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1.
Int J Mol Sci ; 22(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668086

RESUMO

The present study investigated the effect of unilateral axotomy of urinary bladder trigone (UBT)-projecting nerve fibers from the right anterior pelvic ganglion (APG) on changes in the chemical coding of their neuronal bodies. The study was performed using male pigs with immunohistochemistry and quantitative real-time PCR (qPCR). The animals were divided into a control (C), a morphological (MG) or a molecular biology group (MBG). APG neurons supplying UBT were revealed using the retrograde tracing technique with Fast Blue (FB). Unilateral axotomy resulted in an over 50% decrease in the number of FB+ neurons in both APG ganglia. Immunohistochemistry revealed significant changes in the chemical coding of FB+ cells only in the right ganglion: decreased expression of dopamine-B-hydroxylase (DBH)/tyrosine hydroxylase (TH) and up-regulation of the vesicular acetylcholine transporter (VAChT)/choline acetyltransferase (ChAT), galanin (GAL), vasoactive intestinal polypeptide (VIP) and brain nitric oxide synthase (bNOS). The qPCR results partly corresponded with immunofluorescence findings. In the APGs, genes for VAChT and ChAT, TH and DBH, VIP, and NOS were distinctly down-regulated, while the expression of GAL was up-regulated. Such data may be the basis for further studies concerning the plasticity of these ganglia under experimental or pathological conditions.


Assuntos
Gânglios Simpáticos/fisiologia , Fibras Nervosas/fisiologia , Neurônios/fisiologia , Pelve/fisiologia , Bexiga Urinária/fisiologia , Animais , Axotomia , Catecolaminas/metabolismo , Colina O-Acetiltransferase/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Masculino , Vias Neurais/metabolismo , Neuropeptídeos/metabolismo , Pelve/inervação , Suínos , Tirosina 3-Mono-Oxigenase/metabolismo , Bexiga Urinária/inervação
2.
J Urol ; 205(1): 206-212, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32716692

RESUMO

PURPOSE: We sought to determine whether prolonged interventional test phase increases cumulative success rate and compared success rates between early responders (ie within 1 week) and those in need for reprogramming (due to lack of efficacy) of sacral neuromodulation after 1-year followup. MATERIALS AND METHODS: In a single tertiary center prospective study (August 2015 to November 2018) 90 patients refractory to first line treatment were eligible for sacral neuromodulation, including 48 overactive bladder wet (53%), 8 overactive bladder dry (9%) and 34 nonobstructive urinary retention (38%). Patients were evaluated at weekly intervals during test phase and those not successful were reprogrammed. This could be repeated after the second week. Primary outcome was success rate after 3-week test phase and after 1-year followup. Statistical analysis was done by nonparametric tests for numeric (Mann-Whitney U) and categorical (chi2) data. RESULTS: After 3 weeks of test period 56 patients (62%) were considered successful. Prolonged interventional testing increased cumulative success. A 1-year followup showed no significant difference in success rate between early responders and those in need for reprogramming (chi2, p=0.562). There was no difference in age (Mann-Whitney U, p=0.222), sex (chi2, p=0.952) or indication (chi2, p= 0.975). CONCLUSIONS: A 3-week test phase with close followup increases cumulative success rate. During this supervised 3-week test phase 42% of the initial nonresponders after the first week became successful candidates after reprogramming. Patients who required this additional programming did equally as well as those without need for reprogramming. A supervised 3-week test phase is therefore strongly recommended.


Assuntos
Assistência ao Convalescente/métodos , Terapia por Estimulação Elétrica/métodos , Plexo Lombossacral/fisiopatologia , Bexiga Urinária Hiperativa/terapia , Retenção Urinária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia por Estimulação Elétrica/instrumentação , Eletrodos Implantados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/fisiopatologia , Retenção Urinária/fisiopatologia
3.
J Urol ; 205(1): 213-218, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32856985

RESUMO

PURPOSE: Neurogenic lower urinary tract dysfunction is a significant source of morbidity for individuals with spinal cord injury and is managed with a range of treatment options that differ in efficacy, tolerability and cost. The effect of insurance coverage on bladder management, symptoms and quality of life is not known. We hypothesized that private insurance is associated with fewer bladder symptoms and better quality of life. MATERIALS AND METHODS: This is a cross-sectional, retrospective analysis of 1,226 surveys collected as part of the prospective Neurogenic Bladder Research Group SCI Registry. We included patients with complete insurance information, which was classified as private or public insurance. The relationship between insurance and bladder management, bladder symptoms and quality of life was modeled using multinomial logistic regression analysis. Spinal cord injury quality of life was measured by the Neurogenic Bladder Symptom Score. RESULTS: We identified 654 privately insured and 572 publicly insured individuals. The demographics of these groups differed by race, education, prevalence of chronic pain and bladder management. Publicly insured patients were more likely to be treated with indwelling catheters or spontaneous voiding and less likely to take bladder medication compared to those with private insurance. On multivariate analysis insurance type was not associated with differences in bladder symptoms (total Neurogenic Bladder Symptom Score) or in urinary quality of life. CONCLUSIONS: There is an association between insurance coverage and the type of bladder management used following spinal cord injury, as publicly insured patients are more likely to be treated with indwelling catheters. However, insurance status, controlling for bladder management, did not impact bladder symptoms or quality of life.


Assuntos
Disparidades em Assistência à Saúde/estatística & dados numéricos , Cobertura do Seguro/estatística & dados numéricos , Seguro Saúde/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Traumatismos da Medula Espinal/complicações , Bexiga Urinaria Neurogênica/terapia , Adulto , Cateteres de Demora/economia , Cateteres de Demora/estatística & dados numéricos , Estudos Transversais , Feminino , Disparidades em Assistência à Saúde/economia , Humanos , Cobertura do Seguro/economia , Seguro Saúde/economia , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Satisfação do Paciente/economia , Estudos Prospectivos , Qualidade de Vida , Estudos Retrospectivos , Traumatismos da Medula Espinal/economia , Traumatismos da Medula Espinal/terapia , Resultado do Tratamento , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Bexiga Urinaria Neurogênica/diagnóstico , Bexiga Urinaria Neurogênica/economia , Bexiga Urinaria Neurogênica/etiologia , Cateterismo Urinário/economia , Cateterismo Urinário/estatística & dados numéricos
4.
Life Sci ; 258: 118179, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758626

RESUMO

OBJECTIVE: To evaluate whether approved gastroprokinetic agent, acotiamide exerts a direct excitatory effect on bladder to help explain the reported meaningful reduction of post-void residual urine volume (PVR) in detrusor underactivity (DU) patients after thrice daily oral intake of acotiamide 100 mg for 2 weeks. METHODS: Effect of acotiamide [1-16 µM] was assessed on nerve-mediated contractions evoked by electrical field stimulation (EFS) for 5 s with 5 ms pulse trains of 10 V in longitudinal, mucosa intact rat and human bladder strips to construct frequency response curve (1-32 Hz) and repeat 10 Hz stimulation at 60s interval. Effect of acotiamide 2 µM on spontaneous and carbachol evoked contractions was also assessed. RESULTS: Acotiamide 2 µM significantly enhanced the Atropine and Tetrodotoxin (TTX)-sensitive EFS evoked contractions of rat and human bladder at 8-32 Hz (Two-way ANOVA followed Sidak's multiple comparison; *p < 0.01) and on repeat 10 Hz stimulation (Paired Student's t-test; *p < 0.05), while producing a modest effect on the spontaneous contractions and a negligible effect on the carbachol evoked contractions. CONCLUSIONS: Enhancement of TTX-sensitive evoked contractions of rat and human bladder by acotiamide is consistent with the enhancement of excitatory neuro-effector transmission mainly through prejunctional mechanisms. Findings highlight immense therapeutic potential of antimuscarinics with low M3 receptor affinity like acotiamide in Underactive bladder (UAB)/DU treatment.


Assuntos
Benzamidas/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Inativa/tratamento farmacológico , Bexiga Urinária/patologia , Animais , Benzamidas/química , Benzamidas/farmacologia , Carbacol/farmacologia , Estimulação Elétrica , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Ratos Sprague-Dawley , Tiazóis/química , Tiazóis/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervação
5.
Am J Physiol Renal Physiol ; 318(6): F1430-F1440, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32363884

RESUMO

The prevalence of underactive bladder (UAB) increases with age, suggesting a link between age-related processes and lower urinary tract (LUT) symptoms; however, the underlying mechanisms of age-related UAB are poorly understood. Understanding how aging affects LUT reflexes may help in the development of new treatments by identifying mechanistic targets. In this work, we studied the relationship between age and systems-level function of the LUT and tested the hypothesis that aging is related to weakening of reflexes that control voiding. Three groups of anesthetized female rats, young (4-7 mo old), mature (11-14 mo old), and old (18-24 mo old), were used to quantify the effect of aging on LUT reflexes. A double-lumen catheter enabled us to control the bladder volume and urethral flow rate independently, under quasi-isovolumetric bladder conditions. We systematically investigated the reflex bladder contractions evoked by combinations of rates of urethral infusion and bladder fill volumes as a function of age. Urethral infusion with the same flow rate evoked bladder contractions (via the augmenting reflex) in old animals less often than in younger animals. Furthermore, old animals needed more fluid in their bladders (relative to their bladder capacity) before urethra flow-evoked bladder contractions could be triggered at all, suggesting a delay in the switch of the LUT to "voiding mode." Old rats also showed longer and weaker bladder contractions than young or mature rats. Taken together, this suggests there is an age-related functional weakening and loss of sensitivity in LUT reflexes, which may contribute to age-related UAB symptoms.


Assuntos
Sintomas do Trato Urinário Inferior/fisiopatologia , Músculo Liso/inervação , Reflexo Anormal , Uretra/inervação , Bexiga Inativa/fisiopatologia , Bexiga Urinária/inervação , Micção , Fatores Etários , Animais , Modelos Animais de Doenças , Feminino , Sintomas do Trato Urinário Inferior/etiologia , Mecanotransdução Celular , Contração Muscular , Pressão , Ratos Sprague-Dawley , Fatores de Risco , Bexiga Inativa/etiologia , Urodinâmica
6.
Am J Physiol Renal Physiol ; 318(6): F1357-F1368, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32308021

RESUMO

Selective electrical stimulation of the pudendal nerve exhibits promise as a potential therapy for treating overactive bladder (OAB) across species (rats, cats, and humans). More recently, pelvic nerve (PelN) stimulation was demonstrated to improve cystometric bladder capacity in a PGE2 rat model of OAB. However, PelN stimulation in humans or in an animal model that is more closely related to humans has not been explored. Therefore, our objective was to quantify the effects of PGE2 and PelN stimulation in the cat. Acute cystometry experiments were conducted in 14 α-chloralose-anesthetized adult, neurologically intact female cats. Intravesical PGE2 decreased bladder capacity, residual volume, threshold contraction pressure, and mean contraction pressure. PelN stimulation reversed the PGE2-induced decrease in bladder capacity and increased evoked external urethral sphincter electromyographic activity without influencing voiding efficiency. The increases in bladder capacity generated by PelN stimulation were similar in the rat and cat, but the stimulation parameters to achieve this effect differed (threshold amplitude at 10 Hz in the rat vs. twice threshold amplitude at 1 Hz in the cat). These results highlight the potential of PGE2 as a model of OAB and provide further evidence that PelN stimulation is a promising approach for the treatment of OAB symptoms.


Assuntos
Dinoprostona , Terapia por Estimulação Elétrica , Contração Muscular , Músculo Liso/inervação , Pelve/inervação , Bexiga Urinária Hiperativa/terapia , Bexiga Urinária/inervação , Urodinâmica , Animais , Gatos , Modelos Animais de Doenças , Feminino , Pressão , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária Hiperativa/fisiopatologia
7.
PLoS One ; 15(3): e0230355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226049

RESUMO

OBJECTIVE: To systematically review outcomes in patients with refractory overactive bladder (OAB) patients who underwent sacral neuromodulation therapy (SNM) therapy after unsuccessful onabotulinumtoxinA (BTX) therapy, and to compare outcomes with those who SNM as initial therapy. METHODS: A systematic search of Cochrane Library, Pubmed and Embase databases from July 2002 to November 2019, to analyze randomized controlled trials and retrospective studies of SNM therapy after failed initial BTX therapy. Two reviewers independently screened the studies and extracted data. A quality assessment of the included literature was conducted using Newcastle-Ottawa Scale (NOS), and Stata 12.0 software was used to conduct a meta-analysis of the collected data. RESULTS: A total of seven studies involving 319 patients were finally included. The success rate in refractory OAB patients who used SNM therapy after failed BTX therapy was 58.5%, 95% CI (0.47-0.70). There was no significant difference between refractory OAB patients who chose SNM as replacement therapy after failed BTX therapy and those who used SNM therapy as first choice [RR = 0.96, 95%CI (0.72-1.26), P = 0.735]. CONCLUSION: OAB patients for whom an initial choice of BTX therapy ends in failure or dissatisfaction may consider switching to SNM therapy. There is no difference in outcomes between these patients and those whose first choice was SNM therapy.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Terapia por Estimulação Elétrica/métodos , Plexo Lombossacral/fisiopatologia , Bexiga Urinária Hiperativa/terapia , Bexiga Urinária/efeitos dos fármacos , Humanos , Plexo Lombossacral/efeitos dos fármacos , Satisfação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Falha de Tratamento , Bexiga Urinária/inervação , Bexiga Urinária Hiperativa/fisiopatologia
8.
Trials ; 21(1): 166, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046754

RESUMO

BACKGROUND: Urgency is a complaint of sudden, compelling desire to pass urine, which is difficult to defer, caused by involuntary contraction of the detrusor muscle during the bladder-filling stage. To enable detrusor inhibition, electrotherapy resources such as transcutaneous tibial nerve stimulation (TTNS) and parasacral transcutaneous electrical stimulation (PTES) have been used. The objective this study is to publish the study protocol that aims to investigate whether urgency decreases after treatment with both of the techniques. METHODS: This randomized controlled clinical trial will include 99 women, aged more than 18 years old, with urgency (score ≥ 8 in the Overactive Bladder-Validated 8-Question Awareness Tool [OAB-V8]). Women will be randomly allocated into three groups: TTNS, PTES, and placebo. The following questionnaires will be applied: the Anamnesis Record, the Incontinence Questionnaire Overactive Bladder, the King's Health Questionnaire, the 24-Hour Voiding Diary, and the OAB-V8, at four different time points: at baseline prior to the first session, at the 6th session, the 12th session and at follow-up. The current used for the transcutaneous electrical stimulation will be a symmetrical balanced biphasic pulsed current, for 12 sessions, twice a week, for 20 minutes. Qualitative variables will be displayed as frequency and percentage, quantitative variables as mean and standard deviation. Comparison of urgency severity among groups will be performed with a repeated measures ANOVA, considering the effect of the three groups and the four evaluations, and interactions among them. DISCUSSION: The present study aims to contribute evidence for a more in-depth discussion on electrode positioning for electrostimulation used in urgency treatment. It should be emphasized that, based on the possibility of confirming the hypothesis that urgency will decrease in a similar way after both treatments (TTNS and PTES), the PTES will be used as an option for positioning the electrodes alternatively to the tibial nerve region in special populations, such as amputees or people with severe lower limb sensory impairment. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (ReBEC) ID: RBR-9rf33n, date of registration: 17 May 2018.


Assuntos
Estimulação Elétrica Nervosa Transcutânea/métodos , Bexiga Urinária Hiperativa/terapia , Incontinência Urinária de Urgência/terapia , Adulto , Eletrodos , Feminino , Seguimentos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sacro/inervação , Índice de Gravidade de Doença , Nervo Tibial/fisiopatologia , Estimulação Elétrica Nervosa Transcutânea/instrumentação , Resultado do Tratamento , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/fisiopatologia , Incontinência Urinária de Urgência/diagnóstico , Incontinência Urinária de Urgência/etiologia , Incontinência Urinária de Urgência/fisiopatologia
9.
J Stroke Cerebrovasc Dis ; 29(4): 104620, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32033903

RESUMO

We describe a case of a 57-year-old man who, immediately after a right parietal ischemic stroke, showed urodynamically determined bladder sensory decrement during filling and an underactive detrusor during voiding, both of which were ameliorated during the course of his treatment. The lower urinary tract symptom (LUTS) occurs in stroke in up to 60% of patients, when it involves the frontal and insular cortices. In addition, LUTS does occur in parietal stroke as seen in our patient, presumably by sensory deafferentiation within the brain that is relevant to the central regulation of the micturition reflex.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Isquemia Encefálica/complicações , Sintomas do Trato Urinário Inferior/etiologia , Lobo Parietal/irrigação sanguínea , Acidente Vascular Cerebral/complicações , Bexiga Inativa/etiologia , Bexiga Urinária/inervação , Urodinâmica , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/terapia , Humanos , Sintomas do Trato Urinário Inferior/diagnóstico , Sintomas do Trato Urinário Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Reflexo , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia , Resultado do Tratamento , Bexiga Inativa/diagnóstico , Bexiga Inativa/fisiopatologia , Micção
10.
Neurourol Urodyn ; 39(3): 916-925, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32040866

RESUMO

AIMS: The urethral dysfunction produced by a rat model of peripheral neurogenic detrusor underactivity (DU) using pelvic nerve crush (PNC) injury was characterized and then tested with the administration of tadalafil, a phosphodiesterase type 5 (PDE 5) inhibitor. METHODS: Ten days after producing PNC rats, awake cystometrograms (CMGs) and isovolumetric cystometrograms with urethral perfusion pressure (IC-UPP) measurements were performed. Also, in control rats, IC-UPP was recorded before and after intravenous atropine administration to determine if the reduction of bladder contraction pressure affects urethral relaxation during voiding. Then, CMG and IC-UPP measurements in PNC rats were recorded after intravenous administration of tadalafil. Lastly, real-time polymerase chain reaction was used to measure transcript levels of neuronal nitric oxide synthases (nNOS), endothelial nitric oxide synthases, and PDE 5 in urethral specimens from PNC and control rats. RESULTS: PNC rats demonstrated the characteristics of DU in CMG. Also, PNC rats exhibited significant decreases in isovolumetric bladder contraction amplitudes and urethral relaxation. Atropine attenuated the amplitude of isovolumetric bladder contractions; however, atropine did not affect urethral relaxation in control rats. Tadalafil decreased postvoid residual and increased voiding efficiency without changing bladder contraction amplitude in PNC rats. Also, tadalafil improved the amplitude of urethral relaxation during bladder contraction in PNC rats. Urethral nNOS transcript levels were upregulated in PNC rats compared to control rats. CONCLUSIONS: PNC rats revealed both DU and impaired urethral relaxation. PDE 5 inhibition in PNC rats enhanced urethral relaxation during voiding, resulting in improved voiding efficiency. Thus, urethral dysfunction could be a potential target for the treatment of inefficient voiding associated with neurogenic DU.


Assuntos
Traumatismos dos Nervos Periféricos/fisiopatologia , Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Uretra/efeitos dos fármacos , Bexiga Urinaria Neurogênica/fisiopatologia , Bexiga Inativa/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Animais , Lesões por Esmagamento/fisiopatologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Feminino , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pelve , Ratos , Ratos Sprague-Dawley , Uretra/inervação , Uretra/metabolismo , Uretra/fisiopatologia , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Micção/fisiologia
11.
Am J Physiol Renal Physiol ; 318(4): F1006-F1016, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003596

RESUMO

Corticotropin-releasing factor (CRF) regulates diverse physiological functions, including bladder control. We recently reported that Crf expression is under genetic control of Aoah, the locus encoding acyloxyacyl hydrolase (AOAH), suggesting that AOAH may also modulate voiding. Here, we examined the role of AOAH in bladder function. AOAH-deficient mice exhibited enlarged bladders relative to wild-type mice and had decreased voiding frequency and increased void volumes. AOAH-deficient mice had increased nonvoiding contractions and increased peak voiding pressure in awake cystometry. AOAH-deficient mice also exhibited increased bladder permeability and higher neuronal firing rates of bladder afferents in response to stretch. In wild-type mice, AOAH was expressed in bladder projecting neurons and colocalized in CRF-expressing neurons in Barrington's nucleus, an important brain area for voiding behavior, and Crf was elevated in Barrington's nucleus of AOAH-deficient mice. We had previously identified aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor-γ as transcriptional regulators of Crf, and conditional knockout of AhR or peroxisome proliferator-activated receptor-γ in Crf-expressing cells restored normal voiding in AOAH-deficient mice. Finally, an AhR antagonist improved voiding in AOAH-deficient mice. Together, these data demonstrate that AOAH regulates bladder function and that the AOAH-Crf axis is a therapeutic target for treating voiding dysfunction.


Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Neurônios/enzimologia , Bexiga Urinária/inervação , Transtornos Urinários/enzimologia , Micção , Urodinâmica , Animais , Compostos Azo/farmacologia , Núcleo de Barrington/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hidrolases de Éster Carboxílico/deficiência , Hidrolases de Éster Carboxílico/genética , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Contração Muscular , Neurônios/efeitos dos fármacos , PPAR gama/genética , PPAR gama/metabolismo , Pressão , Pirazóis/farmacologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Transtornos Urinários/tratamento farmacológico , Transtornos Urinários/genética , Transtornos Urinários/fisiopatologia , Urodinâmica/efeitos dos fármacos
12.
J Pharmacol Exp Ther ; 373(2): 239-247, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32102918

RESUMO

Transient receptor potential (TRP) melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (Aδ-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (N-[(R)-3,3-difluoro-4-hydroxy-1-(2H-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels. Intravenously administered KPR-5714 inhibited the hyperactivity of mechanosensitive C-fibers of bladder afferents and dose-dependently increased the intercontraction interval shortened by intravesical instillation of acetic acid in anesthetized rats. Furthermore, we examined the effects of KPR-5714 on voiding behavior in conscious rats with cerebral infarction and in those exposed to cold in metabolic cage experiments. Cerebral infarction and cold exposure induced a significant decrease in the mean voided volume and increase in voiding frequency in rats. Orally administered KPR-5714 dose-dependently increased the mean voided volume and decreased voiding frequency without affecting total voided volume in these models. This study demonstrates that KPR-5714 improves OAB in three different models by inhibiting exaggerated activity of mechanosensitive bladder C-fibers and suggests that KPR-5714 may provide a new and useful approach to the treatment of OAB. SIGNIFICANCE STATEMENT: TRPM8 is involved in bladder sensory transduction and plays a role in the abnormal activation in hypersensitive bladder disorders. KPR-5714, as a novel and selective TRPM8 antagonist, may provide a useful treatment for the disorders related to the hyperactivity of bladder afferent nerves, particularly in overactive bladder.


Assuntos
Vias Aferentes/efeitos dos fármacos , Canais de Cátion TRPM/antagonistas & inibidores , Bexiga Urinária/efeitos dos fármacos , Vias Aferentes/fisiologia , Animais , Infarto Cerebral/fisiopatologia , Feminino , Células HEK293 , Humanos , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPM/fisiologia , Bexiga Urinária/inervação , Bexiga Urinária Hiperativa/tratamento farmacológico , Micção/efeitos dos fármacos
13.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R428-R434, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913685

RESUMO

Nonobstructive urinary retention (NOUR) is a medical condition without an effective drug treatment, but few basic science studies have focused on this condition. In α-chloralose-anesthetized cats, the bladder was cannulated via the dome and infused with saline to induce voiding that could occur without urethral outlet obstruction. A nerve cuff electrode was implanted for tibial nerve stimulation (TNS). The threshold (T) intensity for TNS to induce toe twitch was determined initially. Repeated (6 times) application of 30-min TNS (5 Hz, 0.2 ms, 4-6T) significantly (P < 0.05) increased bladder capacity to 180% of control and reduced the duration of the micturition contraction to 30% of control with a small decrease in contraction amplitude (80% of control), which resulted in urinary retention with a low-voiding efficiency of 30% and a large amount of residual volume equivalent to 130% of control bladder capacity. This NOUR condition persisted for >2 h after the end of repeated TNS. However, lower frequency TNS (1 Hz, 0.2 ms, 4T) applied during voiding partially reversed the NOUR by significantly (P < 0.05) increasing voiding efficiency to 60% and reducing residual volume to 70% of control bladder capacity without changing bladder capacity. These results revealed that tibial nerve afferent input can activate either an excitatory or an inhibitory central nervous system mechanism depending on afferent firing frequencies (1 vs. 5 Hz). This study established the first NOUR animal model that will be useful for basic science research aimed at developing new treatments for NOUR.


Assuntos
Estimulação Elétrica , Nervo Tibial/fisiopatologia , Bexiga Urinária/inervação , Retenção Urinária/etiologia , Micção , Urodinâmica , Animais , Gatos , Modelos Animais de Doenças , Terapia por Estimulação Elétrica , Feminino , Masculino , Fatores de Tempo , Retenção Urinária/fisiopatologia , Retenção Urinária/terapia
14.
Urology ; 136: 88-94, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31794815

RESUMO

OBJECTIVE: To determine whether the presence of detrusor overactivity (DO) is associated with the 12-week and 12-month clinical outcomes of selective bladder denervation (SBD) in women with refractory overactive bladder (OAB). METHODS: Prospective single institutional study of refractory OAB females who underwent a urodynamic study and were categorized according to DO status (DO- vs DO+) prior to receiving SBD. RESULTS: Among the 23 patients, 10 were DO- and 13 were DO+. Both groups reported improvement at 12 weeks on the 24-hour pad weight test, in urgency urinary incontinence (UUI) and urgency. At 12 months, both groups still reported improvement in urgency, but only the DO- group reported reduction on the pad weight test and only the DO+ group maintained improvement in the UUI rate. Clinical success (≥50% reduction in UUI) was achieved by all DO- and by 69% of DO+ patients at 12 weeks, and by 60% of DO- and 92% of DO+ patients at 12 months. Treatment benefit (Treatment Benefit Scale ≤2) was reported in 90% of DO- and 85% of DO+ patients at 12 weeks, and in 60% of DO- and 85% of DO+ patients at 12 months. When directly comparing both group outcomes, the only significant difference was the greater reduction of UUI in the DO- group at 12 weeks (-9.0 vs -6.5; P = .045). CONCLUSION: Refractory OAB females appear to be effectively treated by SBD regardless of baseline DO status. DO status does not seem to be associated with the 12-week and 12-month outcomes of SBD.


Assuntos
Denervação/métodos , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Procedimentos Cirúrgicos Urológicos/métodos
15.
Am J Physiol Renal Physiol ; 318(2): F298-F314, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31790304

RESUMO

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been implicated in IC/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. In the present study, we show, using a mouse ex vivo bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of subpopulations of afferents to bladder distension. Histamine also recruited "silent afferents" that were previously unresponsive to bladder distension. Furthermore, in vivo intravesical histamine enhanced activation of dorsal horn neurons within the lumbosacral spinal cord, indicating increased afferent signaling in the central nervous system. Quantitative RT-PCR revealed significant expression of histamine receptor subtypes (Hrh1-Hrh3) in mouse lumbosacral dorsal root ganglia (DRG), bladder detrusor smooth muscle, mucosa, and isolated urothelial cells. In DRG, Hrh1 was the most abundantly expressed. Acute histamine exposure evoked Ca2+ influx in select populations of DRG neurons but did not elicit calcium transients in isolated primary urothelial cells. Histamine-induced mechanical hypersensitivity ex vivo was abolished in the presence of the histamine H1 receptor antagonist pyrilamine and was not present in preparations from mice lacking transient receptor potential vanilloid 1 (TRPV1). Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with histamine H1 receptor and TRPV1. This hypersensitivity translates to increased sensory input and activation in the spinal cord, which may underlie the symptoms of bladder hypersensitivity and pain experienced in IC/BPS.


Assuntos
Cistite Intersticial/metabolismo , Histamina/administração & dosagem , Hiperalgesia/metabolismo , Mecanorreceptores/efeitos dos fármacos , Mecanotransdução Celular/efeitos dos fármacos , Receptores Histamínicos H1/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Bexiga Urinária/inervação , Administração Intravesical , Animais , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Cistite Intersticial/fisiopatologia , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Hiperalgesia/fisiopatologia , Masculino , Mecanorreceptores/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Limiar da Dor/efeitos dos fármacos , Pressão , Receptores Histamínicos H1/metabolismo , Canais de Cátion TRPV/deficiência , Canais de Cátion TRPV/genética , Urotélio/efeitos dos fármacos , Urotélio/metabolismo
16.
Neurourol Urodyn ; 39(1): 181-189, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31724210

RESUMO

AIMS: We sought to determine whether somatic lumbar nerve transfer to the pelvic nerve's anterior vesical branch after sacral decentralization for detrusor muscle reinnervation also leads to aberrant innervation of the bladder outlet. METHODS: Twenty-six female mongrel hound dogs underwent transection of sacral dorsal and ventral spinal roots (ie, sacral decentralization). Immediately afterward, 12 received genitofemoral nerve transfer and 9 received femoral nerve branch transfer. Five were left sacrally decentralized. Controls included 3 sham-operated and 6 unoperated. Eight months postsurgery, the bladder and urethra were injected with retrograde tracing dyes cystoscopically. After 3 weeks, detrusor and urethral pressures were assayed electrophysiologically immediately before euthanasia and characterization of neural reinnervation. RESULTS: Electrical stimulation of spinal cords or roots did not lead to increased urethral sphincter pressure in nerve transfer animals, compared with decentralized animals, confirming a lack of functional reinnervation of the bladder outlet. In contrast, mean detrusor pressure increased after lumbar cord/root stimulation. In sham/unoperated animals, urethral and bladder dye injections resulted in labeled neurons in sacral level neural structures (dorsal root ganglia [DRG], sympathetic trunk ganglia [STG], and spinal cord ventral horns); labeling absent in decentralized animals. Urethral dye injections did not result in labeling in lumbar or sacral level neural structures in either nerve transfer group while bladder dye injections lead to increased labeled neurons in lumbar level DRG, STG, and ventral horns, compared to sacrally decentralized animals. CONCLUSION: Pelvic nerve transfer for bladder reinnervation does not impact urethral sphincter innervation.


Assuntos
Transferência de Nervo/métodos , Nervos Espinhais/transplante , Uretra/inervação , Bexiga Urinária/inervação , Animais , Cães , Estimulação Elétrica , Feminino , Neurônios/fisiologia
17.
Neurourol Urodyn ; 39(1): 108-115, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31579964

RESUMO

AIM: To investigate the role of p38 MAP kinase in lower urinary tract dysfunction in mice with spinal cord injury (SCI). METHODS: Cystometry and external urethral sphincter-electromyography were performed under an awake condition in 4-week SCI female mice. Two weeks after SCI, a catheter connected to an osmotic pump filled with a p38 mitogen-activated protein kinase (MAPK) inhibitor or artificial cerebrospinal fluid (CSF) was implanted into the intrathecal space of L6-S1 spinal cord for continuous intrathecal instillation at infusion rate of 0.51 µL/h for 2 weeks before the urodynamic study. L6 dorsal root ganglia were then removed from CSF and p38 MAPK inhibitor-treated SCI mice as well as from CSF-treated normal (spinal intact) mice to evaluate the levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) transcripts by real-time polymerase chain reaction. RESULTS: In p38 MAPK inhibitor-treated SCI mice, nonvoiding contractions during bladder filling, bladder capacity, and post-void residual volume were significantly reduced while micturition pressure and voiding efficiency were significantly increased in comparison to these measurements in CSF-treated SCI mice. The expression of TRPV1, TNF-α, and iNOS messenger RNA was increased in SCI mice compared with expression in spinal intact mice and significantly decreased after p38 MAPK inhibitor treatment. CONCLUSIONS: The p38 MAPK signaling pathway in bladder sensory neurons or in the spinal cord plays an important role in storage and voiding problems such as detrusor overactivity and inefficient voiding after SCI.


Assuntos
Sistema de Sinalização das MAP Quinases , Traumatismos da Medula Espinal/fisiopatologia , Transtornos Urinários/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Eletromiografia , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Inibidores de Proteínas Quinases/uso terapêutico , Traumatismos da Medula Espinal/complicações , Canais de Cátion TRPV/biossíntese , Canais de Cátion TRPV/genética , Fator de Necrose Tumoral alfa , Uretra/fisiopatologia , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Transtornos Urinários/etiologia , Urodinâmica/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
18.
J Invest Surg ; 33(4): 381-386, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30380342

RESUMO

Background: Radical hysterectomy could result in dysfunctions of pelvic organs and a decline in quality of life. Method: 298 patients who had underwent laparoscopic radical hysterectomy were retrospectively analyzed in this study, of which 216 patients had underwent laparoscopic nerve-sparing radical hysterectomy (LNSRH) and 82 had underwent classical laparoscopic radical hysterectomy (LRH). The mean duration of the postoperative catheterization, a questionnaire and an urodynamic examination were used to assess the bladder functions. Results: The mean duration of the postoperative catheterization in the LNSRH group was shorter than that in the LRH group (13 days versus 18 days, p < 0.01). The incidences of tension urinary incontinence, postoperative voiding time and dysuria symptoms in the LNSRH group, but not in the LRH group, had recovered to preoperative levels in the following 6 months. The frequency of nocturnal urination had recovered to preoperative level at 12 months post-operation in the LNSRH group. The maximum flow rate (MFR), average flow rate (AFR), first voiding sense (FVS), maximum voiding sense (MVS) and maximum detrusor pressure (MDP) in the LNSRH group were better than those in the LRH group (p < 0.05), and patients in the LRH group suffered much more frequently from tension urinary incontinence, prolonged urination time, dysuria and urinary endless compared with those in the LNSRH group (p < 0.05). Conclusion: LNSRH can effectively retain the bladder function, but we should pay attention to the invasion of peripheral nerves.


Assuntos
Histerectomia/métodos , Laparoscopia/métodos , Tratamentos com Preservação do Órgão/métodos , Nervos Periféricos/fisiologia , Bexiga Urinária/fisiologia , Neoplasias do Colo do Útero/cirurgia , Feminino , Humanos , Histerectomia/efeitos adversos , Laparoscopia/efeitos adversos , Invasividade Neoplásica/prevenção & controle , Tratamentos com Preservação do Órgão/efeitos adversos , Nervos Periféricos/patologia , Nervos Periféricos/cirurgia , Qualidade de Vida , Recuperação de Função Fisiológica/fisiologia , Estudos Retrospectivos , Resultado do Tratamento , Bexiga Urinária/inervação , Urodinâmica , Neoplasias do Colo do Útero/patologia
19.
Cell Tissue Res ; 379(2): 373-387, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31446446

RESUMO

Contractile behaviour of the urinary bladder and its sympathetic inhibition during storage phases are not well understood. Here, we explore muscularis mucosae (MM) as a predominant mucosal contractile element and the capability of sympathetic nerves to relax detrusor smooth muscle (DSM) or MM. Distribution of α-smooth muscle actin (α-SMA)-immunoreactive cells was compared in pig, human, guinea pig, rat and mouse bladders by immunohistochemistry, while contractility of the bladder mucosa was compared in these species by isometric tension recordings. In pig, human and guinea pig bladders, DSM and MM located in the lamina propria expressed α-SMA immunoreactivity, while both rat and mouse bladders lacked a MM. Consistent with this presence or absence of MM, bladder mucosa of pig, human and guinea pig but not rat and mouse developed spontaneous phasic contractions (SPCs). Distribution of tyrosine hydroxylase (TH)-immunoreactive sympathetic nerve fibres was compared in pig DSM, MM, trigone and urethra, as were their sympathetic nerve-evoked contractile/relaxing responses examined. In pig DSM or MM, where TH-immunoreactive sympathetic fibres exclusively projected to the vasculature, sympathetic relaxations were difficult to demonstrate. In contrast, sympathetic contractions were invariably evoked in pig trigone and urethra where the smooth muscle cells receive TH-immunoreactive sympathetic innervations. Thus, SPCs of bladder mucosa appear to predominantly arise from the MM displaying species differences. Despite the currently accepted concept of sympathetic nerve-mediated DSM relaxation during the storage phase, it is unlikely that neurally released noradrenaline acts on ß-adrenoceptors to relax either DSM or MM due to the anatomical lack of sympathetic innervation.


Assuntos
Contração Muscular/fisiologia , Especificidade de Órgãos , Sistema Nervoso Simpático/fisiologia , Bexiga Urinária/inervação , Bexiga Urinária/fisiologia , Actinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Cobaias , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/fisiologia , Músculo Liso/fisiologia , Especificidade da Espécie , Suínos
20.
J Neurosurg Spine ; 32(2): 258-268, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703192

RESUMO

OBJECTIVE: Previous patient surveys have shown that patients with spinal cord or cauda equina injuries prioritize recovery of bladder function. The authors sought to determine if nerve transfer after long-term decentralization restores bladder and sphincter function in canines. METHODS: Twenty-four female canines were included in this study. Transection of sacral roots and hypogastric nerves (S Dec) was performed in 6 animals, and 7 animals underwent this procedure with additional transection of the L7 dorsal roots (L7d+S Dec). Twelve months later, 3 L7d+S Dec animals underwent obturator-to-pelvic nerve and sciatic-to-pudendal nerve transfers (L7d+S Dec+Reinn). Eleven animals served as controls. Squat-and-void behaviors were tracked before and after decentralization, after reinnervation, and following awake bladder-filling procedures. Bladders were cystoscopically injected with Fluoro-Gold 3 weeks before euthanasia. Immediately before euthanasia, transferred nerves were stimulated to evaluate motor function. Dorsal root ganglia were assessed for retrogradely labeled neurons. RESULTS: Transection of only sacral roots failed to reduce squat-and-void postures; L7 dorsal root transection was necessary for significant reduction. Three L7d+S Dec animals showing loss of squat-and-void postures post-decentralization were chosen for reinnervation and recovered these postures 4-6 months after reinnervation. Each showed obturator nerve stimulation-induced bladder contractions and sciatic nerve stimulation-induced anal sphincter contractions immediately prior to euthanasia. One showed sciatic nerve stimulation-induced external urethral sphincter contractions and voluntarily voided twice following nonanesthetized bladder filling. Reinnervation was confirmed by increased labeled cells in L2 and the L4-6 dorsal root ganglia (source of obturator nerve in canines) of L7d+S Dec+Reinn animals, compared with controls. CONCLUSIONS: New neuronal pathways created by nerve transfer can restore bladder sensation and motor function in lower motor neuron-lesioned canines even 12 months after decentralization.


Assuntos
Transferência de Nervo , Raízes Nervosas Espinhais/lesões , Bexiga Urinária/inervação , Bexiga Urinária/cirurgia , Animais , Cães , Feminino , Regeneração Nervosa/fisiologia , Transferência de Nervo/métodos , Radiculopatia/fisiopatologia , Sacro/fisiopatologia , Traumatismos da Medula Espinal/cirurgia , Uretra/inervação , Uretra/fisiopatologia , Micção/fisiologia
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