Acute effects of empagliflozin on open-loop baroreflex function and urine output in streptozotocin-induced type 1 diabetic rats.

Although sympathetic suppression is considered one of the mechanisms for cardioprotection afforded by sodium-glucose cotransporter 2 (SGLT2) inhibitors, whether SGLT2 inhibition acutely modifies sympathetic arterial pressure (AP) regulation remains unclear. We examined the acute effect of an SGLT2 inhibitor, empagliflozin (10 mg/kg), on open-loop baroreflex static characteristics in streptozotocin (STZ)-induced type 1 diabetic and control (CNT) rats (n = 9 each). Empagliflozin significantly increased urine flow [CNT: 25.5 (21.7-31.2) vs. 55.9 (51.0-64.5), STZ: 83.4 (53.7-91.7) vs. 121.2 (57.0-136.0) µL·min-1·kg-1, median (1st-3rd quartiles), P < 0.001 for empagliflozin and STZ]. Empagliflozin decreased the minimum sympathetic nerve activity (SNA) [CNT: 15.7 (6.8-18.4) vs. 10.5 (2.9-19.0), STZ: 36.9 (25.7-54.9) vs. 32.8 (15.1-37.5) %, P = 0.021 for empagliflozin and P = 0.003 for STZ], but did not significantly affect the peripheral arc characteristics assessed by the SNA-AP relationship. Despite the significant increase in urine flow and changes in several baroreflex parameters, empagliflozin preserved the overall sympathetic AP regulation in STZ-induced diabetic rats. The lack of a significant change in the peripheral arc may minimize reflex sympathetic activation, thereby enhancing a cardioprotective benefit of empagliflozin.

Investigating the Impact of Estrogen Levels on Voiding Characteristics, Bladder Structure, and Related Proteins in a Mouse Model of Menopause-Induced Lower Urinary Tract Symptoms.

Lower urinary tract symptoms (LUTS) are common in postmenopausal women. These symptoms are often linked to decreased estrogen levels following menopause. This study investigated the relationship between estrogen levels, alterations in bladder tissue structure, bladder function, and the incidence of urinary frequency. An age-appropriate bilateral ovariectomized mouse model (OVX) was developed to simulate conditions of estrogen deficiency. Mice were divided into three groups: a sham-operated control group, OVX, and an estradiol-treated group. The assessments included estrogen level measurement, urination frequency, cystometry, histological analysis, immunofluorescence staining, and real-time quantitative PCR. Additionally, we quantified the expression of the mechanosensitive channel proteins Piezo1 and TRPV4 in mouse bladder tissues. Lower estrogen levels were linked to increased voiding episodes and structural changes in mouse bladder tissues, notably a significant increase in Collagen III fiber deposition. There was a detectable negative relationship between estrogen levels and the expression of Piezo1 and TRPV4, mechanosensitive proteins in mouse bladder tissues, which may influence voiding frequency and nocturia. Estrogen treatment could improve bladder function, decrease urination frequency, and reduce collagen deposition in the bladder tissues. This study explored the connection between estrogen levels and urinary frequency, potentially setting the stage for novel methods to address frequent urination symptoms in postmenopausal women.

PDE5 inhibitor potentially improves polyuria and bladder storage and voiding dysfunctions in type 2 diabetic rats.

PURPOSE: Bladder dysfunction associated with type 2 diabetes mellitus (T2DM) includes urine storage and voiding disorders. We examined pathological conditions of the bladder wall in a rat T2DM model and evaluated the effects of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil. MATERIALS AND METHODS: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats were used as the T2DM and control groups, respectively. Tadalafil was orally administered for 12 weeks. Micturition behavior was monitored using metabolic cages, and bladder function was evaluated by cystometry. Bladder blood flow was evaluated by laser speckle imaging, and an organ bath bladder distention test was used to measure adenosine triphosphate (ATP) release from the bladder urothelium. The expression levels of vesicular nucleotide transporter (VNUT), hypoxia markers, pro-inflammatory cytokines and growth factors in the bladder wall were measured using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Bladder wall contractions in response to KCl and carbachol were monitored using bladder-strip tests. RESULTS: With aging, OLETF rats had higher micturition frequency and greater urine volume than LETO rats. Although bladder capacity was not significantly different, non-voiding bladder contraction occurred more frequently in OLETF rats than in LETO rats. Bladder blood flow was decreased and ATP release was increased with higher VNUT expression in OLETF rats than in LETO rats. These effects were suppressed by tadalafil administration, with accompanying decreased HIF-1α, 8-OHdG, IL-6, TNF-α, IGF-1, and bFGF expression. The impaired contractile responses of bladder strips to KCl and carbachol in OLETF rats with aging were restored by tadalafil administration. CONCLUSIONS: The T2DM rats had polyuria, increased ATP release induced by decreased bladder blood flow and impaired contractile function. PDE5 inhibition improved these changes and may prevent T2DM-associated urinary frequency and bladder storage and voiding dysfunctions.

Differential effects of exercise and hormone treatment on spinal cord injury-induced changes in micturition and morphology of external urethral sphincter motoneurons.

Background: Spinal cord injury (SCI) results in lesions that destroy tissue and spinal tracts, leading to deficits in locomotor and autonomic function. We have previously shown that after SCI, surviving motoneurons innervating hindlimb muscles exhibit extensive dendritic atrophy, which can be attenuated by treadmill training or treatment with gonadal hormones post-injury. We have also shown that following SCI, both exercise and treatment with gonadal hormones improve urinary function. Animals exercised with forced running wheel training show improved urinary function as measured by bladder cystometry and sphincter electromyography, and treatment with gonadal hormones improves voiding patterns as measured by metabolic cage testing. Objective: The objective of the current study was to examine the potential protective effects of exercise or hormone treatment on the structure and function of motoneurons innervating the external urethral sphincter (EUS) after contusive SCI. Methods: Gonadally intact young adult male rats received either a sham or a thoracic contusion injury. Immediately after injury, one cohort of animals was implanted with subcutaneous Silastic capsules filled with estradiol (E) and dihydrotestosterone (D) or left blank; continuous hormone treatment occurred for 4 weeks post-injury. A separate cohort of SCI-animals received either 12 weeks of forced wheel running exercise or no exercise treatment starting two weeks after injury. At the end of treatment, urinary void volume was measured using metabolic cages and EUS motoneurons were labeled with cholera toxin-conjugated horseradish peroxidase, allowing for assessment of dendritic morphology in three dimensions. Results: Locomotor performance was improved in exercised animals after SCI. Void volumes increased after SCI in all animals; void volume was unaffected by treatment with exercise, but was dramatically improved by treatment with E + D. Similar to what we have previously reported for hindlimb motoneurons after SCI, dendritic length of EUS motoneurons was significantly decreased after SCI compared to sham animals. Exercise did not reverse injury-induced atrophy, however E + D treatment significantly protected dendritic length. Conclusions: These results suggest that some aspects of urinary dysfunction after SCI can be improved through treatment with gonadal hormones, potentially through their effects on EUS motoneurons. Moreover, a more comprehensive treatment regime that addresses multiple SCI-induced sequelae, i.e., locomotor and voiding deficits, would include both hormones and exercise.

Linear Correlation Between Mean Arterial Pressure and Urine Output in Critically Ill Patients.

OBJECTIVE: Mean arterial pressure (MAP) plays a significant role in regulating tissue perfusion and urine output (UO). The optimal MAP target in critically ill patients remains a subject of debate. We aimed to explore the relationship between MAP and UO. DESIGN: A retrospective observational study. SETTING: A general ICU in a tertiary medical center. PATIENTS: All critically ill patients admitted to the ICU for more than 10 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: MAP values and hourly UO were collected in 5,207 patients. MAP levels were categorized into 10 groups of 5 mm Hg (from MAP < 60 mm Hg to MAP > 100 mg Hg), and 656,423 coupled hourly mean MAP and UO measurements were analyzed. Additionally, we compared the UO of individual patients in each MAP group with or without norepinephrine (NE) support or diuretics, as well as in patients with acute kidney injury (AKI).Hourly UO rose incrementally between MAP values of 65-100 mm Hg. Among 2,226 patients treated with NE infusion, mean UO was significantly lower in the MAP less than 60 mm Hg group (53.4 mL/hr; 95% CI, 49.3-57.5) compared with all other groups (p < 0.001), but no differences were found between groups of 75 less than or equal to MAP. Among 2500 patients with AKI, there was a linear increase in average UO from the MAP less than 60 mm Hg group (57.1 mL/hr; 95% CI, 54.2-60.0) to the group with MAP greater than or equal to 100 mm Hg (89.4 mL/hr; 95% CI, 85.7-93.1). When MAP was greater than or equal to 65 mm Hg, we observed a statistically significant trend of increased UO in periods without NE infusion. CONCLUSIONS: Our analysis revealed a linear correlation between MAP and UO within the range of 65-100 mm Hg, also observed in the subgroup of patients treated with NE or diuretics and in those with AKI. These findings highlight the importance of tissue perfusion to the maintenance of diuresis and achieving adequate fluid balance in critically ill patients.

Development of a Novel Prediction Tool for Response to First-Line Treatments of Monosymptomatic Nocturnal Enuresis: A Randomized, Controlled, International, Multicenter Study (DRYCHILD).

PURPOSE: Nocturnal urine volume and bladder reservoir function are key pathogenic factors behind monosymptomatic nocturnal enuresis (MNE). We investigated the predictive value of these together with other demographic and clinical variables for response to first-line treatments in children with MNE. MATERIALS AND METHODS: A randomized, controlled, international, multicenter study was conducted in 324 treatment-naïve children (6-14 years old) with primary MNE. The children were randomized to treatment with or without prior consideration of voiding diaries. In the group where treatment choice was based on voiding diaries, children with nocturnal polyuria and normal maximum voided volume (MVV) received desmopressin (dDAVP) treatment, and children with reduced MVV and no nocturnal polyuria received an enuresis alarm. In the other group, treatment with dDAVP or alarm was randomly allocated. RESULTS: A total of 281 children (72% males) were qualified for statistical analysis. The change of responding to treatment was 21% higher in children where treatment was individualized compared to children where treatment was randomly selected (risk ratio = 1.21 [1.02-1.45], P = .032). In children with reduced MVV and no nocturnal polyuria (35% of all children), individualized treatment was associated with a 46% improvement in response compared to random treatment selection (risk ratio = 1.46 [1.14-1.87], P = .003). Furthermore, we developed a clinically relevant prediction model for response to dDAVP treatment (receiver operating characteristic curve 0.85). CONCLUSIONS: The present study demonstrates that treatment selection based on voiding diaries improves response to first-line treatment, particularly in specific subtypes. Information from voiding diaries together with clinical and demographic information provides the basis for predicting response. CLINICAL TRIAL REGISTRATION NO.: NCT03389412.

Brain carbon monoxide can suppress the rat micturition reflex through brain γ-aminobutyric acid receptors.

OBJECTIVES: To investigate roles of brain carbon monoxide (CO), an endogenous gasotransmitter, in regulation of the rat micturition reflex. METHODS: In urethane-anesthetized (0.8 g/kg, ip) male rats, evaluation of urodynamic parameters was started 1 h before intracerebroventricular administration of CORM-3 (CO donor) or ZnPP (non-selective inhibitor of heme oxygenase, a CO producing enzyme) and continued for 2 h after the administration. We also investigated effects of centrally pretreated SR95531 (GABAA receptor antagonist) or SCH50911 (GABAB receptor antagonist) on the CORM-3-induced response. RESULTS: CORM-3 significantly prolonged intercontraction intervals (ICIs) without changing maximal voiding pressure (MVP), while ZnPP significantly shortened ICI and reduced single-voided volume and bladder capacity without affecting MVP, post-voided residual volume, or voiding efficiency. The ZnPP-induced ICI shortening was reversed by CORM-3. The CORM-3-induced ICI prolongation was significantly attenuated by centrally pretreated SR95531 or SCH50911, respectively. CONCLUSIONS: Brain CO can suppress the rat micturition reflex through brain γ-aminobutyric acid (GABA) receptors.

Pirfenidone improves voiding function by suppressing bladder fibrosis in underactive bladder rats.

Underactive bladder (UAB), characterized by a complex set of symptoms with few treatment options, can significantly reduce the quality of life of affected people. UAB is characterized by hyperplasia and fibrosis of the bladder wall as well as decreased bladder compliance. Pirfenidone is a powerful anti-fibrotic agent that inhibits the progression of fibrosis in people with idiopathic pulmonary fibrosis. In the current study, we evaluated the efficacy of pirfenidone in the treatment of bladder fibrosis in a UAB rat model. UAB was induced by crushing damage to nerve bundles in the major pelvic ganglion. Forty-two days after surgery, 1 mL distilled water containing pirfenidone (100, 300, or 500 mg/kg) was orally administered once every 2 days for a total of 10 times for 20 days to the rats in the pirfenidone-treated groups. Crushing damage to the nerve bundles caused voiding dysfunction, resulting in increased bladder weight and the level of fibrous related factors in the bladder, leading to UAB symptoms. Pirfenidone treatment improved urinary function, increased bladder weight and suppressed the expression of fibrosis factors. The results of this experiment suggest that pirfenidone can be used to ameliorate difficult-to-treat urological conditions such as bladder fibrosis. Therefore, pirfenidone treatment can be considered an option to improve voiding function in patient with incurable UAB.

Fluid distribution during surgery in the flat recumbent, Trendelenburg, and the reverse Trendelenburg body positions.

BACKGROUND: The distribution and elimination of infused crystalloid fluid is known to be affected by general anesthesia, but it is unclear whether changes differ depending on whether the patient is operated in the flat recumbent position, the Trendelenburg ("legs up") position, or the reverse Trendelenburg ("head up") position. METHODS: Retrospective data on hemodilution and urine output obtained during and after infusion of 1-2 L of Ringer's solution over 30-60 min were collected from 61 patients undergoing surgery under general anesthesia and 106 volunteers matched with respect to the infusion volume and infusion time. Parameters describing fluid distribution in the anesthetized and awake subjects were compared by population volume kinetic analysis. RESULTS: General anesthesia decreased the rate constant for urine output by 79% (flat recumbent), 91% (legs up) and 91% (head up), suggesting that laparoscopic surgery per se intensified the already strong anesthesia-induced fluid retention. General anesthesia also decreased the rate constant governing the return of the distributed fluid to the plasma by 32%, 15%, and 70%, respectively. These results agree with laboratory data showing a depressive effect of anesthetic drugs on lymphatic pumping, and further suggest that the "legs up" position facilitates lymphatic flow, whereas the "head up" position slows this flow. Both Trendelenburg positions increased swelling of the "third fluid space". CONCLUSIONS: General anesthesia caused retention of infused fluid with preferential distribution to the extravascular space. Both Trendelenburg positions had a modifying influence on the kinetic adaptations that agreed with the gravitational forces inflicted by tilting to body.

Time-dependent progress of lower urinary tract dysfunction in streptozotocin-induced diabetic rats with or without low-dose insulin treatment.

Objectives: To examine time-dependent functional and structural changes of the lower urinary tract in streptozotocin-induced diabetic rats with or without low-dose insulin treatment and explore the pathophysiological characteristics of insulin therapy on lower urinary tract dysfunction (LUTD) caused by diabetes mellitus (DM). Methods: Female Sprague-Dawley rats were divided into five groups: normal control (NC) group, 4 weeks insulin-treated DM (4-DI) group, 4 weeks DM (4-DM) group, 8 weeks insulin-treated DM (8-DI) group and 8 weeks DM (8-DM) group. DM was initially induced by i.p. injection of streptozotocin (65 mg/kg), and then the DI groups received subcutaneous implantation of insulin pellets under the mid dorsal skin. Voiding behavior was evaluated in metabolic cages. The function of bladder and urethra in vivo were evaluated by simultaneous recordings of the cystometrogram and urethral perfusion pressure (UPP) under urethane anesthesia. The function of bladder and urethra in vitro were tested by organ bath techniques. The morphologic changes of the bladder and urethra were investigated using Hematoxylin-Eosin and Masson's staining. Results: Both 4-and 8-weeks diabetic rats have altered micturition patterns, including increased 12-h urine volume, urinary frequency/12 hours and voided volume. In-vivo urodynamics showed the EUS bursting activity duration is longer in 4-DM group and shorter in 8-DM group compared to NC group. UPP change in 8-DM were significantly lower than NC group. While none of these changes were found between DI and NC groups. Organ bath showed the response to Carbachol and EFS in bladder smooth muscle per tissue weights was decreased significantly in 4- and 8-weeks DM groups compared with insulin-treated DM or NC groups. In contrast, the contraction of urethral muscle and maximum urethral muscle contraction per gram of the tissue to EFS stimulation were significantly increased in 4- and 8-weeks DM groups. The thickness of bladder smooth muscle was time-dependently increased, but the thickness of the urethral muscle had no difference. Conclusions: DM-induced LUTD is characterized by time-dependent functional and structural remodeling in the bladder and urethra, which shows the hypertrophy of the bladder smooth muscle, reduced urethral smooth muscle relaxation and EUS dysfunction. Low-dose insulin can protect against diuresis-induced bladder over-distention, preserve urethral relaxation and protect EUS bursting activity, which would be helpful to study the slow-onset, time-dependent progress of DM-induced LUTD.

Protective effect of equol intake on bladder dysfunction in a rat model of bladder outlet obstruction.

OBJECTIVES: This study evaluates the impact of equol, a metabolite of soy isoflavone, on bladder dysfunction in rats with bladder outlet obstruction (BOO). In addition, we investigate its potential as a neuroprotective agent for the obstructed bladder and discuss its applicability in managing overactive bladder (OAB). METHODS: Eighteen male Sprague-Dawley rats were divided into three groups (six rats per group) during the rearing period. The Sham and C-BOO groups received an equol-free diet, while the E-BOO group received equol supplementation (0.25 g/kg). At 8 weeks old, rats underwent BOO surgery, followed by continuous cystometry after 4 weeks of rearing. The urinary oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde) were measured, and the bladder histology was analyzed using hematoxylin-eosin, Masson's trichrome, and immunohistochemical staining (neurofilament heavy chain for myelinated nerves, peripherin for unmyelinated nerves, and malondialdehyde). RESULTS: Equol reduced BOO-induced smooth muscle layer fibrosis, significantly prolonged the micturition interval (C-BOO: 193 s, E-BOO: 438 s) and increased the micturition volume (C-BOO: 0.54 mL, E-BOO: 1.02 mL) compared to the C-BOO group. Equol inhibited the increase in urinary and bladder tissue malondialdehyde levels. While the C-BOO group exhibited reduced peripherin alone positive nerve fibers within the smooth muscle layer, equol effectively attenuated this decline. CONCLUSIONS: Equol reduces lipid peroxidation and smooth muscle layer fibrosis in the bladder and exhibited neuroprotective effects on bladder nerves (peripheral nerves) and prevented the development of bladder dysfunction associated with BOO in rats. Consumption of equol is promising for the prevention of OAB associated with BOO.

Recent Developments in On-Demand Voiding Therapies.

One cannot survive without regularly urinating and defecating. People with neurologic injury (spinal cord injury, traumatic brain injury, stroke) or disease (multiple sclerosis, Parkinson's disease, spina bifida) and many elderly are unable to voluntarily initiate voiding. The great majority of them require bladder catheters to void urine and "manual bowel programs" with digital rectal stimulation and manual extraction to void stool. Catheter-associated urinary tract infections frequently require hospitalization, whereas manual bowel programs are time consuming (1 to 2 hours) and stigmatizing and cause rectal pain and discomfort. Laxatives and enemas produce defecation, but onset and duration are unpredictable, prolonged, and difficult to control, which can produce involuntary defecation and fecal incontinence. Patients with spinal cord injury (SCI) consider recovery of bladder and bowel function a higher priority than recovery of walking. Bladder and bowel dysfunction are a top reason for institutionalization of elderly. Surveys indicate that convenience, rapid onset and short duration, reliability and predictability, and efficient voiding are priorities of SCI individuals. Despite the severe, unmet medical need, there is no literature regarding on-demand, rapid-onset, short-duration, drug-induced voiding therapies. This article provides in-depth discussion of recent discovery and development of two candidates for on-demand voiding therapies. The first, [Lys3,Gly8,-R-γ-lactam-Leu9]-NKA(3-10) (DTI-117), a neurokinin2 receptor agonist, induces both urination and defecation after systemic administration. The second, capsaicin (DTI-301), is a transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor agonist that induces defecation after intrarectal administration. The review also presents clinical studies of a combination drug therapy administered via iontophoresis and preclinical studies of neuromodulation devices that induce urination and defecation. SIGNIFICANCE STATEMENT: A safe and effective, on-demand, rapid-onset, short-duration, drug-induced, voiding therapy could eliminate or reduce need for bladder catheters, manual bowel programs, and colostomies in patient populations that are unable to voluntarily initiate voiding. People with spinal injury place more importance on restoring bladder and bowel control than restoring their ability to walk. This paradigm-changing therapy would reduce stigmatism and healthcare costs while increasing convenience and quality of life.

Exploring the impact of anticholinergic burden on urinary independence: insights from a post-stroke cohort of older adults.

BACKGROUND: Anticholinergic burden is associated with adverse events in the older adults. However, there is a lack of evidence regarding its effect on urinary independence in stroke patients. AIM: This study examined the association between increased anticholinergic burden during hospitalization and urinary independence in post-stroke patients undergoing rehabilitation. METHOD: This observational cross-sectional study included stroke patients admitted to a post-acute rehabilitation hospital between 2020 and 2022 who were not independently urinating. The degree of urinary independence was assessed using the Functional Independence Measure-Bladder (FIM-Bladder), a subscale of the motor domain of the FIM, and urinary independence was defined as FIM-Bladder ≥ 6. Anticholinergic burden was assessed using the anticholinergic risk scale (ARS), and changes in ARS during hospitalization were calculated by subtracting the value at admission from the value at discharge. The study outcome was urinary independence at discharge. Logistic regression analysis was used to examine whether change in ARS score was independently associated with the outcome. Statistical significance was set at P < 0.05. RESULTS: Of the 573 patients enrolled, 312 patients (mean age 77.5 years, 51.9% male) were included in the analysis. ARS increased during hospitalization in 57 patients (18.3%). Change in ARS score was independently associated with urinary independence (odds ratio: 0.432, 95% confidence interval: 0.247-0.756, P = 0.003). CONCLUSION: Increased anticholinergic burden in post-stroke patients who require assistance with urination is significantly associated with less independent urination. Anticholinergic agents may need to be introduced cautiously in patients who require assistance with urination.

Inhibition of CXCR4 in Spinal Cord and DRG with AMD3100 Attenuates Colon-Bladder Cross-Organ Sensitization.

BACKGROUND: Cross-sensitization of pelvic organs is one theory for why symptoms of gut sickness and interstitial cystitis/bladder pain syndrome overlap. Experimental colitis has been shown to trigger bladder hyperactivity and hyperalgesia in rats. The chemokine receptor CXCR4 plays a key role in bladder function and central sensitization. We aim to study the role of CXCR4 and its inhibitor AMD3100 in colon-bladder cross-organ sensitization. METHODS: The colitis model was established by rectal infusion of trinitrobenzene sulfonic acid. Western blot and immunofluorescence were used to assess the expression and distribution of CXCR4. Intrathecal injection of AMD3100 (a CXCR4 inhibitor) and PD98059 (an ERK inhibitor) were used to inhibit CXCR4 and downstream extracellular signal-regulated kinase (ERK) in the spinal cord and dorsal root ganglion (DRG). Intravesical perfusion of resiniferatoxin was performed to measure the pain behavior counts of rats, and continuous cystometry was performed to evaluate bladder voiding function. RESULTS: Compared to the control group, CXCR4 was expressed more in bladder mucosa and colon mucosa, L6-S1 dorsal root ganglion (DRG), and the corresponding segment of the spinal dorsal horn (SDH) in rats with colitis. Moreover, intrathecal injection of the AMD3100 suppressed bladder overactivity, bladder hyperalgesia, and mastocytosis symptoms caused by colitis. Furthermore, AMD3100 effectively inhibited ERK activation in the spinal cord induced by experimental colitis. Finally, treatment with PD98059 alleviated bladder overactivity and hyperalgesia caused by colitis. CONCLUSION: Increased CXCR4 in the DRG and SDH contributes to colon inflammation-induced bladder overactivity and hyperalgesia partly via the phosphorylation of spinal ERK. Treatment targeting the CXCR4/ERK pathway might provide a potential new approach for the comorbidity between the digestive system and the urinary system.

The nephroprotective effects of Daucus carota and Eclipta prostrata against cisplatin-induced nephrotoxicity in rats.

The overuse of cisplatin (>50 mg/m2) is limited to nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. The objective of this study was to investigate the nephroprotective effects of Daucus carota and Eclipta prostrata extracts on cisplatin-induced nephrotoxicity in Wistar albino rats. The study involved male Wistar albino rats of 8 weeks weighing 220-270 g. A single injection of 5 mg/kg was injected into the rats for nephrotoxicity. Rats were divided into four groups based on dose conentrations. Blood and urine samples of rats were collected on the 0, 7th, 14th, and 21st days for nephrological analysis. The results showed that Cis + DC/Cis + EP (600 mg/kg) significantly (p < 0.001) increased the body weight and reduced the kidney weight of cisplatin-induced nephrotoxicity in rats (p < 0.001) as compared to Cis group. The results showed that 600 mg/kg administration of Cis + DC/Cis +EP successfully (p < 0.005) improved the urine and plasmin creatinine, Na, and K level compared to the Cis group. Histopathological results confirmed that Cis + EP/Cis + DC effectively improved the renal abnormalities. It is concluded that the co-administration of Cis + EP extract showed exceptional nephroprotective effects at a dose rate of 600 mg/kg.

Carbohydrate hastens hypervolemia achieved through ingestion of aqueous sodium solution in resting euhydrated humans.

PURPOSE: Ingesting beverages containing a high concentration of sodium under euhydrated conditions induces hypervolemia. Because carbohydrate can enhance interstitial fluid absorption via the sodium-glucose cotransporter and insulin-dependent renal sodium reabsorption, adding carbohydrate to high-sodium beverages may augment the hypervolemic response. METHODS: To test this hypothesis, we had nine healthy young males ingest 1087 ± 82 mL (16-17 mL per kg body weight) of water or aqueous solution containing 0.7% NaCl, 0.7% NaCl + 6% dextrin, 0.9% NaCl, or 0.9% NaCl + 6% dextrin under euhydrated conditions. Each drink was divided into six equal volumes and ingested at 10-min intervals. During each trial, participants remained resting for 150 min. Measurements were made at baseline and every 30 min thereafter. RESULTS: Plasma osmolality decreased with water ingestion (P ≤ 0.023), which increased urine volume such that there was no elevation in plasma volume from baseline (P ≥ 0.059). The reduction in plasma osmolality did not occur with ingestion of solution containing 0.7% or 0.9% NaCl (P ≥ 0.051). Consequently, urine volume was 176-288 mL smaller than after water ingestion and resulted in plasma volume expansion at 60 min and later times (P ≤ 0.042). In addition, net fluid balance was 211-329 mL greater than after water ingestion (P ≤ 0.028). Adding 6% dextrin to 0.7% or 0.9% NaCl solution resulted in plasma volume expansion within as little as 30 min (P ≤ 0.026), though the magnitudes of the increases in plasma volume were unaffected (P ≥ 0.148). CONCLUSION: Dextrin mediates an earlier hypervolemic response associated with ingestion of high-sodium solution in resting euhydrated young men. (247/250 words).

Metformin abrogates the voiding dysfunction induced by prolonged methylglyoxal intake.

Methylglyoxal (MGO) is a reactive carbonyl species found at high levels in blood of diabetic patients. The anti-hyperglycemic drug metformin can scavenger MGO and reduce the formation of advanced glycation end products (AGEs). Here, we aimed to investigate if MGO-induced bladder dysfunction can be reversed by metformin. Male C57/BL6 mice received 0.5% MGO in drinking water for 12 weeks, and metformin (300 mg/kg, daily gavage) was given in the last two weeks. The bladder functions were evaluated by performing voiding behavior assays, cystometry and in vitro bladder contractions. MGO intake markedly elevated the levels of MGO and fluorescent AGEs in serum and reduced the mRNA expression and activity of glyoxalase (Glo1) in bladder tissues. Glucose levels were unaffected among groups. MGO intake also increased the urothelium thickness and collagen content of the bladder. Void spot assays in conscious mice revealed an increased void volume in MGO group. The cystometric assays in anesthetized mice revealed increases of basal pressure, non-voiding contractions frequency, bladder capacity, inter-micturition pressure and residual volume, which were accompanied by reduced voiding efficiency in MGO group. In vitro bladder contractions to carbachol, α,ß-methylene ATP and electrical-field stimulation were significantly greater in MGO group. Metformin normalized the changes of MGO and AGEs levels, Glo1 expression and activity, urothelium thickness and collagen content. The MGO-induced voiding dysfunction were all restored by metformin treatment. Our findings strongly suggest that the amelioration of MGO-induced voiding dysfunction by metformin relies on its ability to scavenger MGO, preventing its accumulation in blood.

Linh Phu Khang Tue Tinh inhibited prostate proliferation in rats induced benign prostatic hyperplasia by testosterone propionate.

ETHNOPHARMACOLOGICAL RELEVANCE: Benign prostatic hyperplasia (BPH) is the hyperproliferation of the stromal and the epithelial cells within the prostatic transition zone. In recent years, phytotherapy have been studied with the concern for increasing quality of life, improving lower urinary tract symptoms (LUTS) as well as reducing prostate volume and the frequency of adverse events was similar to that of placebo. Linh Phu Khang Tue Tinh (LPKTT) capsules are formulated from 4 herbs widely used in traditional Vietnamese medicine - Panax notoginseng (Burkill) F.H.Chen - Tam that (radix), Crinum asiaticum L. - Náng hoa trang or giant crinum lily, Polygonum cuspidatum Willd. ex Spreng. (= Reynoutria japonica Houtt) - Cot cu khí or Japanese knotweed (radix), Oldenlandia herbacea (L.) Roxb. (formerly known as Hedyotis diffusa Spreng.) - Bach hoa xà thie^t thao or slender oldenlandia (herb). The preparation has been used in traditional Vietnamese medicine to treat nocturia, weak urine stream, urinary tract infection. According to modern studies, these herbs have anti-inflammation, antitumor, and antioxidant activities. AIMS OF THE STUDY: Evaluating the effects of LPKTT capsules on the development of BPH using a rat model of BPH induced by testosterone propionate (TP). MATERIALS AND METHODS: 60 male Wistar rats, 10-12 weeks of age, weight 200-250 g were separated into six groups: (G1) a normal control group that was taken orally phosphate-buffered saline (p.o.; PBS.) with corn oil (subcutaneous injection- Sc); (G2) a BPH model group that received PBS (p.o) with TP (Sc); (G3) a positive control group that received dutasteride (25 µg/kg BW/24 h, p.o.) with TP (Sc); (G4) a positive control group that received alfuzosin HCl (1.8 mg/kg BW/24 h, p.o.) with TP (s.c.) and (G5 and G6) LPKTT groups that received LPKTT at 289.8 or 869.4 mg/kg(p.o.) respectively, with TP (s.c.). BPH model was induced by Sc of TP, 3 mg/kg for 4 weeks. After that, rats were received NaCl/Dutasteride/Alfuzosin/LPKTT for the next 28 days. On the 56th day, assessed the results were through the indicators: micturition frequency, voided volume, total voided volume, the prostate and body weights, the ratio of prostate weight to body weight, prostate histology. RESULTS: LPKTT reduced micturition frequency and increased the voided volume when compared to the control group (p < 0.01). The results were equivalent to those of the alfuzosin ones (G4). LPKTT lowered prostate weight and the ratio of prostate weight to body weight when compared to the control group (p < 0.01). These reductions were the same in the dutasteride ones. Histomorphology in G5 and G6 also showed that LPKTT inhibited TP induced prostatic hyperplasia. The results were similar to that in the dutasteride group. Microscopic images of prostate in G5 and G6 were almost similar to that of G1. CONCLUSION: LPKTT capsules work to inhibit prostate proliferation in rats induced BPH by TP.

Therapeutic effect of modulating the NLRP3-regulated transforming growth factor-ß signaling pathway on interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder with complex pathogenesis and lacks effective treatment. Chronic inflammation is the main pathogenesis of Hunner-type IC/BPS. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome-related transforming growth factor-ß (TGF-ß)/Smad signaling pathway plays a crucial role in inflammation-related tissue fibrosis. Lipopolysaccharide (LPS) and protamine sulfate (LPS/PS) were instilled into the mouse bladder twice a week for 5 consecutive weeks to establish a chronic inflammation-induced IC/BPS model (LPS/PS model). Following LPS/PS treatment, curcumin (oral, 100 mg/kg; a potent NLRP3 modulator) was administered for 2 weeks in the curcumin treatment group, and normal saline was used for the sham group. Bladder function was evaluated by performing the voiding spot assay and examining the status of urothelial denudation and fibrosis in bladder tissues. The expression of NLRP3 inflammasome, interleukin-1ß, TGF-ß, Smad, vimentin, and E-cadherin in bladder tissues was evaluated through immunohistochemistry staining. Results revealed that the repeated instillation of LPS/PS leads to voiding dysfunction, bladder urothelium denudation, and detrusor muscle fibrosis through the upregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway and the increased epithelial-mesenchymal transition process in bladder tissues. The downregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway in bladder tissues through curcumin effectively mitigated bladder injury in the LPS/PS model. In conclusion, the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway plays a crucial role in bladder injury in the LPS/PS model, and modulation of this pathway, such as by using curcumin, can effectively mitigate the sequelae of chronic inflammation-induced IC/BPS.