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2.
Medicine (Baltimore) ; 99(14): e19673, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243402

RESUMO

INTRODUCTION: Interstitial cystitis (IC), as a common disease in urology, is prolonged and repeated. IC has caused great harm to the patient's physical and psychological. Traditional Chinese medicine (TCM) is characterized by overall concepts and dialectical treatment. It provides clinicians with safer and more reliable alternatives in terms of clinical prescriptions and prepared medicines, and also improves the quality of life of patients with IC. Therefore, in this study, we will use the research method of randomized controlled trials to explore the effects of TCM combined with western medicine on renal function and urine metabolism on middle-aged women with IC. METHODS/DESIGN: Use randomized controlled trials. According to the proposed diagnostic, inclusion, and exclusion criteria. Sixty patients with interstitial bladder inflammation that met the criteria were randomized into a treatment group and a control group of 30 cases each. The intervention group was treated with integrated traditional Chinese and western medicine. The control group was given conventional Western medicine treatment. The course of treatment is 8 weeks. Interstitial bladder inflammation symptoms score (ICS worker), problem score (worker CPI), pelvic pain and urinary urgency symptoms, and urodynamics were used as the evaluation criteria. DISCUSSION: This trial may provide evidence regarding the clinical effectiveness, safety, and cost-effectiveness of TCM for patients with IC. TRIAL REGISTRATION: ClinicalTrials.gov, ChiCTR2000029971, Registered on 17 February 2020.


Assuntos
Cistite Intersticial/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa/métodos , Agentes Urológicos/farmacologia , Cistite Intersticial/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Resultado do Tratamento , Urodinâmica/efeitos dos fármacos
3.
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
4.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R418-R427, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913682

RESUMO

Genes for the epithelial sodium channel (ENaC) subunits are expressed in a circadian manner, but whether this results in time-of-day differences in activity is not known. Recent data show that protein expression of ENaC subunits is higher in kidneys from female rats, yet females are more efficient in excreting an acute salt load. Thus, our in vivo study determined whether there is a time-of-day difference as well as a sex difference in the response to ENaC inhibition by benzamil. Our results showed that the natriuretic and diuretic responses to a single dose of benzamil were significantly greater in male compared with female rats whether given at the beginning of the inactive period [Zeitgeber time 0 (ZT0), 7 AM] or active period (ZT12, 7 PM). However, the response to benzamil was not significantly different between ZT0 and ZT12 dosing in either male or female rats. There was no difference in renal cortical α-ENaC protein abundance between ZT0 and ZT12 or males and females. Given previous reports of flow-induced stimulation of endothelin-1 (ET-1) production and sex differences in the renal endothelin system, we measured urinary ET-1 excretion to assess the effects of increased urine flow on intrarenal ET-1. ET-1 excretion was significantly increased following benzamil administration in both sexes, but this increase was significantly greater in females. These results support the hypothesis that ENaC activity is less prominent in maintaining Na+ balance in females independent of renal ET-1. Because ENaC subunit genes and protein expression vary by time of day and are greater in female rat kidneys, this suggests a clear disconnect between ENaC expression and channel activity.


Assuntos
Amilorida/análogos & derivados , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Canais Epiteliais de Sódio/efeitos dos fármacos , Rim/efeitos dos fármacos , Natriurese/efeitos dos fármacos , Ciclos de Atividade , Amilorida/farmacologia , Animais , Endotelina-1/urina , Canais Epiteliais de Sódio/metabolismo , Feminino , Rim/metabolismo , Masculino , Ovariectomia , Ratos Sprague-Dawley , Eliminação Renal/efeitos dos fármacos , Fatores Sexuais , Fatores de Tempo , Urodinâmica/efeitos dos fármacos
5.
Am J Physiol Endocrinol Metab ; 318(3): E343-E356, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891537

RESUMO

Diabetic nephropathy (DN) is one of the most important renal complications associated with diabetes, and the mechanisms are yet to be fully understood. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin-D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The aim of the present study was to explore the potential mechanism by which 1,25(OH)2D3 reduced oxidative stress in diabetic rat kidneys. In this study, we established a vitamin D-deficient spontaneous diabetes model: 5-6 wk of age Zucker diabetic fatty (ZDF) rats were treated with or without 1,25(OH)2D3 for 7 wk, age-matched Zucker lean rats served as control. Results showed that ZDF rats treated with 1,25(OH)2D3 had decreased body mass, food intake, water intake, and urine volume. 1,25(OH)2D3 ameliorated urine glucose, blood glucose and abnormal glucose tolerance. Additionally, 1,25(OH)2D3 significantly lowered microalbuminuria, decreased the glomerular basement membrane thickness, and in some degree inhibited glomerular hypertrophy, mesangial expansion, and tubular dilatation. Furthermore, 1,25(OH)2D3 attenuated renal oxidative damage, as reflected by the levels of malondialdehyde, reduced glutathione, 4-hydroxynonenal, 8-hydroxy-2'-deoxyguanosine, and reactive oxygen species production, and notably inhibited poly(ADP-ribose) polymerase-1 (PARP1), activated sirtuin 1 (SIRT1), and decreased the expression of NADPH oxidase 4 (NOX4). Of interest, the abovementioned proteins could be involved in the antioxidant mechanism of 1,25(OH)2D3 in diabetic rat kidneys. Our study showed that oxidative stress might be a major contributor to DN pathogenesis and uncovered the antioxidant role of 1,25(OH)2D3 in diabetic nephropathy that was associated with the PARP1/SIRT1/ NOX4 pathway.


Assuntos
Calcitriol/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/prevenção & controle , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Glucose/metabolismo , Teste de Tolerância a Glucose , Masculino , Ratos , Ratos Zucker , Urodinâmica/efeitos dos fármacos
6.
Urology ; 135: 38-43, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31600558

RESUMO

OBJECTIVE: To evaluate differences in adverse events (AE) in asymptomatic patients with a positive urine dip (UD) at time of intradetrusor onabotulinumtoxinA (BTX-A) injection vsthose with a defined negative UD. MATERIALS AND METHODS: All intradetrusor BTX-A injections were retrospectively reviewed at a single institution between 2016 and 2018. Exclusion criteria included an indwelling catheter, recent positive urine culture, recent antibiotic course, or absence of UD on the day of injection. A positive UD was defined using 7 different definitions with varying combinations of any level of positive blood, leukocyte esterase, or nitrite. Negative UDs were defined those excluded from the positive UD group. We compared multiple positive UD-defined groups to their respective negative UD cohorts with regards to outcomes and demographics. RESULTS: A total of 212 patients underwent 335 cycles of BTX-A injections over a 2-year period. The average age was 65 years (range: 21-90). The majority received 100 units (73%) of BTX-A for a non-neurogenic diagnosis (73%). The overall rate of AEs, urinary tract infection, and urinary retention was 14.6%, 9%, and 3%, respectively. In all groups, the most common AE was urinary tract infection followed by urinary retention. There were no major Clavien-Dindo-defined complications. There was no statistically significant difference in the total or categorical AE rates between positive and negative UD groups using all 7 definitions of a positive UD (P = .05-1.0). CONCLUSION: These data do not support the practice of obtaining a preprocedure UD in asymptomatic patients undergoing intradetrusor BTX-A injection for any indication; test results are unable to predict outcomes or AEs.


Assuntos
Toxinas Botulínicas Tipo A/efeitos adversos , Fármacos Neuromusculares/efeitos adversos , Bexiga Urinária Hiperativa/tratamento farmacológico , Retenção Urinária/epidemiologia , Infecções Urinárias/epidemiologia , Administração Intravesical , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas/terapia , Toxinas Botulínicas Tipo A/administração & dosagem , Feminino , Humanos , Injeções Intramusculares/efeitos adversos , Injeções Intramusculares/métodos , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/administração & dosagem , Estudos Retrospectivos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/fisiopatologia , Retenção Urinária/etiologia , Infecções Urinárias/etiologia , Infecções Urinárias/urina , Urodinâmica/efeitos dos fármacos , Adulto Jovem
7.
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
8.
Crit Care Resusc ; 21(4): 258-64, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31778632

RESUMO

OBJECTIVE: To compare the physiological and biochemical effects of a single intravenous dose of furosemide or acetazolamide in critically ill patients. DESIGN: Single centre, pilot randomised controlled trial. SETTING: Large tertiary adult intensive care unit (ICU). PARTICIPANTS: Twenty-six adult ICU patients deemed to require diuretic therapy. INTERVENTION: Single dose of intravenous 40 mg furosemide or 500 mg acetazolamide. MAIN OUTCOME MEASURES: Data were collected on urine output, cumulative fluid balance, and serum and urine biochemistry for 6 hours before and 6 hours after diuretic administration. RESULTS: Study patients had a median age of 55 years (IQR, 50-66) and median APACHE III score of 44 (IQR, 37-52). Furosemide caused a much greater increase in-urine output and much greater median mass chloride excretion (121.7 mmol [IQR, 81.1-144.6] v 23.3 mmol [IQR, 20.4-57.3]; P < 0.01) than acetazolamide. Furosemide also resulted in a progressively more negative fluid balance while acetazolamide resulted in greater alkalinisation of the urine (change in median urinary pH, +2 [IQR, 1.75-2.12] v 0 [IQR, 0-0.5]; P = 0.02). In keeping with this effect, furosemide alkalinised and acetazolamide acidified plasma (change in median serum pH, +0.03 [IQR, 0.01-0.04] v -0.01 [IQR, -0.04 to 0]; P = 0.01; change in median serum HCO3-, +1.5 mmol/L [IQR, 0.75-2] v -2 mmol/L [IQR, -3 to 0]; P < 0.01). CONCLUSIONS: Furosemide is a more potent diuretic and chloriuretic agent than acetazolamide in critically ill patients, and achieves a threefold greater negative fluid balance. Compared with acetazolamide, furosemide acidifies urine and alkalinises plasma. Our findings imply that combination therapy might be a more physiological approach to diuresis in critically ill patients.


Assuntos
Acetazolamida/farmacologia , Acetazolamida/farmacocinética , Estado Terminal/terapia , Diuréticos/farmacologia , Diuréticos/farmacocinética , Furosemida/farmacologia , Furosemida/farmacocinética , Acetazolamida/administração & dosagem , Adulto , Idoso , Diuréticos/administração & dosagem , Eletrólitos/sangue , Furosemida/administração & dosagem , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento , Urodinâmica/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/efeitos dos fármacos
9.
Toxins (Basel) ; 11(11)2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652991

RESUMO

Botulinum neurotoxin (BoNT) can counteract the highly frequent involuntary muscle contractions and the uncontrolled micturition events that characterize the neurogenic detrusor overactivity (NDO) due to supra-sacral spinal cord lesions. The ability of the toxin to block the neurotransmitter vesicular release causes the reduction of contractions and improves the compliance of the muscle and the bladder filling. BoNT is the second-choice treatment for NDO once the anti-muscarinic drugs have lost their effects. However, the toxin shows a time-dependent efficacy reduction up to a complete loss of activity. The cellular mechanisms responsible for BoNT effects exhaustion are not yet completely defined. Similarly, also the sites of its action are still under identification. A growing amount of data suggest that BoNT, beyond the effects on the efferent terminals, would act on the sensory system recently described in the bladder mucosa. The specimens from NDO patients no longer responding to BoNT treatment displayed a significant increase of the afferent terminals, likely excitatory, and signs of a chronic neurogenic inflammation in the mucosa. In summary, beyond the undoubted benefits in ameliorating the NDO symptomatology, BoNT treatment might bring to alterations in the bladder sensory system able to shorten its own effectiveness.


Assuntos
Toxinas Botulínicas Tipo A/efeitos adversos , Toxinas Botulínicas Tipo A/uso terapêutico , Fármacos Neuromusculares/efeitos adversos , Fármacos Neuromusculares/uso terapêutico , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Urodinâmica/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Clostridium botulinum/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/efeitos dos fármacos
10.
Am J Physiol Renal Physiol ; 317(4): F1010-F1021, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390233

RESUMO

Glucagon-like peptide-1 (GLP-1), an incretin hormone, has diuretic and natriuretic effects. The present study was designed to explore the possible underlying mechanisms for the diuretic and natriuretic effects of GLP-1 via renal nerves in rats. Immunohistochemistry revealed that GLP-1 receptors were avidly expressed in the pelvic wall, the wall being adjacent to afferent renal nerves immunoreactive to calcitonin gene-related peptide, which is the dominant neurotransmitter for renal afferents. GLP-1 (3 µM) infused into the left renal pelvis increased ipsilateral afferent renal nerve activity (110.0 ± 15.6% of basal value). Intravenous infusion of GLP-1 (1 µg·kg-1·min-1) for 30 min increased renal sympathetic nerve activity (RSNA). After the distal end of the renal nerve was cut to eliminate the afferent signal, the increase in efferent renal nerve activity during intravenous infusion of GLP-1 was diminished compared with the increase in total RSNA (17.0 ± 9.0% vs. 68.1 ± 20.0% of the basal value). Diuretic and natriuretic responses to intravenous infusion of GLP-1 were enhanced by total renal denervation (T-RDN) with acute surgical cutting of the renal nerves. Selective afferent renal nerve denervation (A-RDN) was performed by bilateral perivascular application of capsaicin on the renal nerves. Similar to T-RDN, A-RDN enhanced diuretic and natriuretic responses to GLP-1. Urine flow and Na+ excretion responses to GLP-1 were not significantly different between T-RDN and A-RDN groups. These results indicate that the diuretic and natriuretic effects of GLP-1 are partly governed via activation of afferent renal nerves by GLP-1 acting on sensory nerve fibers within the pelvis of the kidney.


Assuntos
Vias Aferentes/efeitos dos fármacos , Diurese/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Rim/efeitos dos fármacos , Rim/inervação , Natriurese/efeitos dos fármacos , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Denervação , Peptídeo 1 Semelhante ao Glucagon/biossíntese , Receptor do Peptídeo Semelhante ao Glucagon 1/biossíntese , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/imunologia , Células HEK293 , Humanos , Pelve Renal/efeitos dos fármacos , Pelve Renal/inervação , Masculino , Ratos , Ratos Sprague-Dawley , Circulação Renal/efeitos dos fármacos , Sódio/urina , Sistema Nervoso Simpático/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos
11.
Urology ; 133: 72-77, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31465791

RESUMO

OBJECTIVE: To assess whether intraurethral anesthesia decreased voiding efficiency (VE), reduced catheterization pain, and impacted urodynamic parameters in healthy adult females. METHODS: In a randomized, double-blind, placebo-controlled trial, participants received two 5 mL doses of either intraurethral aqueous gel or 4% lidocaine gel. The primary outcome was VE during randomized condition uroflow, defined as voided volume/(voided volume + residual volume). The secondary outcomes were pain during catheterization and to confirm previously reported pressure-flow changes. A sample size of 10 per group was planned to detect a clinically significant decrease in VE with a power (1-ß) of 0.99. RESULTS: From October to December 2018, 23 women were screened and 18 were randomized to receive placebo (n = 10) or lidocaine (n = 8). Baseline uroflow VE was similar between the placebo and lidocaine groups (88 ± 6.6% vs 91 ± 5.8%, P = .33). After study drug administration, the changes in VE (post-pre) were similar between placebo and lidocaine groups (-5.4 ± 14% vs 1.7 ± 6.4%, P = .21). Visual analog scores were similar following catheterizations (26.7 ± 12.8 mm vs 36.9 ± 26.8 mm, P = .34). The lidocaine group exhibited lower average flow rates per voided volume (0.04 ± 0.02 s-1 vs 0.02 ± 0.01 s-1, P = .04). CONCLUSION: Intraurethral administration of 4% lidocaine did not decrease VE compared to placebo and did not change pain scores following catheterization. In the lidocaine group, the average flow rate per voided volume was lower. The decrease in flow rate after local anesthesia to the urethra may indicate that urethral sensory feedback contributes to voiding in human micturition.


Assuntos
Anestésicos Locais/administração & dosagem , Lidocaína/administração & dosagem , Dor/prevenção & controle , Cateterismo Urinário , Micção/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Administração Tópica , Adulto , Anestésicos Locais/farmacologia , Método Duplo-Cego , Feminino , Humanos , Lidocaína/farmacologia , Uretra , Cateterismo Urinário/efeitos adversos
12.
Am J Physiol Renal Physiol ; 317(4): F815-F824, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31364378

RESUMO

Downregulation of heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX2), and nitric oxide synthase-2 (NOS2) in the kidneys of Dahl rodents causes salt sensitivity, while restoring their expression aids in Na+ excretion and blood pressure reduction. Loading cholesterol into collecting duct (CD) cells represses fluid shear stress (FSS)-mediated COX2 activity. Thus, we hypothesized that cholesterol represses flow-responsive genes necessary to effectuate Na+ excretion. To this end, CD cells were used to test whether FSS induces these genes and if cholesterol loading represses them. Mice fed either 0% or 1% cholesterol diet were injected with saline, urine volume and electrolytes were measured, and renal gene expression determined. FSS-exposed CD cells demonstrated increases in HO-1 mRNA by 350-fold, COX2 by 25-fold, and NOS2 by 8-fold in sheared cells compared with static cells (P < 0.01). Immunoblot analysis of sheared cells showed increases in HO-1, COX2, and NOS2 protein, whereas conditioned media contained more HO-1 and PGE2 than static cells. Cholesterol loading repressed the sheared mediated protein abundance of HO-1 and NOS2 as well as HO-1 and PGE2 concentrations in media. In cholesterol-fed mice, urine volume was less at 6 h after injection of isotonic saline (P < 0.05). Urinary Na+ concentration, urinary K+ concentration, and osmolality were greater, whereas Na+ excretion was less, at the 6-h urine collection time point in cholesterol-fed versus control mice (P < 0.05). Renal cortical and medullary HO-1 (P < 0.05) and NOS2 (P < 0.05) mRNA were repressed in cholesterol-fed compared with control mice. Cholesterol acts to repress flow induced natriuretic gene expression, and this effect, in vivo, may contribute to renal Na+ avidity.


Assuntos
Colesterol/farmacologia , Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Animais , Pressão Sanguínea , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Túbulos Renais Coletores/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Potássio/urina , Ratos , Ratos Endogâmicos Dahl , Sódio/urina , Cloreto de Sódio na Dieta , Urodinâmica/efeitos dos fármacos
13.
Strahlenther Onkol ; 195(10): 934-939, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31363801

RESUMO

PURPOSE: The urinary bladder is one major organ at risk in radiotherapy of pelvic malignancies. The radiation response manifests in early and chronic changes in bladder function. These are based on inflammatory effects and changes in urothelial cell function and proliferation. This study evaluates the effect of bortezomib as an anti-proliferative and anti-inflammatory compound in an established mouse bladder model. The early radiation-induced bladder dysfunction in the mouse occurs in two phases during the first month after irradiation (phase I: day 0-15, phase II: days 16-30). MATERIALS AND METHODS: Daily bortezomib injections (0.02 mg/ml, subcutaneously) were administered between days 0-15 or 15-30 in separate groups. Single graded radiation doses were administered in five dose groups. Cystometry was carried out before (individual control) and during the first month after irradiation. When bladder capacity was decreased by ≥50%, mice were considered as responders. Statistical analysis was performed by the SPSS software version 24. RESULTS: Daily bortezomib injections between days 0-15 resulted in a significant decrease in responders for phase I. There was no significant effect with daily bortezomib injections between days 16-30. CONCLUSION: Two separate waves of acute radiation-induced urinary bladder dysfunction have distinct mechanisms that need further biological studies.


Assuntos
Bortezomib/farmacologia , Lesões Experimentais por Radiação/tratamento farmacológico , Bexiga Urinária/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C3H , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/efeitos da radiação , Órgãos em Risco/efeitos da radiação , Bexiga Urinária/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Urodinâmica/efeitos da radiação
15.
Int J Urol ; 26(9): 917-923, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31317583

RESUMO

OBJECTIVES: To study the effect of cerebrolysin on bladder function after spinal cord injury using functional measurements in rats. METHODS: A total of 60 female rats were enrolled in this study. After induction of complete transection at T9-T10 spinal vertebrae, cerebrolysin was injected intraperitoneally, and daily in three dosages until 7 days (1 week) and continued until 28 days (4 weeks) in three groups to show the impact of that on the bladder function. Urodynamic parameters were measured in the different groups. RESULTS: Cerebrolysin injection in a dose of 1 mL/kg for 1 week showed a slight improvement in urodynamic parameters. However, infusion of 2.5 and 5 mL/kg cerebrolysin for 1 week caused an elevation in contractions and a decrease in compliance. In long-term 2.5 mL/kg cerebrolysin injection, an improvement in compliance was observed, despite relative contractions. Furthermore, the bladder pressure pattern in the 2.5 mL/kg infused rats for 4 weeks was similar to the control group, but in the group receiving 5 mL/kg cerebrolysin for 4 weeks, reduced bladder contractions and function were observed. CONCLUSIONS: Our findings suggest that cerebrolysin might be able to inhibit the emergence of neurogenic detrusor overactivity in spinal cord injured female rats.


Assuntos
Aminoácidos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Traumatismos da Medula Espinal/complicações , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intraperitoneais , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Ratos , Ratos Wistar , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Bexiga Urinaria Neurogênica/etiologia , Bexiga Urinaria Neurogênica/fisiopatologia , Urodinâmica/efeitos dos fármacos , Urodinâmica/fisiologia
16.
Neurourol Urodyn ; 38(6): 1540-1550, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31180583

RESUMO

OBJECTIVES: To investigate if intravesical administration during spinal shock of resiniferatoxin (RTX), an ultrapotent desensitizing agonist of transient receptor potential vanilloid-1 (TRPV1), would silence TRPV1-expressing bladder afferents at an early stage of disease progression and modulate neurogenic detrusor overactivity (NDO) emergence. MATERIALS AND METHODS: Rats submitted to largely incomplete spinal cord transection at T8/9 spinal segment were treated with intravesical RTX (50 nM) or its vehicle during spinal shock. Four weeks after spinal lesion, bladder-reflex activity was evaluated by cystometry under urethane anesthesia, after which the bladder, spinal cord, and dorsal root ganglia were collected and processed. RESULTS: We found improvements on bladder function several weeks after early intravesical RTX administration, including a marked decrease of intravesical pressures and amplitude of bladder contractions. Such strong long-lasting urodynamic effects resulted from the very potent desensitizing activity of RTX on peripheral terminals of sensory afferents, an effect restricted to the bladder. CONCLUSION: Our results support that an early intervention with RTX could potentially attenuate NDO development and ensuing urinary incontinence, with a dramatic impact on the quality of life of spinal cord injury patients.


Assuntos
Diterpenos/uso terapêutico , Traumatismos da Medula Espinal/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/etiologia , Administração Intravesical , Animais , Peptídeo Relacionado com Gene de Calcitonina/biossíntese , Diterpenos/administração & dosagem , Feminino , Proteína GAP-43/biossíntese , Gânglios Espinais/diagnóstico por imagem , Neurônios Aferentes , Ratos , Ratos Wistar , Reflexo , Traumatismos da Medula Espinal/fisiopatologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/biossíntese , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Urodinâmica/efeitos dos fármacos
17.
Low Urin Tract Symptoms ; 11(4): 248-254, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250566

RESUMO

The aim of this study was to determine whether aging-related detrusor underactivity (DU) involves a decrease in 5-hydroxytryptamine (5-HT-positive)-expressing urethral cells and whether 5-HT stimulation of urethral sensory fibers improves detrusor function. Cystometries were performed in young (6 months) and aged (18-24 months) female Wistar rats. Aged rats with voiding contractions (VC) that were 2SD below the mean of those in young rats were considered to have DU. Bladder voiding efficiency (BVE) was calculated during saline or 5-HT solution cystometries. Rats were perfusion-fixed with a fixative solution (paraformaldehyde, PFA 4%) through the circulatory system and the urethra sectioned to count the number of 5-HT-immunoreactive (IR) cells. Isovolumetric cystometry was performed while irrigating the urethra with saline or 5µM-HT solution. Two-tailed unpaired t tests were used to determine the significance of differences. In aged DU rats, the mean (±SD) VC frequency was 0.24 ± 0.07 per minute, with an amplitude of 15 ± 3 cm H2 O. The mean (±SD) number of 5-HT-IR cells in the urethra of aged DU and young rats was 90 ± 11 and 182 ± 25, respectively (P < 0.01). 5-HT improved the mean (±SD) BVE of aged DU rats from 49 ± 3% to 78 ± 2% (P < 0.001). In isovolumetric cystometries, detrusor pressure during irrigation of the urethra with saline was 18 ± 1 cm H2 O, compared with 39 ± 2 cm H2 O during irrigation with 5-HT solution (P < 0.05). In rats, DU associated with aging is accompanied by a decrease in the number of 5-HT-positive cells. The results suggest that decreased 5-HT availability decreases urethral sensory fiber excitation, leading to a decrease the number of effective VC.


Assuntos
Serotonina/uso terapêutico , Uretra/efeitos dos fármacos , Bexiga Inativa/tratamento farmacológico , Envelhecimento/fisiologia , Animais , Feminino , Ratos , Ratos Wistar , Serotonina/metabolismo , Uretra/citologia , Uretra/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Bexiga Inativa/metabolismo , Bexiga Inativa/fisiopatologia , Urodinâmica/efeitos dos fármacos
18.
Toxicol Lett ; 311: 27-36, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31039415

RESUMO

Methotrexate (MTX) is a derivate of folic acid, commonly used as an anchor drug for the treatment and management of malignant diseases and autoimmune disorders. However, nephrotoxicity is an important drawback of MTX therapy. Unfortunately, there are not enough studies reporting the nature of the renal failure induced by MTX. Thus, the aim of this study was to evaluate the time course of renal handling of water and electrolytes in male Wistar rats, after the exposure to a unique dose of MTX (80 mg/kg b.w.). Experiments were carried out at day 2, day 4, day 8 and day 14 after MTX administration. Several parameters of kidney function related to water and electrolytes handling were evaluated. Renal expression and urinary excretion of aquaporin-2 (AQP2) and Na-K-2Cl-cotransporter (NKCC2) were determined by Western blotting. MTX produced alterations on water handling on the second day after treatment, showing a significant increase in solute free water reabsorption which might be mediated by the increased expression of AQP2 in apical membranes. On the other hand, MTX produced alterations on electrolytes handling on the fourth day after treatment, showing a significant decrease of sodium chloride excretion, mediated at least in part, by the increase renal expression of NKCC2. These results provide valuable information to clinical practice in order to be able to find therapeutic targets that diminish adverse effects and health deterioration. Moreover, MTX treatment altered AQP2 and NKCC2 urinary excretion allowing postulating these transporters as potential biomarkers of MTX induced nephrotoxicity.


Assuntos
Aquaporina 2/metabolismo , Eletrólitos/metabolismo , Nefropatias/induzido quimicamente , Túbulos Renais/efeitos dos fármacos , Metotrexato/toxicidade , Reabsorção Renal/efeitos dos fármacos , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Água/metabolismo , Animais , Biomarcadores/metabolismo , Cloretos/metabolismo , Nefropatias/metabolismo , Túbulos Renais/metabolismo , Masculino , Potássio/metabolismo , Ratos Wistar , Sódio/metabolismo , Fatores de Tempo , Urodinâmica/efeitos dos fármacos
19.
Am J Physiol Renal Physiol ; 317(2): F388-F398, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141399

RESUMO

Diabetic bladder dysfunction (DBD) affects up to 50% of all patients with diabetes, characterized by symptoms of both overactive and underactive bladder. Although most diabetic bladder dysfunction studies have been performed using models with type 1 diabetes, few have been performed in models of type 2 diabetes, which accounts for ~90% of all diabetic cases. In a type 2 rat model using a high-fat diet (HFD) and two low doses of streptozotocin (STZ), we examined voiding measurements and functional experiments in urothelium-denuded bladder strips to establish a timeline of disease progression. We hypothesized that overactive bladder symptoms (compensated state) would develop and progress into symptoms characterized by underactive bladder (decompensated state). Our results indicated that this model developed the compensated state at 1 wk after STZ and the decompensated state at 4 mo after STZ administration. Diabetic bladders were hypertrophied compared with control bladders. Increased volume per void and detrusor muscle contractility to exogenous addition of carbachol and ATP confirmed the development of the compensated state. This enhanced contractility to carbachol was not due to increased levels of M3 receptor expression. Decompensation was characterized by increased volume per void, number of voids, and contractility to ATP but not carbachol. Thus, progression from the compensated to decompensated state may involve decreased contractility to muscarinic stimulation. These data suggest that the compensated state of DBD progresses temporally into the decompensated state in the male HFD/STZ model of diabetes; therefore, this male HFD/STZ model can be used to study the progression of DBD.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Contração Muscular , Sistema Nervoso Parassimpático/fisiopatologia , Bexiga Urinária Hiperativa/fisiopatologia , Bexiga Inativa/fisiopatologia , Bexiga Urinária/inervação , Urodinâmica , Trifosfato de Adenosina/farmacologia , Animais , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica , Progressão da Doença , Masculino , Contração Muscular/efeitos dos fármacos , Força Muscular , Sistema Nervoso Parassimpático/efeitos dos fármacos , Ratos Sprague-Dawley , Estreptozocina , Fatores de Tempo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária Hiperativa/etiologia , Bexiga Inativa/etiologia , Urodinâmica/efeitos dos fármacos
20.
Neurourol Urodyn ; 38(6): 1524-1532, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31074529

RESUMO

AIMS: To assess the impact of chronic high-fat diet (HFD) on behavioral voiding patterns, detrusor contractility, and smooth muscle mitochondrial function in male mice. MATERIALS AND METHODS: Male C57BL/6J mice (6 weeks) were fed a control or HFD for 20 weeks. Bladder function was assessed by void spot assays. Bladders were collected and detrusor contractility to carbachol (10-9 -10-5 M), and electrical field stimulation (EFS, 0.5-32 Hz) in the presence and absence of atropine was measured. Homogenized detrusor samples were placed in oxygraphs to assess the rate of oxygen consumption of the mitochondria within the detrusor in the presence of different substrates. Mitochondrial hydrogen peroxide (H2 O2 ) emission was measured fluorometrically. Detrusor citrate synthase activity was measured via enzyme activity kit and Western blots assessed the electron transport chain (ETC) protein content. RESULTS: HFD significantly increased body weight, adiposity, and blood glucose levels. HFD mice demonstrated increased voiding frequency and increased EFS-induced detrusor contractility. There were no changes in detrusor relaxation or cholinergic-medicated contraction. Mitochondrial respiration was decreased with HFD and H2 O 2 emission was increased. The relative amount of mitochondria in the detrusor was similar between groups. However, ETC complexes V and III were increased following HFD. CONCLUSIONS: Chronic HFD increased adiposity, lead to more frequent voiding, and enhanced EFS-mediated detrusor contractions. Mitochondrial respiration was decreased and H2 O 2 emission increased following HFD. Further research is required to determine if alterations in mitochondrial function could play a role in the development of HFD-induced bladder dysfunction.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Mitocôndrias Musculares/metabolismo , Bexiga Urinária/fisiopatologia , Adiposidade , Animais , Carbacol/farmacologia , Estimulação Elétrica , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Agonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , Consumo de Oxigênio , Bexiga Urinária/metabolismo , Urodinâmica/efeitos dos fármacos
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