Muscarinic receptor binding of the novel radioligand, [3h]imidafenacin in the human bladder and parotid gland.

The aim of the current study was to demonstrate highly specific and direct binding activity of tritium ([(3)H])-labeled imidafenacin for labeling muscarinic receptors in human bladder and parotid gland. Specific binding of [(3)H]imidafenacin in human tissues was saturable, reversible, and of high affinity. The Kd value for specific [(3)H]imidafenacin binding in the human bladder was approximately 3 times higher than that in the parotid gland. Unlabeled imidafenacin as well as the clinically used antimuscarinic agents, oxybutynin, tolterodine, and solifenacin, competed with [(3)H]imidafenacin for binding sites in the human bladder and parotid gland in a concentrationdependent manner, which indicated pharmacological specificity of [(3)H]imidafenacin binding sites. The Ki for imidafenacin in the human bladder approximately corresponded to pharmacological potency for the competitive blockade of carbachol-induced contractions of bladder, indicating a close correlation between binding affinity of imidafenacin to bladder muscarinic receptors and its pharmacological effects in the bladder. In conclusion, the current study is the first to provide direct evidence to demonstrate that imidafenacin bound muscarinic receptors in the human bladder, supporting its clinical relevance as a therapeutic agent for overactive bladder. [(3)H]Imidafenacin may also be a useful radioligand for labeling the M3 subtype of muscarinic receptors with higher selectivity than other radioligands.

[Questionnaire survey on medical care for male urethritis in community clinics in Shiga prefecture].

Six regional medical associations in Shiga prefecture agreed to cooperate in an investigation of medical care for male gonococcal and chlamydial urethritis. In June 2011, we sent a questionnaire to 372 medical offices in Shiga prefecture, and analyzed replies of respondents. Ten urologists and 175 non-urologists responded to the survey (response rate 49.7%). Among 185 physicians, 52 (10 urologists and 42 nonurologists) have treated male patients with gonococcal and chlamydial urethritis. More than 20% (42/175) of non-urological clinics are involved in the medical management. At initial diagnosis for sexually transmitted male urethritis, all urologists select the nucleic acid amplification method (100%), whereas many non-urologists do not (35%). For the treatment of chlamydial urethritis, non-urologists select levofloxacin (LVFX, 52.8%) rather than azithromycin (AZM, 22.0%), whereas urologists use AZM (78.0%) mostly but do not use LVFX (0%) (p = 0.023). For the treatment of gonococcal urethritis, non-urologists prefer oral new quinolones (53.1%) compared to urologists (25.0%) (p = 0. 74). For cure judgment of gonoccocal and chlamydial urethritis, many non-urologists rely on the improvement of subjective symptoms (50 and 47%), but urologists do not (10 and 0%) (p = 0.022 and 0.026, respectively). As for recognition of the clinical guideline for sexually transmitted disease, most urologists (90%) know it, but few non-urologists (13%) do (p < 0.001). We found that non-urological clinics make a great contribution to the medical treatment for male gonococcal and chlamydial urethritis in Shiga prefecture. It is important to standardize the medical care for sexually transmitted male urethritis by familiarizing non-urological practitioners with the clinical guideline.

Eviprostat activates cAMP signaling pathway and suppresses bladder smooth muscle cell proliferation.

Eviprostat is a popular phytotherapeutic agent for the treatment of lower urinary tract symptoms (LUTS). At present, the signaling mechanisms underlying its therapeutic effects are still poorly understood. Given that cAMP has been reported to suppress cell hyperplasia and hypertrophy in various pathological situations, we asked whether the effect of Eviprostat could be ascribed to the activation of the cAMP signaling pathway. In the study, exposure of cAMP response element (CRE)-secreted alkaline phosphatase (SEAP) (CRE-SEAP)-reporter cells to Eviprostat elevated SEAP secretion, which was associated with an increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and cAMP-response element-binding protein (CREB), as well as enhanced expression of CRE-regulated protein connexin43, indicating an activation of the cAMP signaling pathway. Consistent with these observations, Eviprostat-induced expression of Cx43 was abolished in the presence of adenylyl cyclase inhibitor SQ22536 or PKA inhibitor H89, whereas it was mimicked by adenylyl cyclase activator, forskolin. Further analysis demonstrated that Eviprostat significantly potentiated the effect of phosphodiesterase 3 (PDE3) inhibitor, but not that of PDE4 inhibitor, on CRE activation. Moreover, Eviprostat suppressed PDGF-induced activation of ERK and Akt and inhibited cell proliferation and hillock formation in both mesangial cells and bladder smooth muscle cells. Collectively, activation of the cAMP signaling pathway could be an important mechanism by which Eviprostat exerts its therapeutic effects for LUTS.

Change over Time in the Risk of Death among Japanese COVID-19 Cases Caused by the Omicron Variant Depending on Prevalence of Sublineages.

To assess temporal changes to the risk of death in COVID-19 cases caused by the Omicron variant, we calculated age-standardized case fatality rates (CFR) in patients aged ≥40 years over nine diagnostic periods (3 January to 28 August 2022) in ten Japanese prefectures (14.8 million residents). Among 552,581 study subjects, we found that there were 1836 fatalities during the isolation period (up to 28 days from date of onset). The highest age-standardized CFR (0.85%, 95% confidence interval (CI):0.78-0.92) was observed in cases diagnosed in the second 4-week period (January 31 to February 27), after which it declined significantly up to the 6th 4-week period (0.23%, 95% CI: 0.13-0.33, May 23 to June 19). The CFR then increased again but remained at 0.39% in the eighth period (July 18 to August 28). The CFR in cases with the BA.2 or BA.5 sublineages in the age range 60-80 years was significantly lower than that with BA.1 infections (60 years: 0.19%, 0.02%, 0.053%, respectively; 70 years: 0.91%, 0.33%, 0.39%; ≥80 years: 3.78%, 1.96%, 1.81%, respectively). We conclude that the risk of death in Japanese COVID-19 patients infected with Omicron variants declined through February to mid-June 2022.

[Small intestinal metastasis from renal cell carcinoma: a case report].

A 52-year-old man who had been treated with sorafenib for lung metastasis of renal cell carcinoma (RCC) presented to our hospital with iron-deficiency anemia. He had undergone right nephrectomy for RCC (clear cell carcinoma, pT1bN0M0) 11 years ago and lung metastasis developed 6 years after the surgery. Although upper gastrointestinal endoscopy and colonoscopy were performed on suspicion of gastrointestinal bleeding, no abnormality was detected. Capsule endoscopy and single balloon small bowel endoscopy disclosed a hemorrhagic submucosal tumor in the jejunum. Laparoscopic partial jejunectomy was performed, and pathological examination indicated metastatic RCC to the small intestine. After the operation, anemia improved but he died 8 months later because of intrabronchial bleeding from the metastatic lesion of the lung. Metastatic RCC of the small intestine is relatively rare, its diagnosis is difficult. Recently, new diagnostic tools such as capsule endoscopy and balloon-assisted endoscopy have been developed, and they are useful in diagnosing gastrointestinal bleeding (OGIB) which can not be detected by traditional enteroscopy. If patients with advanced RCC show gastrointestinal bleeding of uncertain etiology, we should perform aggressive examination of the digestive tract with these diagnostic tools.

Bladder outlet obstruction induced expression of prostaglandin E2 receptor subtype EP4 in the rat bladder: a possible counteractive mechanism against detrusor overactivity.

PURPOSE: Prostaglandins have been implicated as endogenous modulators of bladder function under physiological and pathological conditions. We examined how the expression of each EP receptor subtype changed in association with bladder outlet obstruction and focused on the functional role of EP4 receptor subtype in the bladder with outlet obstruction. MATERIALS AND METHODS: We assessed the gene expression of EP receptor subtypes by reverse transcriptase-polymerase chain reaction. EP4 protein localization was determined by immunohistochemistry. The effect of the selective EP4 agonist ONO-AE1-329 on 50 mM KCl induced contraction of rat bladder strips was examined in vitro. Continuous infusion cystometrograms were done to examine the effect of intravesical perfusion of ONO-AE1-329 on the micturition reflex in urethane anesthetized rats. RESULTS: EP4 receptor genes were largely expressed in bladders with outlet obstruction but absent in controls. EP4 receptor proteins were clearly detected in obstructed bladder detrusor smooth muscle and epithelium. ONO-AE1-329 (100 µM) significantly relaxed KCl induced contraction of bladder strips from rats with bladder outlet obstruction. A significant correlation was found between the relaxant effect of ONO-AE1-329 and whole bladder weight. In rats with bladder outlet obstruction intravesical infusion of 10 µM ONO-AE1-329 significantly increased bladder capacity without changing micturition pressure while it had no effect in controls. CONCLUSIONS: Activation of the EP4 receptors expressed in bladders with outlet obstruction may suppress detrusor muscle contraction and afferent activity. This might be a compensatory mechanism to counteract the deterioration of storage function in bladders with outlet obstruction.

Decreased expression of the epithelial Ca2+ channel TRPV5 and TRPV6 in human renal cell carcinoma associated with vitamin D receptor.

PURPOSE: We investigated the expression of epithelial Ca(2+) channel TRPV (transient receptor potential vanilloid subfamily) 5 and 6, and vitamin D receptor in primary human renal cell carcinoma and benign peritumor tissues, and assessed the possible association between TRPV5/6 and vitamin D receptor expression. MATERIALS AND METHODS: Fresh-frozen primary tumor and peritumor tissues from 27 patients diagnosed with renal cell carcinoma were analyzed for TRPV5/6 and vitamin D receptor expression by quantitative reverse transcriptase-polymerase chain reaction, Western blot and immunohistochemistry. RESULTS: Quantitative reverse transcriptase-polymerase chain reaction revealed that TRPV5/6 and vitamin D receptor expression was decreased 38.11, 4.44 and 3.20 times in renal cell carcinoma vs normal kidney tissue (p = 0.012, 0.002 and 0.020, respectively). Relatively higher expression was noted for chromophobe renal cell carcinoma than for the other renal cell carcinoma subtypes. Vitamin D receptor mRNA expression significantly correlated with that of TRPV6 (r = 0.508, p = 0.007) and TRPV5 (r = 0.697, p = 0.032) in renal cell carcinoma. Western blot showed results similar to those of reverse transcriptase-polymerase chain reaction. Different expression was detected between kidney and renal cell carcinoma tissue. Immunohistochemical analysis verified strong detection of TRPV5/6 and vitamin D receptor in distal nephrons but demonstrated weak or no immunostaining much more often in renal cell carcinoma. CONCLUSIONS: Decreased TRPV5/V6 expression was noted in renal cell carcinoma, which correlated with vitamin D receptor. Different expression was also detected among the different renal cell carcinoma histopathological subtypes. Our observations suggest that altered vitamin D receptor expression may be associated with renal cell carcinoma carcinogenesis via TRPV5/6.

Predictive factors for the effect of the α1-D/A adrenoceptor antagonist naftopidil on subjective and objective criteria in patients with neurogenic lower urinary tract dysfunction.

OBJECTIVES: • To assess the effect of α1-D/A adrenoceptor antagonist naftopidil on patients with neurogenic lower urinary tract dysfunction (NLUTD) and voiding difficulty. • To explore the effectiveness of naftopidil in these patients by using urodynamic variables, including pressure flow study (PFS), and to find good and simple parameters (International Prostate Symptom Score (IPSS), Post-void residual urine (PVR), and uroflowmetry (UFM) parameters) as substitution of PFS for predicting the effect of naftopidil. PATIENTS AND METHODS: • The main inclusion and exclusion criteria were, IPSS ≥8, voiding symptoms with IPSS ≥5, IPSS-quality of life (QOL) ≥2, PVR ≥50 mL, and without prostatic enlargement ≥ 20 mL. • After initial assessment, patients were stepwisely administered for 12 weeks with the following: placebo for 2 weeks, naftopidil 25 mg/day for 2 weeks, naftopidil 50 mg/day for 2 weeks, and naftopidil 75 mg/day for 6 weeks. At the end of both placebo and 6 weeks' naftopidil 75 mg/day, their IPSS, UFM, PVR, and PFS were assessed. • A total of 82 Japanese patients (men 40, women 42) with lower urinary tract symptoms complicated by NLUTD, with a mean age of 63.9 years, were included from private or institutional clinics. • The lesions were spinal cord 42, and peripheral nervous system 40. The spinal cord lesions were all lumbar spine (injury or lumbar canal stenosis). RESULTS: • In all patients, pressure at maximum urinary flow rate (P(det) Q(max) ) in PFS significantly decreased (P < 0.05), and maximum urinary flow rate in UFM significantly increased (P < 0.01). Analysis of data for men and for women also showed a significant decrease in PVR, %PVR, and total IPSS score. • The degree of improvement of voided volume, PVR (%), and IPSS in patients with PVR <300 mL was significantly greater than those in patients with PVR ≥300 mL. • The degree of improvement of P(det) Q(max) in PFS, and IPSS in patients with bladder contractility was significantly greater than that in patients without bladder contractility. CONCLUSIONS: • α1-D/A adrenoceptor antagonist naftopidil has a significant effect on both symptoms and urodynamic variables of patients of both genders with NLUTD in Japan. • PVR <300 mL and bladder contractility are predictive factors for the efficacy of naftopidil on patients with NLUTD.

Suppression of NF-kappaB by cyclosporin a and tacrolimus (FK506) via induction of the C/EBP family: implication for unfolded protein response.

Immunosuppressive agents cyclosporin A (CsA) and tacrolimus (FK506) inhibit cytokine production by activated lymphocytes through interfering with calcineurin. However, little is known about their effects on the function of nonlymphoid cells. We found that, in renal tubular cells, induction of MCP-1 by inflammatory cytokines was blunted by CsA and FK506. This suppression was correlated with induction of unfolded protein response (UPR) evidenced by endogenous and exogenous indicators. The induction of UPR by these agents was reversible and observed generally in other nonimmune cells. Furthermore, administration with CsA in reporter mice caused rapid, systemic induction of UPR in vivo. In TNF-alpha-treated cells, suppression of MCP-1 by CsA or FK506 was associated with blunted responses of NF-kappaB, the crucial regulator of MCP-1. The suppression of NF-kappaB was reproduced by other inducers of UPR including AB(5) subtilase cytotoxin, tunicamycin, thapsigargin, and A23187. CsA and FK506, as well as other UPR inducers, caused up-regulation of C/EBP family members, especially C/EBPbeta and CHOP (C/EBP homologous protein), and overexpression of either C/EBPbeta or CHOP significantly attenuated TNF-alpha-triggered NF-kappaB activation. Furthermore, down-regulation of C/EBPbeta by small interfering RNA substantially reversed the suppressive effect of CsA on TNF-alpha-induced MCP-1 expression. These results suggested that CsA and FK506 confer insensitiveness to TNF-alpha on resident cells through UPR-dependent induction of the C/EBP family members.

Functional roles of TRPV1 channels in lower urinary tract irritated by acetic acid: in vivo evaluations of the sex difference in decerebrate unanesthetized mice.

Sex-specific differences in activity of the lower urinary tract (LUT) responding to acid irritation in mice have been revealed. This study, using continuous infusion cystometry with acetic acid (AA; pH 3.0), was conducted to examine whether the transient receptor potential vanilloid type 1 (TRPV1) channels expressed in the mouse LUT are involved in the sex difference in functional responses of the bladder and urethra to irritation. No differences were found between effects of capsazepine (a TRPV1 blocker; 100 microM) and those of its vehicle on any of the cystometric changes by intravesical AA in either female or male mice. However, capsazepine eliminated the acid-induced sex differences in parameters associated with bladder contraction phase (i.e., maximal voiding pressure, closing peak pressure, 2nd-phase contraction, bladder contraction duration), whereas capsazepine did not affect those in parameters associated with bladder-filling period (i.e., intercontraction interval, actual collecting time). In males, capsazepine reduced the number of bladder contractions accompanying fluid dribbling at 2nd-phase contraction, which is indicative of the urethral response to irritation, whereas in females it increased the number. Together, these results suggest the possibilities that TRPV1 channels in the bladder and urethra are involved in the sex difference in the LUT response to acid irritation and that these participate, e.g., via "cross talk" between the bladder and urethra, in the fine-tuning of intravesical pressure (or bladder emptying) at the bladder contraction phase under irritated LUT conditions but not in sensing for bladder filling during the storage period, although the contribution of the mechanism may be small.

The forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction: pathophysiology of voiding dysfunction and pharmacological therapy.

Normal lower urinary tract function consists of voiding and storage. During voiding, the pontine micturition reflex center orders the sacral parasympathetic nucleus to increase parasympathetic activity, resulting in urinary bladder detrusor contraction via activation of post-synaptic muscarinic receptors (M2/3) and in the relaxation of both urethral and prostatic smooth muscle by nitric oxide (NO). In addition, the rhabdosphincter relaxes by inhibition of the pudendal nucleus at the sacral portion. During the storage phase, increase in sympathetic activity relaxes the urinary bladder via activation of post-synaptic beta(3)-receptors and in the contraction of both urethral and prostatic smooth muscles via alpha(1)-adrenoceptor. Many factors influence voiding function, including lower urinary tract disorders (benign prostatic hyperplasia in males, urethral stricture) and neurological disorders (central and peripheral). Theories of pharmacotherapy for voiding dysfunction are 1) increase detrusor contractility and 2) decrease urethral resistance. The former includes agonists for muscarinic receptors and cholinesterase inhibitor; and the latter includes alpha(1)-adrenoceptor antagonists, NO donors, benzodiazepines, baclofen, dantrolene, and boturinum toxin.

[Two cases of infants with acute renal failure due to bilateral obstructive ureteral stones associated with rotavirus gastroenteritis].

We report on 2 infants with acute renal failure caused by bilateral obstructive ureteral stones associated with rotavirus gastroenteritis. A 28-month boy and a 13-month boy with several days history of watery diarrhea and vomiting were referred to our hospital because of anuria. They were diagnosed acute post-renal failure due to obstructive bilateral ureteral stones based on the findings of ultrasound scan and computed tomography. Immediately, percutaneous nephrostomy tubes were inserted for urinary drainage, serum levels of creatinine and uric acid returned to normal within several days. Sandy stones were excreted through the nephrostomy tubes with urine after urinary alkalization, which were proved to be mainly ammonium acid urate. Ammonium acid urate is rare in developed countries, but some cases of bilateral urolithiasis causing acute renal failure in infants with rotavirus gastroenteritis were reported in recent years. It has been known that the cause of acute renal failure is renal azotemia resulting from sustained hypovolemia, but post-renal causes due to ammonium acid urate stones should be taken into consideration.

Blockade of Acid-Sensing Ion Channels Increases Urinary Bladder Capacity With or Without Intravesical Irritation in Mice.

We conducted this study to examine whether acid-sensing ion channels (ASICs) are involved in the modulation of urinary bladder activity with or without intravesical irritation induced by acetic acid. All in vivo evaluations were conducted during continuous infusion cystometry in decerebrated unanesthetized female mice. During cystometry with a pH 6.3 saline infusion, an i.p. injection of 30 µmol/kg A-317567 (a potent, non-amiloride ASIC blocker) increased the intercontraction interval (ICI) by 30% (P < 0.001), whereas vehicle injection had no effect. An intravesical acetic acid (pH 3.0) infusion induced bladder hyperactivity, with reductions in ICI and maximal voiding pressure (MVP) by 79% (P < 0.0001) and 29% (P < 0.001), respectively. A-317567 (30 µmol/kg i.p.) alleviated hyperreflexia by increasing the acid-shortened ICI by 76% (P < 0.001). This dose produced no effect on MVP under either intravesical pH condition. Further analysis in comparison with vehicle showed that the increase in ICI (or bladder capacity) by the drug was not dependent on bladder compliance. Meanwhile, intravesical perfusion of A-317567 (100 µM) had no effect on bladder activity during pH 6.0 saline infusion cystometry, and drug perfusion at neither 100 µM nor 1 mM produced any effects on bladder hyperreflexia during pH 3.0 acetic acid infusion cystometry. A-317567 has been suggested to display extremely poor penetrability into the central nervous system and thus to be a peripherally active blocker. Taken together, our results suggest that blockade of ASIC signal transduction increases bladder capacity under normal intravesical pH conditions and alleviates bladder hyperreflexia induced by intravesical acidification and that the site responsible for this action is likely to be the dorsal root ganglia.

Corrigendum: Blockade of Acid-Sensing Ion Channels Increases Urinary Bladder Capacity With or Without Intravesical Irritation in Mice.

[This corrects the article DOI: 10.3389/fphys.2020.592867.].

Sex differences in the expression profile of acid-sensing ion channels in the mouse urinary bladder: a possible involvement in irritative bladder symptoms.

OBJECTIVE: To investigate the expressions and sex differences of acid-sensitive ion channels (i.e. ASIC and transient receptor potential channel V1, TRPV1; both key receptors for extracellular protons that might underlie the acid-evoked pain perception) and other nociceptive ion channels in the mouse bladder. MATERIALS AND METHODS: Mucosa and muscle layers of the urinary bladder were separately taken from male and female mice. The gene expressions of ASIC subunits, TRPV1, TRPA1 and TRPM8 were quantified using real-time reverse transcriptase-polymerase chain reaction. The localization of ASIC protein was explored using immunohistochemistry. Continuous-filling cystometry was used to examine the effects of capsazepine, a TRPV1 blocker, on the bladder response to acetic acid. RESULTS: ASIC1 was the dominant ASIC subunit expressed in bladder epithelium, whereas both ASIC1 and ASIC2 were expressed in bladder smooth muscle. ASIC3 expression was much less abundant, but localized in the subepithelial region. In the mucosa, the ASIC1 gene was more highly expressed in male than in female mice, whereas the expression level of ASIC2 in the bladder muscle was higher in female than in male mice. The expression of TRPV1 in the bladder showed a sex difference (male < female), but it was much lower than ASIC genes. Furthermore, the intravesical administration of 100 microm capsazepine showed no effect on bladder irritation by acetic acid. TRPA1 and TRPM8 did not show sex differences in their expression. CONCLUSION: The expression of ASIC subunit in the bladder was abundant and showed significant sex differences. Thus, ASICs might be involved in the sex difference in the bladder response to acidic irritation.

Clinical guideline for male lower urinary tract symptoms.

This article is a shortened version of the clinical guideline for lower urinary tract symptoms (LUTS), which has been developed in Japan for symptomatic men aged 50 years and over irrespective of presumed diagnoses. The guideline was formed on the PubMed database between 1995 and 2007 and other relevant sources. The causes of male LUTS are diverse and attributable to diseases/dysfunctions of the lower urinary tract, prostate, nervous system, and other organ systems, with benign prostatic hyperplasia, bladder dysfunction, polyuria, and their combination being most common. The mandatory assessment should comprise medical history, physical examination, urinalysis, and measurement of serum prostate-specific antigen. Symptom and quality of life questionnaires, bladder diary, residual urine measurement, urine cytology, urine culture, measurement of serum creatinine, and urinary tract ultrasonography would be optional tests. The Core Lower Urinary Tract Symptom Score Questionnaire may be useful in quickly capturing important symptoms. Severe symptoms, pain symptoms, and other clinical problems would indicate urological referral. One should be careful not to overlook underlying diseases such as infection or malignancy. The treatment should be initiated with conservative therapy and/or medicine such as alpha(1)-blockers. Treatment with anticholinergic agents should be reserved only for urologists, considering the risk of urinary retention. The present guideline should help urologists and especially non-urologists treat men with LUTS.

Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder.

In bladder outlet obstruction (BOO), mechanical stress and ischemia/hypoxia are implicated in structural and functional alterations of the urinary bladder. Because mechanical stress and hypoxia may trigger endoplasmic reticulum (ER) stress, we examined involvement of ER stress in the damage of the bladder caused by BOO. An experimental model of BOO was established in rats by complete ligature of the urethra for 24 h, and bladders were subjected to northern blot analysis and assessment of apoptosis. Isolated urinary bladders and bladder-derived smooth muscle cells (BSMCs) were also exposed to mechanical strain and hypoxia and used for analyses. To examine involvement of ER stress in the damage of the bladder, the effects of a chemical chaperone 4-phenylbutyrate (4-PBA) were evaluated in vitro and in vivo. Outlet obstruction for 24 h induced expression of ER stress markers, GRP78 and CCAAT/enhancer-binding protein-homologous protein (CHOP), in the bladder. It was associated with induction of markers for mechanical stress (cyclooxygenases 2) and hypoxia (vascular endothelial growth factor and glyceraldehyde-3-phosphate dehydrogenase). When isolated bladders and BSMCs were subjected to mechanical strain, induction of GRP78 and CHOP was not observed. In contrast, when BSMCs were exposed to hypoxic stress caused by CoCl2 or thenoyltrifluoroacetone (TTFA), substantial upregulation of GRP78 and CHOP was observed, suggesting involvement of hypoxia in the induction of ER stress. In the bladder subjected to BOO, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells increased in the epithelial cells and BSMCs. Similarly, treatment with TTFA or CoCl2 induced apoptosis of BSMCs, and 4-PBA significantly attenuated ER stress and apoptosis triggered by these agents. Furthermore, in vivo administration with 4-PBA significantly reduced apoptosis in the bladder subjected to BOO. These results suggested that outlet obstruction caused ER stress via hypoxic stress in the bladder and that hypoxia-triggered ER stress may be involved in the induction of apoptosis in BOO.

Differential impact of lower urinary tract symptoms on generic and disease-specific quality of life in men and women.

INTRODUCTION: We investigated how generic and disease-specific measures differ in estimating the quality of life (QoL) impact of lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: A total of 172 men and 67 women >or=40 years old who attended the public lectures completed the questionnaire comprising the International Prostate Symptom Score, benign prostatic hyperplasia impact index and SF-36 Health Survey. The multiple regression analysis was performed to evaluate the QoL impact of LUTS. RESULTS: Both storage and voiding symptoms showed significant correlations with disease-specific QoL. Among men, voiding symptom correlated more closely with disease-specific QoL than storage symptom did, and this finding was reversed among women. Storage but not voiding symptoms showed a significant correlation with generic QoL. Among men, storage symptom correlated more closely with mental health than physical health, and the reversed finding was obtained among women. Generic QoL, especially physical health, was significantly influenced by some comorbid diseases, but disease-specific QoL was not. CONCLUSIONS: The QoL impact of LUTS was differentially estimated by disease-specific and generic measures with sex differences.

Roles of mechanosensitive ion channels in bladder sensory transduction and overactive bladder.

In the storage phase, mechanical stretch stimulates bladder afferents. These signals generate sensations and trigger voiding responses, however the precise mechanisms by which mechanical stimuli excite bladder afferents are yet to be explored. For mechanosensory transduction, the presence of mechanosensors is essential in the peripheral sensory systems including sensory nerve endings, urothelium and others. There is increasing evidence that mechanosensitive ion channels, such as degenerin/epithelial Na(+) channel (ENaC) and transient receptor potential (TRP) channel families, play key roles in the mechanosensory transduction of the urinary bladder. Pharmacological interventions targeting mechanosensitive ion channels may provide a new strategy for the treatment of bladder dysfunction.