Naoki Yoshimura

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (381)1138.71 Total impact

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    ABSTRACT: We investigated the effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on the sneeze induced continence reflex as well as bladder function in rats with cerebral infarction (CI). Under urethane anesthesia, the effect of duloxetine (1 mg/kg i.v.) on the amplitude of urethral responses during sneezing (A-URS) as well as urethral baseline pressure (UBP) at the mid-urethra was evaluated in normal female adult rats and CI rats. Tilt leak point pressure (tilt LPP) was also measured. In normal and CI rats, continuous cystometry was evaluated before and after duloxetine injection. In CI rats, UBP was 43% lower compared with normal rats, but A-URS did not differ in two groups. Duloxetine increased A-URS and UBP by 31% and 21%, respectively, in normal rats, but did not affect either in CI rats. Also, in CI rats, LPP was 29% lower compared with normal rats. Duloxetine increased LPP in normal rats, but not in CI rats. CI reduced intercontraction intervals without affecting the amplitude of bladder contractions compared with normal rats. Duloxetine prolonged intercontraction intervals in CI rats, but not in normal rats. These results suggest that CI induces not only bladder overactivity, but also SUI, which may account for mixed incontinence in CI patients. After CI, duloxetine reduced bladder overactivity, but failed to enhance the active urethral closure mechanisms during sneezing, suggesting that disorganization of the brain network after CI might influence the effect of duloxetine on lower urinary tract function. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    The Journal of urology 03/2015; DOI:10.1016/j.juro.2015.03.091 · 3.75 Impact Factor
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    ABSTRACT: To investigate the voiding function in a rat model of lumbar canal stenosis (LCS) using pharmacologic and molecular approaches. Sixty-one female Sprague-Dawley rats were broadly split into a sham and an LCS group. A hole was surgically drilled in the L5-L6 epidural space and filled with a rectangular piece of silicone rubber. Metabolic cage study at week 2 and continuous cystometry (CMG) under urethane anesthesia at weeks 2 and 4 were performed. During CMG, prostaglandin E2 or sulprostone, an prostaglandin E receptor 1 and prostaglandin E receptor 3 agonist was administered locally and intravenously, respectively, and the bladder was then harvested for histology and Western blot. Compared with sham, the LCS group showed dribbling urination and progressive increase in bladder size. CMG under urethane anesthesia in the LCS group was marked by overflow incontinence and acontractile bladder. Administration of intravesical prostaglandin E2 (200 μM) or intravenous sulprostone (0.1 mg/kg) in the sham group induced bladder overactivity, but decreased the compliance and failed to restore the bladder emptying function in the LCS group. The LCS group showed edematous changes and muscle thinning at week 2, which were partially restored by week 4. Histologic changes were accompanied by downregulation of agrin protein (64.0%) at week 2 and upregulation of M2 receptor (65.4%) at week 4. Expression of M3, protein gene product 9.5, and nerve growth factor did not differ between groups. LCS-induced underactive bladder is associated with altered expression of agrin and M2 receptor. The underactive bladder model is clinically relevant, and the findings indicate potential molecular targets for new therapies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urology 03/2015; DOI:10.1016/j.urology.2015.01.017 · 2.13 Impact Factor
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    ABSTRACT: This study examined whether the laser-capture microdissection (LCM) method can achieve separation of urothelial cells from detrusor cells or superficial urothelial cells from intermediate/basal urothelial cells, using α-smooth muscle actin (SMA) and cytokeratin 20 (CK20). In addition, we investigated the changes in expression of muscarinic receptors in laser-captured urothelial and detrusor cells in rats with chronic cystitis. Female SD rats were injected with cyclophosphamide (75 mg/kg) intraperitoneally at day 1, 4, 7 and 10 to induce chronic cystitis. Saline was injected in the same protocol for controls. Bladder specimens were cut at 8 μm thickness, fixed in 70 % ethanol and lightly stained by hematoxylin and eosin, and then superficial urothelium, intermediate/basal urothelium and detrusor muscles were laser-captured separately. Real-time PCR was performed to examine expressions of α-SMA, CK20, muscarinic 2 receptors (M2R) and muscarinic 3 receptors (M3R). The expression of α-SMA mRNA in detrusor muscle cells was 200 times higher than that in urothelial cells in controls. CK20 mRNA expression in apical urothelial cells was 55 times more than that in detrusor muscle and four times more than that in intermediate/basal urothelial cells. Expressions of M2R and M3R mRNA were increased in urothelial cells and decreased in detrusor muscles following chronic cystitis. The LCM could be useful for tissue collection of detrusor muscle and different layers of urothelial cells with minimal contamination of other cell types, and cell type-specific changes in molecular expression could accurately be analyzed. Increased expression of urothelial MR might enhance urothelial-afferent interactions to induce bladder overactivity/pain conditions associated with bladder inflammation.
    International Urology and Nephrology 02/2015; DOI:10.1007/s11255-015-0926-z · 1.29 Impact Factor
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    ABSTRACT: Objectives:This study investigated the mechanisms inducing autonomic dysreflexia due to enhanced bladder-to-vascular reflexes in rats with spinal cord injury (SCI).Methods:SCI was produced by the transection of the Th4-5 spinal cord in female Sprague-Dawley rats. At 4 weeks after SCI, changes in blood pressure during graded increases in intravesical pressure (20-60 cm H2O) were measured in spinal-intact (SI) and SCI rats under urethane anesthesia. In five animals, effects of C-fiber desensitization induced by intravesical application of resiniferatoxin (RTX), a TRPV1 agonist, on the bladder-to-vascular reflex were also examined. Nerve growth factor (NGF) levels of mucosa and detrusor muscle layers of the bladder were measured by enzyme-linked immunosorbent assay. The expression levels of TRPV1 and TRPA1 channels were also examined in laser captured bladder afferent neurons obtained from L6 DRG, which were labeled by DiI injected into the bladder wall.Results:In SI and SCI rats, systemic arterial blood pressure was increased in a pressure-dependent manner during increases in the intravesical pressure, with significantly higher blood pressure elevation at the intravesical pressure of 20 cm H2O in SCI rats vs SI rats. The arterial blood pressure responses to bladder distention were significantly reduced by RTX-induced desensitization of C-fiber bladder afferent pathways. SCI rats had higher NGF protein levels in the bladder and higher TRPV1 and TRPA1 mRNA levels in bladder afferent neurons compared with SI rats.Conclusions:The bladder-to-vascular reflex induced by TRPV1-expressing C-fiber afferents during bladder distention is enhanced after SCI in association with increased expression of NGF in the bladder and TRP channels in bladder afferent neurons.Spinal Cord advance online publication, 23 December 2014; doi:10.1038/sc.2014.233.
    Spinal Cord 12/2014; 189(4):e13–e14. DOI:10.1016/j.juro.2013.02.1409 · 1.70 Impact Factor
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    ABSTRACT: BACKGROUND Prostatic inflammation is reportedly associated with the development of prostatic hyperplasia. We investigated the effects of prostatic inflammation on expression levels of androgen-responsive genes and growth factors in the rat prostate.METHODS Prostatic inflammation was induced by Escherichia coli (strain 1677) injection (0.2 ml of 1 × 108 CFU/ml) into the prostatic urethra of male Sprague–Dawley rats, and ventral lobes of the prostate were harvested on day 84. Rats were given 10 mg/kg celecoxib during the last month in the COX-2 inhibitor treated group. Histopathology and multiplex enzyme-linked immunosorbent assay (ELISA) for inflammation-related proteins were performed. Glandular epithelial cells and stromal regions were separately isolated using laser-capture microdissection (LCM). Real-time RT-PCR was performed to examine mRNA levels of androgen-responsive genes in the epithelium and tumor growth factor-β1 (TGF-β1) cascade genes in the stroma.RESULTSHematoxylin and eosin staining showed that mild inflammation was distributed diffusely throughout the prostate. Polymorphonuclear cells infiltrated the slightly edematous stroma, but no morphological changes were observed in the epithelium. Immunohistochemically, expression of androgen receptor and TGF-β1 in addition to IL-6 and cyclooxigenase-2 (COX-2) were enhanced in the E. coli inoculated rats. All of these factors were suppressed in the celecoxib-treated rats. Upregulation of IL-1α, IL-1β, IL-6, and RANTES in the E. coli-inoculated rats was normalized by celecoxib treatment. Significant upregulation of androgen receptor and androgen-responsive genes such as Eaf2, ELL2, FKBP5, calreticulin, and ornithine decarboxylase was observed in the LCM-dissected epithelium. Also TGF-β1 and its downstream cascade genes such as Hic-5, collagen 1, and fibronectin were upregulated significantly in the LCM-dissected stroma. The COX-2 inhibitor treatment suppressed upregulation of these genes.CONCLUSIONS Prostatic inflammation changed the expression of androgen-responsive genes in the epithelium and TGF-β1 cascade genes in the stroma. Activation of TGF-β1 cascade genes in the inflamed stroma, as well as altered androgen-responsive gene expression in the epithelium, might be involved in the development of BPH. Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 11/2014; 75(4). DOI:10.1002/pros.22924 · 3.57 Impact Factor
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    ABSTRACT: Neural cross-sensitization has been postulated as a mechanism underlying overlaps of chronic pelvic pain disorders such as bladder pain syndrome/interstitial cystitis (BPS/IC) and irritable bowel syndrome (IBS). Animals with experimental colitis have been used to study the underlying mechanisms for overlapped pelvic pain symptoms, and shown to exhibit bladder overactivity evidenced by frequent voiding; however, it has not directly been evaluated whether pain sensation derived from the lower urinary tract is enhanced in colitis models. Also, the cross-sensitization between the colon and urethra has not been studied previously. In the present study, we therefore investigated pain behaviors induced by nociceptive stimuli in the lower urinary tract and the involvement of C-fiber afferent pathways using rats with colitis induced by intracolonic application of 2,4,6-trinitrobenzenesulfonic acid (TNBS). In TNBS-induced colitis rats at 10days, intravesical application of resiniferatoxin (RTx) induced a significantly greater number of episodes of both licking and freezing behaviors, which were reduced by capsaicin-sensitive C-fiber afferent desensitization. Histochemical studies using fluorescent dye tracers injected into the colon, bladder or urethra showed that dichotomized afferent neurons comprised 6.9-14.5% of L1, L6 and S1 dorsal root ganglion (DRG) neurons innervating the colon or the lower urinary tract. Transient receptor potential vanilloid 1 (TRPV1) mRNA expression was significantly increased in, the bladder, urethra and S1 DRG in colitis rats. An increase in myeloperoxidase (MPO) activity was found in the colon, but not in the bladder or urethra after intracolonic TNBS treatment. These results indicate that TNBS-induced colitis increased pain sensitivity in the bladder and urethra via activation of C-fiber afferent pathways due to colon-to-bladder and colon-to-urethral cross-sensitization, suggesting the contribution of pelvic organ cross-sensitization mechanisms to overlapped pain symptoms in BPS/IC and IBS. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 10/2014; 284C:422-429. DOI:10.1016/j.neuroscience.2014.08.064 · 3.33 Impact Factor
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    ABSTRACT: Adenosine is a neurotransmitter that exerts numerous physiological effects in many organs. However, few studies have focused on the role of adenosine receptors in the control of micturition. Therefore, we examined the role of adenosine A1 and A2A receptors in the control of bladder activity in rats with normal or acetic acid (AA) irritated bladders. Cystometrograms during saline or 0.2% AA infusion were recorded under urethane anesthesia in female Sprague-Dawley rats. After a stabilization period, CCPA (A1 receptor agonist) and/or ZM24138 (A2A receptor antagonist) were administered intravenously (i.v.), intrathecally (i.t.), intracerebroventricularly (i.c.v.), or intravesically. Micturition parameters were recorded and compared before and after drug administration. I.v., i.t., or i.c.v. administration of CCPA or ZM24138 significantly increased intercontraction intervals (ICIs) in both saline and AA infusion groups. During AA infusion, the inhibitory effects induced by i.c.v. CCPA or i.t. ZM24138 were significantly greater than those by i.t. or i.c.v. administration, respectively. Intravesical administration of CCPA, but not ZM24138, significantly increased ICI. These results indicated that: (1) when nociceptive signals from the bladder increase, adenosine A1 receptor-mediated inhibition of micturition is enhanced in the brain, compared to the normal condition, (2) A1 receptor activation also exerts a peripheral inhibitory effect on micturition, and (3) adenosine A2A receptor-mediated excitatory mechanisms are enhanced in the spinal cord following C-fiber bladder afferent stimulation. Thus adenosine A1 receptor agonists and A2A receptor antagonists might be effective for the treatment of overactive bladder and/or bladder hypersensitive disorders, in which C-fiber afferent function is enhanced. Neurourol. Urodynam. © 2013 Wiley Periodicals, Inc.
    Neurourology and Urodynamics 10/2014; 33(8). DOI:10.1002/nau.22487 · 2.46 Impact Factor
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    ABSTRACT: AimsStress urinary incontinence (SUI) is common in post-menopausal women. The present study therefore examined how aging and estrogen deficiency induced by ovariectomy (OVX) affect the urethral continence mechanism that prevents sneeze-induced SUI in rats.Methods Young (3 months old) and middle-aged (12 months old) female rats underwent bilateral OVX or sham operation. Urethral activity was measured by the amplitude of urethral responses during sneezing (A-URS) and urethral baseline pressure (UBP). Apoptotic changes in urethral tissue sections were examined by the TUNEL method.ResultsIn middle-aged rats, UBP, but not A-URS, was significantly decreased compared to young rats. In 3-week OVX rats, A-URS was significantly decreased compared to sham rats in both young and middle-aged groups, and the OVX-induced reduction in A-URS was more pronounced in middle-aged rats. Neither young 3-week OVX nor sham rats leaked during sneezing; however, SUI occurred in 2/8 middle-aged rats with 3-week OVX, and after 6 weeks of OVX, SUI was observed in 5/8 young rats and 6/8 middle-aged rats. In middle-aged rats, TUNEL positive cells were significantly increased in urethral striated muscles whereas, after OVX, the increased number of positive cells was also found in the mucosa.Conclusions These results indicate that aging is more likely to impair baseline urethral function than striated muscle-mediated reflex activity although apoptotic changes are found in urethral striated muscle. Estrogen deficiency additionally impairs the striated muscle-mediated continence reflex. Thus, aging and estrogen deficiency differently and additively affect baseline urethral function and neurally-evoked, striated muscle-mediated urethral continence mechanisms to induce SUI. Neurourol. Urodynam. © 2014 Wiley Periodicals, Inc.
    Neurourology and Urodynamics 10/2014; DOI:10.1002/nau.22690 · 2.46 Impact Factor
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    ABSTRACT: Muscarinic agonists are the most commonly used agents for treating the underactive bladder (UAB). However, because of the absence of pharmacologic specificity for bladder-only effects and possibly as a result of degenerative and other post-synaptic changes involving detrusor smooth muscle cells, they are simply not effective and side effects are common. If safe and effective therapy for UAB is made available, then most experts agree that the potential market would exceed industry expectations, just as antimuscarinic agents for overactive bladder did in the late 1990s. The pharmaceutical and biotechnology industries that have a pipeline to urology and women's health should consider UAB as a potential target condition. A rational approach to treating the pathology of UAB is presented with a discussion of potential targets that may allow the development of safe and effective agents for the treatment of UAB.
    International Urology and Nephrology 09/2014; 46(Supplement 1):35-44. DOI:10.1007/s11255-014-0809-8 · 1.29 Impact Factor
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    ABSTRACT: While the symptomology of underactive bladder (UAB) may imply a primary dysfunction of the detrusor muscle, insights into pathophysiology indicate that both myogenic and neurogenic mechanisms need to be considered. Due to lack of proper animal models, the current understanding of the UAB pathophysiology is limited, and much of what is known about the clinical etiology of the condition has been derived from epidemiological data. We hereby review current state of the art in the understanding of the pathophysiology of and animal models used to study the UAB.
    International Urology and Nephrology 09/2014; 46(Supplement 1):11-21. DOI:10.1007/s11255-014-0808-9 · 1.29 Impact Factor
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    ABSTRACT: Little is known about electrophysiological differences of A-type transient K(+) (KA) currents in nociceptive afferent neurons that innervate somatic and visceral tissues. Staining with isolectin B4 (IB4)-FITC classifies L6-S1 dorsal root ganglion (DRG) neurons into three populations with distinct staining intensities: negative to weak, moderate, and intense IB4 staining. All IB4-intensely stained cells are negative for a fluorescent dye, Fast Blue (FB) injected into the bladder wall, whereas a fraction of somatic neurons labeled by FB injected to the external urethral dermis are intensely stained with IB4. In whole-cell patch clamp recordings, phrixotoxin 2, a Kv4 channel blocker, exhibits voltage-independent inhibition of the KA current in IB4-intensely stained cells, but not the one in bladder-innervating cells. The toxin also shows voltage-independent inhibition of heterologously-expressed Kv4.1 and Kv4.3 currents, whereas its inhibition of Kv4.2 current is totally voltage-dependent. Swapping four-amino acids at the carboxyl portion of the S3 region between Kv4.1 and Kv4.2 transfers this characteristic. RT-PCRs detected Kv4.1 and the long-isoform of Kv4.3 mRNAs without significant Kv4.2 mRNA in L6-S1 DRGs. Higher expression of Kv4.1 and Kv4.3 mRNA was also identified in laser-captured, IB4-stained neurons compared to bladder afferent neurons. These results indicate that phrixotoxin 2 differently acts on channels in the Kv4 family, and that Kv4.1 and/or Kv4.3 subunits functionally participate in the formation of KA channels in a subpopulation of somatic C-fiber neurons, but not in visceral C-fiber neurons innervating the bladder.
    Journal of Neurophysiology 08/2014; DOI:10.1152/jn.00054.2014 · 3.04 Impact Factor
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    ABSTRACT: Background The functional and molecular alterations of nerve growth factor (NGF) and Prostaglandin E2 (PGE2) and its receptors were studied in bladder and urine in streptozotocin (STZ)-induced diabetic rats. Methodology/Principal Findings Diabetes mellitus was induced with a single dose of 45 mg/kg STZ Intraperitoneally (i.p) in female Sprague-Dawley rats. Continuous cystometrogram were performed on control rats and STZ treated rats at week 4 or 12 under urethane anesthesia. Bladder was then harvested for histology, expression of EP receptors and NGF by western blotting, PGE2 levels by ELISA, and detection of apoptosis by TUNEL staining. In addition, 4-hr urine was collected from all groups for urine levels of PGE2, and NGF assay. DM induced progressive increase of bladder weight, urine production, intercontraction interval (ICI) and residual urine in a time dependent fashion. Upregulation of Prostaglandin E receptor (EP)1 and EP3 receptors and downregulation of NGF expression, increase in urine NGF and decrease levels of urine PGE2 at week 12 was observed. The decrease in ICI by intravesical instillation of PGE2 was by 51% in control rats and 31.4% in DM group at week 12. Conclusions/Significance DM induced hyposensitive underactive bladder which is characterized by increased inflammatory reaction, apoptosis, urine NGF levels, upregulation of EP1 and EP3 receptors and decreased bladder NGF and urine PGE2. The data suggest that EP3 receptor are potential targets in the treatment of diabetes induced underactive bladder.
    PLoS ONE 07/2014; 9(7):e102644. DOI:10.1371/journal.pone.0102644 · 3.53 Impact Factor
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    ABSTRACT: We characterized TRK-130, N-[(5R, 6R, 14S)-17-(cyclopropylmethyl)-4, 5-epoxy-3, 14-dihydroxymorphinan-6-yl] phthalimide (naltalimide), an opioid ligand, to clarify the therapeutic potential for overactive bladder (OAB). In radioligand binding assays with cells expressing human μ-opioid receptors (MORs), δ-opioid receptors (DORs), or κ-opioid receptors (KORs), TRK-130 showed high selectivity for MORs (Ki for MORs, DORs, and KORs = 0.268, 121, and 8.97 nM, respectively). In a functional assay (cyclic AMP accumulation) with cells expressing each human opioid receptor subtype, TRK-130 showed potent but partial agonistic activity for MORs [EC50 (Emax) for MORs, DORs, and KORs = 2.39 nM (66.1%), 26.1 nM (71.0%), and 9.51 nM (62.6%), respectively]. In isovolumetric rhythmic bladder contractions (RBCs) in anesthetized guinea pigs, TRK-130 dose-dependently prolonged the shutdown time (the duration of complete cessation of the bladder contractions) (ED30 = 0.0034 mg/kg, i.v.) without affecting amplitude of RBCs. Furthermore, TRK-130 ameliorated formalin-induced frequent urination at doses of higher than 0.01 mg/kg, p.o. in guinea pigs under the freely moving condition. Meanwhile, TRK-130 showed only a negligible effect on the gastrointestinal transit at doses of up to 10 mg/kg, s.c. in mice. These results indicate that TRK-130 is a potent and selective human MOR partial agonist without undesirable opioid adverse effects such as constipation and enhance the storage function by suppressing the afferent limb of the micturition reflex pathway, suggesting that TRK-130 would be a new therapeutic agent for OAB.
    Journal of Pharmacology and Experimental Therapeutics 06/2014; 350(3). DOI:10.1124/jpet.114.214031 · 3.86 Impact Factor
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    ABSTRACT: BACKGROUND Benign prostatic hyperplasia (BPH) is an age-related disease frequently associated with lower urinary tract symptoms (LUTS) that involves hyperplasia of both epithelial and stromal cells. Stromal fibrosis is a distinctive feature of BPH, but the exact mechanisms underlying this phenomenon are poorly understood.METHODS In the current study, proteomics analyses were utilized to identify proteins altered in the BPH stromal compartment from patients with symptomatic BPH. Stromal cells were isolated from histological nodules of BPH by laser capture microdissection (LCM) and subjected to liquid chromatography/mass spectrometry.RESULTSProteins identified included several stromal-specific proteins involved in extracellular matrix (ECM) remodeling, focal adhesion, and cellular junctions. Additionally, the proteomics array identified the presence of luminal epithelial secretory protein PSA. Immunostaining, ELISA, and in situ hybridization analyses of BPH tissues verified the presence of PSA protein but absence of PSA mRNA in the stromal compartment. E-cadherin was down-regulated in BPH epithelial cells compared to normal adjacent tissues, suggesting that alteration of cellular junctions could contribute to the presence of luminal epithelial secreted proteins PSA and KLK2 in the stromal compartment.CONCLUSIONS The above findings suggest that the presence of secreted proteins PSA and KLK2 from prostate luminal epithelial cells in BPH stroma is a hallmark of BPH nodules, which could in part be due to alterations in cellular junction proteins and/or increased epithelial barrier permeability. Elucidating the cause and consequence of these secreted proteins in the stromal compartment of BPH may lead to new understanding of BPH pathogenesis as well as approaches to prevent and/or treat this common disease. Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 06/2014; 74(8). DOI:10.1002/pros.22807 · 3.57 Impact Factor
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    ABSTRACT: The 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. Using female Sprague-Dawley rats, polyethylene catheters were inserted into the colon between two ligations at the levels of 40 and 60 mm rostral to the anus and into the bladder. (1) We examined changes in colon and bladder activity after the application of allyl isothiocyanate (AI, 50 mM, 300 μl), a TRPA1 activator, into the colon or the bladder in an awake condition. Inhibitory effects of the pretreatment with HC-030031 (HC, 3 mg/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. (1) Intercontraction intervals during continuous saline infusion into the bladder (0.04 ml/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. Colon-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.
    International Urogynecology Journal 05/2014; 25(11). DOI:10.1007/s00192-014-2405-y · 2.16 Impact Factor
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    ABSTRACT: To investigate the effects of activation of sensory neuron-specific receptors (SNSRs) on cyclophosphamide (CYP) bladder overactivity in rats. Female Sprague-Dawley rats (235-258 g) were used. Rats were injected with either CYP (200 mg/kg, intraperitoneally) or saline (control). Continuous cystometrograms (0.04 ml/min) were recorded 48 h after CYP or saline injection under urethane anesthesia. After stable micturition cycles were established, a selective rat SNSR1 agonist, bovine adrenal medulla 8-22 (BAM8-22), was administered intravenously or intrathecally. Cyclophosphamide treatment-induced higher baseline pressure and shorter intercontraction intervals compared with the control group. Intravenous administration of BAM8-22 at 10, 30 and 100 μg/kg significantly increased intercontraction intervals in the CYP-treated group. Intrathecal administration of BAM8-22 at 0.03, 0.1 and 0.3 μg also significantly increased intercontraction intervals in the CYP-treated group. Intravenous or intrathecal administration of BAM8-22 did not change baseline pressure or maximum voiding pressure in the CYP-treated group. These findings indicate that activation of SNSRs can suppress CYP-induced bladder overactivity, probably due to suppression of bladder afferent activity.
    International Urology and Nephrology 05/2014; 46(10). DOI:10.1007/s11255-014-0734-x · 1.29 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e193. DOI:10.1016/j.juro.2014.02.713 · 3.75 Impact Factor
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    ABSTRACT: AIMS: The urethral continence reflex during stress conditions such as sneezing or coughing is an important mechanism preventing stress urinary incontinence (SUI). Although the spinal noradrenergic and serotonergic pathways are known to modulate this reflex activity, the role of spinal cholinergic pathways in the control of urethral continence reflex has not been elucidated. We therefore investigated the effect of intrathecal administration of an acetylcholine esterase (AChE) inhibitor, which increases ACh in synaptic terminals, and anti-cholinergic agents on the sneeze-induced urethral reflex in rats. METHODS: Female SD rats were anesthetized with urethane. Urethral function was evaluated during sneezing induced by insertion of the rat whisker into the nostril. Effects of an AChE inhibitor, neostigmine, and muscarinic or nicotinic receptor antagonists administered at the level of L6-S1 spinal cord were examined. RESULTS: Neostigmine dose-dependently and significantly decreased the amplitude of urethral responses during sneezing (A-URS) with an approximately 70% reduction at 3 nmol, without changing urethral baseline pressure. The neostigmine-induced decrease in A-URS was significantly reversed by pretreatment with atropine (nonselective muscarinic receptor antagonist), methoctramine (M2 receptor antagonist) or 4-DAMP (M3 receptor antagonist), but not with pirenzepine (M1 receptor antagonist), tropicamide (M4 receptor antagonist), or mecamylamine (nicotinic receptor antagonist). CONCLUSIONS: These results indicate that an increase in endogenous ACh in the lumbosacral spinal cord inhibits the sneeze-induced urethral continence reflex via activation of M2 and/or M3-muscarinic receptors, implying the inhibitory role of spinal cholinergic pathways in the control of urethral continence reflex under stress conditions such as sneezing. Neurourol. Urodynam. © 2013 Wiley Periodicals, Inc.
    Neurourology and Urodynamics 04/2014; 33(4). DOI:10.1002/nau.22431 · 2.46 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e7. DOI:10.1016/j.juro.2014.02.113 · 3.75 Impact Factor

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7k Citations
1,138.71 Total Impact Points


  • 1994–2015
    • University of Pittsburgh
      • • Department of Urology
      • • Department of Pharmacology and Chemical Biology
      • • Department of Medicine
      Pittsburgh, Pennsylvania, United States
  • 2014
    • Kaohsiung Municipal Ta-Tung Hospital, Taiwan
      Kao-hsiung-shih, Kaohsiung, Taiwan
  • 2013
    • Tottori University
      • Division of Urology
      Tottori, Tottori-ken, Japan
  • 2004–2010
    • Chang Gung Memorial Hospital
      • Division of Urology
      Taipei, Taipei, Taiwan
  • 2009
    • The Jikei University School of Medicine
      • Department of Urology
      Tokyo, Tokyo-to, Japan
  • 2006
    • Chang Gung University
      Hsin-chu-hsien, Taiwan, Taiwan
  • 2005–2006
    • Shinshu University
      Shonai, Nagano, Japan
  • 2001
    • Okayama University
      Okayama, Okayama, Japan
  • 1987–2000
    • Kyoto University
      • • Department of Urology
      • • Department of Pharmacology
      Kioto, Kyōto, Japan
  • 1991
    • Rakuwakai Otowa Hospital
      Kioto, Kyōto, Japan
    • Osaka Saiseikai Nakatsu Hospital
      Ōsaka, Ōsaka, Japan