is inflammatory, we assume that agents presenting an anti-inflammatory potential, such as blebbistatin, are worth special attention. MATERIALS AND METHODS: The experiments were carried out in female Wistar rats. Surgical procedures, cystometric investigations, measurements of bladder edema and urothelium thickness as well as biochemical analyses were performed according to the published literature. RESULTS: As expected, an acute administration of CYP (200 mg/kg, intraperitoneally) induced changes in the cystometric parameters and the levels of the tested biomarkers (ie, interleukin 1-ß, interleukin 6, interleukin 10, tumor necrosis factor-α, nerve growth factor, brain-derived neurotrophic factor, heparin-binding epidermal growth factor-like growth factor, insulin-like growth factor-binding protein 3, C-X-C motif chemokine 10, orosomucoid-1, Tamm-Horsfall protein, hemopexin, and occludin), indicating the development of bladder overactivity and bladder inflammation, respectively. These changes were accompanied by bladder edema and increased urothelium thickness. Intravesical infusion of blebbistatin for 7 days (125 nmol/day) prevented all symptoms of the CYP-induced urotoxicity. CONCLUSIONS: Blebbistatin might be a promising novel agent for the treatment of bladder dysfunctions, like CYP-induced hemorrhage cystitis or bladder overactivity, since it diminished the increased urinary bladder levels of proinflammatory markers and normalized the concentrations of the anti-inflammatory ones. This effect was accompanied by amelioration of bladder edema and permeability, and normalization of both urothelium thickness and values of the cystometric parameters.


Assuntos
Cistite/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Administração Intravesical , Animais , Ciclofosfamida , Cistite/induzido quimicamente , Cistite/fisiopatologia , Modelos Animais de Doenças , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Ratos , Ratos Wistar , Resultado do Tratamento , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária Hiperativa/fisiopatologia
11.
Neurourol Urodyn ; 38(1): 135-143, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30350879

RESUMO

AIMS: Interstitial cystitis and bladder pain syndrome is a prevalent health concern with inadequate treatments. Neuromodulation has emerged as a therapeutic option to treat patients refractory to standard care. The objective of this study was to determine the efficacy and mechanism(s) of sensory pudendal nerve stimulation on bladder function in cystitis rats. METHODS: Female rats were administered saline (n = 8) or cyclophosphamide (CYP, 150 mg/kg IP, n = 16) and single-trial cystometry experiments were conducted under urethane anesthesia 48 h after injection. Electrical stimulation (0.02-0.22 mA, 10-20 Hz) was delivered to the sensory branch of the pudendal nerve and its effect on the bladder and external urethral sphincter were measured. Stimulation trials were also conducted following bilateral hypogastric nerve transection (HGNT) or pharmacological inhibition of beta-adrenergic receptors (propranolol, 1 mg/kg IV) to determine the mechanisms of bladder inhibition. RESULTS: CYP-induced cystitis decreased bladder capacity (P = 0.0352) and bladder compliance (P = 0.024) by up to 38% of control. Electrical stimulation of the sensory pudendal nerve increased bladder capacity (P < 0.0001) in control and CYP rats by up to 51-52% of their respective baselines. HGNT did not influence bladder inhibition generated by sensory pudendal nerve stimulation in control rats, whereas HGNT and propranolol decreased the efficacy of electrical stimulation in CYP rats. CONCLUSIONS: Sympathetic reflex activity mediates sensory pudendal nerve stimulation in CYP treated but not control rats. These studies demonstrate an alternative approach to neuromodulation in cystitis and establish mechanistic changes during stimulation that may enable the development of novel therapeutics.


Assuntos
Cistite/fisiopatologia , Cistite/terapia , Nervo Pudendo/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Bexiga Urinária/fisiopatologia , Animais , Antineoplásicos Alquilantes , Ciclofosfamida , Cistite/induzido quimicamente , Estimulação Elétrica , Feminino , Ratos , Ratos Wistar , Sensação , Uretra/fisiopatologia , Urodinâmica
12.
Am J Physiol Renal Physiol ; 316(1): F113-F120, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30353742

RESUMO

Bladder outlet obstruction (BOO) leads to progressive voiding dysfunction. Acutely, obstruction triggers inflammation that drives bladder dysfunction. Over time, inflammation leads to decreased bladder nerve density and increased fibrosis, responsible for eventual decompensation and irreversibility. We have previously shown that BOO triggers inflammation, reduced bladder nerve density and increased fibrosis via activation of the NLRP3 inflammasome in an acutely obstructed (12-day) rat model. However, as BOO progresses, the bladder may become decompensated with an increase in postvoid residual volume and decreased voiding efficiency. Currently, we have examined rat bladder function and nerve densities after chronic BOO to determine whether NLRP3 plays a role in the decompensation at this stage. Four groups were examined: control, sham-operated, BOO, or BOO+gly (glyburide; an NLRP3 inhibitor). After 42 days, bladder weight, inflammation (Evans blue), urodynamics, and nerve density were measured. BOO greatly enhanced bladder weights and inflammation, while inflammation was prevented by glyburide. Voiding pressures were increased, and flow rates decreased in BOO and BOO+gly groups, demonstrating physical obstruction. No difference in frequency or voided volume was detected. However, postvoid residual volumes were greatly increased in BOO rats while BOO+gly rats were not different than controls. Moreover, there was a dramatic decrease in voiding efficiency in the chronic BOO rats, which was prevented with glyburide treatment. Finally, a reduction in nerve density was apparent with BOO and attenuated with glyburide. Together the results suggest a critical role for NLRP3 in mediating bladder decompensation and nerve density during chronic BOO.


Assuntos
Anti-Inflamatórios/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Cistite/prevenção & controle , Glibureto/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/inervação , Urodinâmica/efeitos dos fármacos , Animais , Sistema Nervoso Autônomo/fisiopatologia , Doença Crônica , Cistite/metabolismo , Cistite/fisiopatologia , Modelos Animais de Doenças , Feminino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Obstrução do Colo da Bexiga Urinária/metabolismo , Obstrução do Colo da Bexiga Urinária/fisiopatologia
13.
Naunyn Schmiedebergs Arch Pharmacol ; 392(4): 437-450, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30552456

RESUMO

Various studies have confirmed that prostaglandins (PG) alter the bladder motor activity and micturition reflex in both human and animals. However, no sufficient data is reported about the effect of cyclooxygenase (COX) inhibitors neither in normal bladder physiology nor in pathological conditions. This study aims to compare the potential effects of some COX inhibitors with varying COX-1/COX-2 selectivities (indomethacin, ketoprofen, and diclofenac) with that of the selective COX-2 inhibitor (DFU) on bladder function. The role played by some PGs and their receptors in controlling detrusor muscle function in normal condition and in cystitis is also studied. Organ bath experiments were performed using isolated rat detrusor muscle. Direct and neurogenic contractions were induced using ACh and electric stimulation (EFS), respectively. A model of hemorrhagic cystitis was induced by single injection of cyclophosphamide (300 mg/kg) in rats, and confirmed by histophathological examination. Results are expressed as mean ± SEM of 5-9 rats. Alprostadil and iloprost (1 nM- 10 µM) concentration-dependently potentiated ACh (100 µM)- and EFS (4 Hz)-induced contraction, with maximum potentiation of 40.01 ± 5.29 and 27.59 ± 6.64%, respectively, in case of ACh contractions. In contrast, ONO-AE1-259 (selective EP2 agonist, 1 nM-10 µM) inhibited muscle contraction. SC51322 (EP1-antagonist, 10 µM) and RO1138452 (IP antagonist, 10 µM) inhibited both direct and neurogenic responses. Hemorrhagic cystitis reduced both ACh and EFS responses as well as the potentiatory effect of iloprost and the inhibitory effect of RO1138452 on ACh contractions. ONO-AE3-237 (DP1 antagonist, 1 µM) significantly potentiated contractions in cystitis but showed no effect in normal bladder. A significant inhibition of contractile response was observed in presence of indomethacin, ketoprofen, and diclofenac at all tested concentrations (20, 50, and 100 µM). Highest effect was induced by diclofenac. The effect of these COX inhibitors on EFS contractions was intensified in case of cystitis, indomethacin being the most potent. Atropine (1 nM) significantly reduced indomethacin effect on ACh contraction only in normal rats. On the other hand, DFU (10-6 M) significantly potentiated the contractile effect of ACh in case of cystitis although it showed no effect in normal rats. EP1 receptors seem to play an important role in rat bladder contractility. DP1 receptors as COX-2, on the other hand, gain an important role only in case of cystitis. The use of non-selective COX inhibitors in cystitis may be associated with bladder hypoactivity; selective COX-2 inhibitors may be a safer option.


Assuntos
Inibidores de Ciclo-Oxigenase/efeitos adversos , Cistite/patologia , Músculo Liso/efeitos dos fármacos , Receptores de Prostaglandina/antagonistas & inibidores , Bexiga Urinária/efeitos dos fármacos , Animais , Ciclo-Oxigenase 1/fisiologia , Ciclo-Oxigenase 2/fisiologia , Ciclofosfamida , Cistite/induzido quimicamente , Cistite/fisiopatologia , Modelos Animais de Doenças , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/patologia , Músculo Liso/fisiologia , Ratos Wistar , Receptores de Prostaglandina/fisiologia , Bexiga Urinária/patologia , Bexiga Urinária/fisiologia
14.
Int Urol Nephrol ; 51(1): 53-59, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30387068

RESUMO

PURPOSE: This study investigated the effect of gabapentin on lower urinary tract dysfunction focusing on urethral activities and cystitis-induced hyperalgesia in a mouse model of painful bladder syndrome/interstitial cystitis (PBS/IC). The electromyography (EMG) of external urethral sphincter (EUS) was difficult to obtain, but contained useful information to examine the drug effect in mice. METHODS: Female C57BL/6J mice were intraperitoneally (ip) administration with either saline or 200 mg/kg of cyclophosphamide (CYP) 48 h before experimental evaluation. Cystitis mice were treated with administration of gabapentin (25 or 50 mg/kg, ip). Cystometry and EUS EMG were obtained and analyzed during continuous bladder infusion. The visceral pain-related visceromotor reflex (VMR) was recorded in response to isotonic bladder distension. RESULTS: Cystitis mice showed shorter inter-contraction intervals and increased occurrence of non-voiding contractions during bladder infusion, with increased VMR during isotonic bladder distension, indicating cystitis-induced bladder hyperalgesia. Gabapentin (50 mg/kg) suppressed effects of CYP on cystometry, but not on EUS EMG activity, during bladder infusion. The effect on urodynamic recordings lasted 4 h. VMR was significantly reduced by gabapentin. CONCLUSIONS: The present study showed that CYP-induced cystitis in mice is a model of visceral hyperalgesia affecting detrusor contractions, not urethral activations. The technique of using EUS EMG to evaluate the drug effects on urethral activities is novel and useful for future investigations. Gabapentin can be as a potential treatment for detrusor overactivity and PBS/IC.


Assuntos
Cistite , Gabapentina/farmacologia , Hiperalgesia , Uretra , Analgésicos/farmacologia , Animais , Cistite/tratamento farmacológico , Cistite/fisiopatologia , Modelos Animais de Doenças , Eletromiografia/métodos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Camundongos , Contração Muscular/efeitos dos fármacos , Resultado do Tratamento , Uretra/efeitos dos fármacos , Uretra/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Urodinâmica/efeitos dos fármacos
15.
Neurourol Urodyn ; 37(8): 2560-2570, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30252154

RESUMO

AIMS: We explored the therapeutic potential of intragastric administration traditional Chinese medicine Glycine tomentella Hayata (I-Tiao-Gung, ITG) extract and its active component Daidzin on cyclophosphamide (CYP)-induced cystitis and bladder hyperactivity in rats. METHODS: Female Wistar rats were divided into control, CYP (200 mg/kg), CYP + ITG (1.17 g/kg/day), CYP + Daidzin (12.5 mg/kg/day), and 1 week of ITG preconditioning with CYP (ITG + CYP) groups. We determined the trans cystometrogram associated with external urethral sphincter electromyogram, and the expression of M2 and M3 muscarinic and P2 × 2 and P2 × 3 purinergic receptors by Western blot in these animals. RESULTS: ITG extract contains 1.07% of Daidzin and 0.77% of Daidzein by high-performance liquid chromatography. Daidzin was more efficient than Daidzein in scavenging H2 O2 activity by a chemiluminescence analyzer. CYP induced higher frequency, shorter intercontraction interval, lower maximal voiding pressure, lower threshold pressure, and Phase-2 emptying contraction with a depressed external urethral sphincter electromyogram activity, and hemorrhagic cystitis in the bladders. The altered parameters by CYP were significantly improved in CYP + ITG, CYP + Daidzin, and ITG + CYP groups. The P2 × 2 and P2 × 3 expressions were significantly upregulated in CYP group, but were depressed in CYP + ITG, CYP + Daidzin, and ITG + CYP groups. The M2 expression was not significantly different among these five groups. The M3 expression was significantly upregulated in CYP group, but was significantly depressed in CYP + ITG, CYP + Daidzin, and ITG + CYP groups. CONCLUSIONS: These data suggest that ITG extract through its active component Daidzin effectively improved CYP-induced cystitis by the action of restoring Phase 2 activity and inhibiting the expressions of P2 × 2, P2 × 3, and M3 receptors.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Isoflavonas/farmacologia , Bexiga Urinária/efeitos dos fármacos , Animais , Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Cistite/fisiopatologia , Eletromiografia , Feminino , Ratos , Ratos Wistar , Receptor Muscarínico M2/efeitos dos fármacos , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/efeitos dos fármacos , Receptor Muscarínico M3/metabolismo , Receptores Purinérgicos P2/efeitos dos fármacos , Receptores Purinérgicos P2/metabolismo , Uretra/efeitos dos fármacos , Uretra/fisiopatologia , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária Hiperativa/fisiopatologia , Micção/efeitos dos fármacos
16.
Brain Res ; 1698: 99-105, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29964025

RESUMO

There is increasing evidence that chronic pain may be associated with events that occur during critical periods of development. Recent studies have identified behavioral, spinal neurophysiological and spinal/peripheral neurochemical differences in rats that have experienced neonatal bladder inflammation (NBI): a putative model of the chronically painful bladder disorder, interstitial cystitis. Stress has been shown to exacerbate symptoms of interstitial cystitis and produces bladder hypersensitivity in animal models. We recently reported that Acute Footshock-induced bladder hypersensitivity was eliminated in otherwise normal rats by prior bilateral lesions of the central nucleus of the amygdala. Since the spinal and peripheral nervous systems of NBI-treated rats are known to differ from normal rats, the present experiments sought to determine whether a supraspinal nervous system structure, the central amygdala, is still necessary for the induction of Acute Footshock-induced hypersensitivity. The effect of bilateral amygdala electrolytic lesions on Acute Footshock-induced bladder hypersensitivity in adult female rats was tested in Control rats which underwent a control protocol as neonates and in experimental rats which experienced NBI. Consistent with our previous report, in Control rats, Acute Footshock-induced bladder hypersensitivity was eliminated by bilateral Amygdala Lesions. In contrast, Acute Footshock-induced bladder hypersensitivity in NBI-treated rats was unaffected by bilateral Amygdala Lesions. These findings provide evidence that NBI results in the recruitment of substrates of bladder hypersensitivity that may differ from those of normal rats. This, in turn, suggests that unique therapeutics may be needed for painful bladder disorders like interstitial cystitis.


Assuntos
Núcleo Central da Amígdala/fisiopatologia , Cistite/fisiopatologia , Hipersensibilidade/fisiopatologia , Estresse Fisiológico/fisiologia , Bexiga Urinária/fisiopatologia , Animais , Animais Recém-Nascidos , Núcleo Central da Amígdala/metabolismo , Modelos Animais de Doenças , Eletrochoque/métodos , Feminino , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/efeitos dos fármacos
17.
Urologiia ; (2): 9-13, 2018 May.
Artigo em Russo | MEDLINE | ID: mdl-29901288

RESUMO

AIM: To investigate the role of hyperbaric oxygen therapy in the management of patients with radiation induced urinary bladder injury (radiation cystitis). MATERIALS AND METHODS: The study comprised 23 patients with late radiation induced urinary bladder injury who were evaluated and treated using hyperbaric oxygen therapy and bladder instillation. Before and after treatment, all patients underwent cystoscopy with the bladder mucosa biopsy. - RESULTS: In all patients, the treatment resulted in positive outcomes manifested by resolution of hematuria, alleviation of dysuria, decrease in urination frequency to 6.5 +/- 0.5 times a day, increase the bladder capacity, which ultimately improved patients the quality of life. Hyperbaric oxygen therapy was well tolerated, there were no adverse effects. Morphological studies confirmed positive clinical changes following hyperbaric oxygen therapy. CONCLUSION: The study findings support wider use of hyperbaric oxygen therapy in the management of radiation cystitis.


Assuntos
Cistite , Oxigenação Hiperbárica , Lesões por Radiação , Bexiga Urinária , Adulto , Idoso , Cistite/diagnóstico por imagem , Cistite/fisiopatologia , Cistite/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Lesões por Radiação/diagnóstico por imagem , Lesões por Radiação/fisiopatologia , Lesões por Radiação/terapia , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/fisiopatologia
18.
Taiwan J Obstet Gynecol ; 57(3): 399-406, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29880173

RESUMO

OBJECTIVES: The cyclophosphamide (CYP)-induced model of cystitis in mice closely fits the symptoms of chronic bladder inflammation. Cystitis was recently found to be due to an altered gap junction protein in a rat model. Thus, this study was conducted to evaluate changes in protein expression and composition in the bladder of CYP-treated mice. MATERIALS AND METHODS: Administration of CYP induced cystitis-related symptoms in mice. Cystometry was assessed and cell junction-associated protein zonula occludens-2 (ZO-2) expression was measured. Voiding interval values (time between voids) were assessed in mice under anesthesia. The bladders were removed for proteomic analysis using label-free quantitative proteomics and liquid chromatography-mass spectrometry. Additionally, immunochemistry (IHC) and Western blot were used to confirm the location and level, respectively, of ZO-2 expression. RESULTS: Compared to the control group, the voiding interval values and urothelial thickness in the bladder in the CYP-treated group were significantly decreased. Additionally, we identified 105 differentially expressed proteins in the bladder of CYP-treated mice with proteomic analysis. These proteins were involved in cell-cell tight junctions, exocytosis, muscle development, contraction, and regulation, immune responses, proteolysis, and cell adhesion. IHC and Western blot confirmed the downregulation of the tight junction protein ZO-2 in the urothelium of bladder. CONCLUSIONS: Our results suggest that downregulation in tight junction protein ZO-2 and urothelium damage may have a role in cystitis-related OAB. These changes could be related to the molecular mechanism of cystitis-related OAB.


Assuntos
Cistite/metabolismo , Junções Íntimas/metabolismo , Bexiga Urinária/metabolismo , Micção , Urotélio/metabolismo , Proteína da Zônula de Oclusão-2/metabolismo , Animais , Western Blotting , Ciclofosfamida/administração & dosagem , Cistite/induzido quimicamente , Cistite/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Bexiga Urinária/patologia , Urotélio/patologia
19.
Exp Mol Med ; 50(5): 1-16, 2018 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-29735991

RESUMO

The Piezo1 channel is a mechanotransduction mediator, and Piezo1 abnormalities have been linked to several clinical disorders. However, the role of the Piezo1 channel in cystitis-associated bladder dysfunction has not been documented. The current study aimed to discover the functional role of this channel in regulating bladder activity during cyclophosphamide (CYP)-induced cystitis. One hundred four female rats were randomly assigned to the control, CYP-4h, CYP-48h and CYP-8d groups. CYP successfully induced acute or chronic cystitis in these rats. CYP treatment for 48h or 8d significantly increased Piezo1 channel expression in bladder interstitial Cajal-like cells (ICC-LCs), and the increase in CYP-8d rats was more prominent. In addition, 2.5 µM Grammostola spatulata mechanotoxin 4 (GsMTx4) significantly attenuated bladder hyperactivity in CYP-8d rats by inhibiting the Piezo1 channel in bladder ICC-LCs. Furthermore, by using GsMTx4 and siRNA targeting the Piezo1 channel, we demonstrated that hypotonic stress-induced Piezo1 channel activation significantly triggered Ca2+ and Na+ influx into bladder ICC-LCs during CYP-induced chronic cystitis. In addition, the Piezo1 channel functionally interacted with the relatively activated reverse mode of Na+/Ca2+ exchanger 1 (NCX1) in bladder ICC-LCs from CYP-8d rats. In conclusion, we suggest that the functional role of the Piezo1 channel in CYP-induced chronic cystitis is based on its synergistic effects with NCX1, which can significantly enhance [Ca2+]i and result in Ca2+ overload in bladder ICC-LCs, indicating that the Piezo1 channel and NCX1 are potential novel therapeutic targets for chronic cystitis-associated bladder hyperactivity.


Assuntos
Ciclofosfamida/efeitos adversos , Cistite/induzido quimicamente , Cistite/fisiopatologia , Proteínas de Membrana/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Telócitos/metabolismo , Bexiga Urinária/fisiopatologia , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular , Ativação do Canal Iônico/efeitos dos fármacos , Modelos Biológicos , Peptídeos/toxicidade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Venenos de Aranha/toxicidade , Estresse Fisiológico/efeitos dos fármacos , Regulação para Cima/genética
20.
J Pharmacol Exp Ther ; 365(2): 327-335, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29530925

RESUMO

Currently, we have assessed the neuronal control of the urinary bladder in radiation cystitis and whether interstitial cells contribute to the condition. Fourteen days after bladder irradiation (20 Gy), rats were sedated and the urinary bladder was cut into two sagittal halves where electrical field stimulation (EFS; 5-20 Hz) was applied on the pelvic nerve afferents or stretch (80 mN) on one-half of the bladder, while contractions were registered on the contralateral half of the bladder in the absence and presence of increasing doses of imatinib (1-10 mg/kg; inhibitor of c-kit-positive interstitial cells), atropine (1 mg/kg; to block muscarinic M3 receptors), or pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (2 mg/kg; P2X1 purinoceptor antagonist). Urinary bladders were also excised for organ bath experiments, Western blot, quantitative polymerase chain reaction, and immunohistochemistry. In vivo, EFS contractions were enhanced after irradiation, and imatinib (1-10 mg/mg) inhibited contractions by EFS and stretched dose-dependently in controls but not in irradiated bladders. In the irradiated bladder in vitro, atropine resistance was increased and imatinib (100 µM) inhibited contractions by EFS and agonists (ATP, methacholine) in irradiated bladders and controls. The urinary bladder expressions of P2X1 purinoceptors, muscarinic M3 receptor, choline acetyltransferase, c-kit, and the agonist of c-kit, stem cell factor, were not changed by irradiation. In conclusion, bladder irradiation affects several levels of neuronal control of the urinary bladder. Interstitial cells may contribute to some of the symptoms associated with radiation cystitis.


Assuntos
Cistite/patologia , Cistite/fisiopatologia , Neurônios/patologia , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Contração Muscular , Ratos
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