Akira Furuta

Pathophysiology of urinary incontinence in murine models.

Urethral closure mechanisms under stress conditions consist of passive urethral closure involving connective tissues, fascia and/or ligaments in the pelvis and active urethral closure mediated by hypogastric, pelvic and pudendal nerves. Furthermore, we have previously reported that the active urethral closure mechanism might be divided into two categories: (i) the central nervous control passing onto Onufs nucleus under sneezing or coughing; and (ii) the bladder‐to‐urethral spinal reflex under Valsalva‐like stress conditions, such as laughing, exercise or lifting heavy objects. There are over 200u2009million people worldwide with urinary incontinence, a condition that is associated with a significant social impact and reduced quality of life. Therefore, basic research for urinary continence mechanisms in response to different stress conditions can play an essential role in developing treatments for stress urinary incontinence. It has been clinically shown that the etiology of stress urinary incontinence is divided into urethral hypermobility and intrinsic sphincter deficiency, which could respectively correspond to passive and active urethral closure dysfunction. In this review, we summarize the representative stress urinary incontinence animal models and the methods to measure leak point pressures under stress conditions, and then highlight stress‐induced urinary continence mechanisms mediated by active urethral closure mechanisms, as well as future pharmacological treatments of stress urinary incontinence. In addition, we introduce our previous reports including sex differences in urethral closure mechanisms under stress conditions and urethral compensatory mechanisms to maintain urinary continence after pudendal nerve injury in female rats.

Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: implication for the pathogenesis of interstitial cystitis/bladder pain syndrome.

Although the pathogenesis of interstitial cystitis/bladder pain syndrome remains unknown, there is a significant correlation of interstitial cystitis/bladder pain syndrome with other chronic pain disorders, such as irritable bowel syndrome, endometriosis and fibromyalgia syndrome. In this review, we highlight evidence supporting neural cross‐talk in the dorsal root ganglia, spinal cord and brain levels, which might play a role in the development of chronic pain disorders through central sensitization. In addition, we focus on transient receptor potential V1 and transient receptor potential A1 as the receptor targets for chronic pain conditions, because transient receptor potential V1 and transient receptor potential A1 act as a nocisensor to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and calcitonin gene‐related peptide in nociceptive sensory neurons. Furthermore, peripheral inflammation produces multiple inflammatory mediators that act on their cognate receptors to activate intracellular signal transduction pathways and thereby modify the expression and function of transient receptor potential V1 and transient receptor potential A1 (peripheral sensitization). During tissue damage and inflammation, oxidative stress, such as reactive oxygen species or reactive carbonyl species is also generated endogenously. The highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross‐talk. Because oxidative stress is considered to induce activation of transient receptor potential A1, we also discuss exogenous and endogenous oxidative stress to elucidate its role in the pathogenesis of interstitial cystitis/bladder pain syndrome and other chronic pain conditions.

Combination therapy with β3-adrenoceptor agonists and muscarinic acetylcholine receptor antagonists: Efficacy in rats with bladder overactivity

To investigate the efficacy of combination therapy of a selective β3‐adrenoceptor agonist (mirabegron) and muscarinic acetylcholine receptor antagonists (a selective muscarinic acetylcholine receptor2 antagonist: methoctramine hemihydrate or a selective muscarinic acetylcholine receptor3 antagonist; 4‐DAMP) compared with monotherapy of either agent in rats with oxotremorine methiodide (a non‐selective muscarinic acetylcholine receptor agonist)‐induced bladder overactivity.

Safety of fondaparinux for prevention of postoperative venous thromboembolism in urological malignancy: A prospective randomized clinical trial.

To prospectively evaluate the safety of postoperative fondaparinux in comparison with low molecular weight heparin in patients undergoing uro‐oncological surgery.

Comparison of inflammatory urine markers in patients with interstitial cystitis and overactive bladder

Introduction and hypothesisChronic inflammatory conditions seem to be a shared characteristic in patients with interstitial cystitis (IC) and overactive bladder (OAB). Thus, we measured 40 inflammatory urine markers in IC patients with or without Hunner’s lesions (HIC and NHIC respectively) and OAB patients.MethodsUrine was collected from consecutive HIC patients, NHIC patients, and age and gender-matched OAB patients with no history of IC, recurrent urinary tract infection or bladder cancer. The diagnosis of IC was based on the Asian IC guideline criteria. A representative 40 inflammatory growth factors, cytokines, and chemokines in urine were measured using a MILLIPLEX immunoassay kit. Statistical differences in these markers among the groups were determined by nonparametric ANOVA followed by multiple comparison test. The diagnostic efficiency of these markers was measured using receiver operating characteristic analysis.ResultsVascular endothelial growth factor (VEGF), interleukin-1α (IL-1α), IL-6, and chemokines including CCL2, CCL5, CXCL1, CXCL8, and CXCL10 were significantly increased in HIC (nu2009=u200930) and NHIC (nu2009=u200930) patients compared with OAB (nu2009=u200928) patients. The significant increases in CXCL8 and CXCL10 were also found in HIC patients compared with NHIC patients. However, there were no significant differences in the other urine markers among the groups. Area under the curves for VEGF, CXCL10, CXCL8, IL-1α, CCL5, CCL2, IL-6, and CXCL1 to detect IC in these patients were 0.87, 0.86, 0.81, 0.80, 0.80, 0.71, 0.66, and 0.50 respectively.ConclusionsThe increases in angiogenesis-associated proteins such as VEGF and CXCL10 may be pathophysiologically important for the development of IC.

Video‐urodynamic effects of mirabegron, a β3‐adrenoceptor agonist, in patients with low‐compliance bladder

To investigate video‐urodynamic effects of mirabegron, a β3‐adrenoceptor agonist, on low‐compliance bladder.

Time-dependent changes in bladder function and plantar sensitivity in a rat model of fibromyalgia syndrome induced by hydrochloric acid injection into the gluteus

What’s known on the subject? and What does the study add?

Cross-sensitization mechanisms between colon and bladder via transient receptor potential A1 stimulation in rats

Introduction and hypothesisThe aim of this study was to analyze the mechanism underlying cross-sensitization between the colon and the bladder via activation of transient receptor potential A1 (TRPA1) channels.MethodsUsing female Sprague–Dawley rats, polyethylene catheters were inserted into the colon between two ligations at the levels of 40 and 60xa0mm rostral to the anus and into the bladder. (1) We examined changes in colon and bladder activity after the application of allyl isothiocyanate (AI, 50xa0mM, 300xa0μl), a TRPA1 activator, into the colon or the bladder in an awake condition. Inhibitory effects of the pretreatment with HC-030031 (HC, 3xa0mg/kg), a TRPA1 inhibitor, on colon-to-bladder cross-sensitization induced by AI instilled in the colon were also investigated. (2) We examined Evans blue (EB) dye extravasation after TRPA1 stimulation in the colon or the bladder to evaluate vascular permeability due to tissue inflammation.Results(1) Intercontraction intervals during continuous saline infusion into the bladder (0.04xa0ml/min) were significantly decreased after the intracolonic AI application, which significantly increased mean intracolonic pressure, indicative of colon-to-bladder cross-sensitization. The AI-induced colon-to-bladder cross-sensitization was completely prevented by the pretreatment with intravenous application of HC. On the other hand, mean intracolonic pressure was significantly decreased after the intravesical AI application, which significantly increased mean intravesical pressure. (2) EB dye extravasation was significantly increased in the AI-treated inflamed organs and also in the bladder following intracolonic AI treatment.ConclusionsColon-to-bladder cross-sensitization is mediated via TRPA1 stimulation in the colon, although TRPA1 expressed in the bladder does not seem to participate in bladder-to-colon cross-sensitization.

Autologous and heterotopic transplantation of adipose stromal vascular fraction ameliorates stress urinary incontinence in rats with simulated childbirth trauma

Introduction Autologous transplantation of adipose stromal vascular fraction (SVF) is a cost-effective and technically accessible option for cell therapy. Clinical study of SVF transplantation for male stress urinary incontinence (SUI) is underway, but the effectiveness remains unknown for female SUI, majority of which is caused by childbirth trauma. Methods Vaginal Distension (VD) rats were generated as in vivo model for female SUI. To quantitate the severity of SUI, leak point pressure (LPP) was measured by placing a bladder catheter. There was a characteristic waveform of LPP with two-peaks, and we counted the second peak as an LPP value. Adipose SVF was separated from inguinal fat and delivered into external urethral sphincter (EUS) through transperineal injection. LPP was measured 7 or 14 days after SVF transplantation. Tissue damage and collagen synthesis around the EUS were visualized by Massons trichrome and eosin staining. Antibody against α-smooth muscle actin (α-SMA) was used to stain smooth muscle or activated stromal cells. Donor SVF cells were distinguished from recipient EUS tissue by tracking with GFP transgene. Results VD procedure decreased the frequency at which the normal LPP waveform appeared and lowered the LPP value. SVF injection normalized the waveform as well as the level of LPP. VD disrupted histological structure of EUS and SVF failed to differentiate into striatal muscles. Instead, SVF increased α-SMA positive cells and collagen synthesis but the phenomena depended on VD stimulus. GFP tracking indicated that the transplanted SVF cells persisted for four weeks and synthesized α-SMA protein simultaneously. Conclusions Autologous transplantation of adipose SVF displayed bulking effects through collagen synthesis. However, such heterotopic activation was dependent on tissue damage.

Effects of combined treatment of tadalafil and tamsulosin on bladder dysfunction via the inhibition of afferent nerve activities in a rat model of bladder outlet obstruction

AbstractPurposeTo investigate the effects of combined treatment of tadalafil (a phosphodiesterase-5 inhibitor) and tamsulosin (an α1-adrenoceptor antagonist) on bladder dysfunction in a rat model of bladder outlet obstruction (BOO).nMethodsCystometry was performed in conscious female BOO rats 6xa0weeks after partially ligation of the urethra. Either tadalafil (0.03, 0.1 and 0.3xa0mg/kg) or tamsulosin (0.001, 0.003 and 0.01xa0mg/kg) was cumulatively applied intravenously at 30-min intervals to examine changes in cystometric parameters and blood pressures. Changes in cystometric parameters and blood pressures were also checked when tadalafil (0.3xa0mg/kg), tamsulosin (0.003xa0mg/kg) or both were intravenously applied.ResultsIn BOO rats, application of either tadalafil (0.3xa0mg/kg) or tamsulosin (0.003, 0.01xa0mg/kg) alone significantly increased threshold pressures and intercontraction intervals whereas there were no significant changes in other cystometric parameters. In addition, because a significant reduction in blood pressures was detected after the administration of tamsulosin (0.01xa0mg/kg), tamsulosin at a lower dose (0.003xa0mg/kg) was used for the combined treatment. The combination therapy of tadalafil and tamsulosin induced a significantly larger rate of increase in intercontraction intervals (1.7 times) compared with monotherapy of either drug (1.3 times each) although the combined therapy did not affect blood pressures.ConclusionsThese results suggest that the combination therapy of tadalafil and tamsulosin can induce the additive inhibitory effects on urinary frequency compared with monotherapy, more likely via inhibition of the afferent limb of micturition reflex rather than the efferent function as evidenced by the increases in threshold pressures and intercontraction intervals without affecting bladder contractile function.