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Fogg RW, Ghatas MP, McCormack B, Shields M, Matthew AN, Grob G, Araia N, Burkett L, Speich JE, Klausner AP. Increased Afferent Nerve Firing Is Correlated With the Detection of Bladder Wall Micromotion in a Perfused Ex-Vivo Porcine Model. Neurourol Urodyn 2025; 44:504-511. [PMID: 39803856 DOI: 10.1002/nau.25661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 11/25/2024] [Accepted: 12/23/2024] [Indexed: 02/04/2025]
Abstract
INTRODUCTION AND OBJECTIVE Observable autonomous rhythmic changes in intravesical pressure, termed bladder wall micromotion, is a phenomenon that has been linked to urinary urgency, the key symptom in overactive bladder (OAB). However, the mechanism through which micromotion drives urinary urgency is poorly understood. In addition, micromotion is inherently difficult to study in human urodynamics due to challenges distinguishing it from normal cyclic physiologic processes such as pulse rate, breathing, rectal contractions, and ureteral jetting. Therefore, the goal of this study was to create a reproducible model of micromotion using an ex-vivo perfused porcine bladder, as well as to describe the relationship between micromotion and afferent nerve signaling. METHODS Porcine bladders were reanimated using ex-vivo perfusion with a physiologic buffer. The pelvic nerve adjacent to the bladder was dissected, grasped with micro-hook electrodes and electroneurogram (ENG) signals were recorded at 20 kHz. Bladders were catheterized and intravesical pressure measurements were taken using a Laborie XT Urodynamics system. Bladders were filled to a fixed volume of 300 mL and control measurements were recorded. The bladders were then washed with 0.001 M carbachol (CCh) solution and refilled to 300 mL to induce micromotion, which was detected as rhythmic changes in intravesical pressure. ENG amplitude was calculated in μV, and nerve firing rate was calculated as number of spikes above baseline threshold per minute. RESULTS Micromotion was induced by carbachol in 12/25 (48.4%) of trials as rhythmic changes in intravesical pressure after the instillation of carbachol but not in any control period. A fast Fourier transform (FFT) algorithm showed average peak dominant frequency component amplitude was significantly higher during the carbachol period when compared to the control period (0.47 vs. 0.01 cm-H2O, p < 0.0001). Peak waveform frequency (1.13 vs. 1.54 cycles/min, p > 0.05) did not differ between control and carbachol periods. With regard to afferent nerve signaling, normalized average amplitude (0.66 ± 0.24 vs. 0.05 ± 0.08 μV) and firing rate (0.68 ± 0.28 vs. 0.18 ± 0.22 spike/min) for all bladders was significantly greater in the carbachol period when compared to the control period (p < 0.001). CONCLUSIONS Micromotion can be induced using instillation of carbachol in a perfused ex-vivo porcine bladder. Increased afferent nerve firing is observed during periods of micromotion. Thus, micromotion may drive afferent nerve signaling and may potentially contribute to urinary urgency, detrusor overactivity, and OAB. The development of an experimental ex-vivo porcine model for micromotion provides a reproducible method to study bladder micromotion and its potential role in the pathophysiology of urinary urgency and voiding dysfunction.
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Affiliation(s)
- Ryan W Fogg
- Department of Surgery, Division of Urology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Mina P Ghatas
- Department of Surgery, Division of Urology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Brendan McCormack
- Department of Surgery, Division of Urology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Michael Shields
- Department of Surgery, Division of Urology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Ashley N Matthew
- Department of Surgery, Division of Urology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Gabrielle Grob
- Department of Surgery, Division of Urology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Nat Araia
- Department of Surgery, Division of Urology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - Linda Burkett
- Department of Obstetrics & Gynecology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
| | - John E Speich
- Department of Mechanical & Nuclear Engineering, Virginia Commonwealth University College of Engineering, Richmond, Virginia, USA
| | - Adam P Klausner
- Department of Surgery, Division of Urology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
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Liu H, Li P, Zhao M, Ma T, Lv G, Liu L, Wen J, Liu J, Yan J, Li J, Xiao Z, Wang W, Wang H, Xiao P, Zhang X. Activation of Piezo1 channels enhances spontaneous contractions of isolated human bladder strips via acetylcholine release from the mucosa. Eur J Pharmacol 2024; 983:176954. [PMID: 39237075 DOI: 10.1016/j.ejphar.2024.176954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/10/2024] [Accepted: 08/27/2024] [Indexed: 09/07/2024]
Abstract
Enhanced spontaneous bladder contractions (SBCs) have been thought one of the important underlying mechanisms for detrusor overactivity (DO). Piezo1 channel has been demonstrated involved in bladder function and dysfunction in rodents. We aimed to investigate the modulating role of Piezo1 in SBCs activity of human bladder. Human bladder tissues were obtained from 24 organ donors. SBCs of isolated bladder strips were recorded in organ bath. Piezo1 expression was examined with reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining. ATP and acetylcholine release in cultured human urothelial cells was measured. Piezo1 is abundantly expressed in the bladder mucosa. Activation of Piezo1 with its specific agonist Yoda1 (100 nM-100 μM) enhanced the SBCs activity in isolated human bladder strips in a concentration-dependent manner. The effect of Yoda1 mimicked the effect of a low concentration (30 nM) of carbachol, which can be attenuated by removing the mucosa, blocking muscarinic receptors with atropine (1 μM), and blocking purinergic receptors with pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS, 30 μM), but not by tetrodotoxin (1 μM). Activation of urothelial Piezo1 with Yoda1 (30 μM) or hypotonic solution induced the release of ATP and acetylcholine in cultured human urothelial cells. In patients with benign prostatic hyperplasia, greater Piezo1 expression was observed in bladder mucosa from patients with DO than patients without DO. We conclude that upregulation and activation of Piezo1 may contribute to DO generation in patients with bladder outlet obstruction by promoting the urothelial release of ATP and acetylcholine. Inhibition of Piezo1 may be a novel therapeutic approach in the treatment of overactive bladder.
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Affiliation(s)
- Hanwen Liu
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Peixin Li
- Department of Urology, Qilu Hospital of Shandong University, Shandong, PR China
| | - Mengmeng Zhao
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Tianjia Ma
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Guangda Lv
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Lei Liu
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Jiliang Wen
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Jiaxin Liu
- Department of Kidney Transplantation, The Second Hospital of Shandong University, Jinan, PR China
| | - Jieke Yan
- Department of Kidney Transplantation, The Second Hospital of Shandong University, Jinan, PR China
| | - Jinyang Li
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Zhiying Xiao
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Wenzhen Wang
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Haoyu Wang
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China
| | - Pan Xiao
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China.
| | - Xiulin Zhang
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR China.
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Chen H, Hoi MPM, Lee SMY. Medicinal plants and natural products for treating overactive bladder. Chin Med 2024; 19:56. [PMID: 38532487 DOI: 10.1186/s13020-024-00884-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 01/02/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Overactive bladder (OAB) presents a high prevalence of 16-18% worldwide. The pathophysiology of OAB is still poorly understood while effective therapy or countermeasure are very limited. On the other hand, medicinal plants and herbal remedies have been utilized for treating lower urinary tract symptoms (LUTS) in both Eastern and Western cultures since ancient times. In recent years, accumulating progress has also been made in OAB treatment research by using medicinal plants. METHODS Relevant literature on the studies of medicinal plants and herbs used to treat OAB was reviewed. The medicinal plants were summarized and categorized into two groups, single-herb medications and herbal formulations. RESULTS The present review has summarized current understanding of OAB's pathophysiology, its available treatments and new drug targets. Medicinal plants and natural products which have been used or have shown potential for OAB treatment were updated and comprehensively categorized. Studies on a wide variety of medicinal plants showed promising results, although only a few phytochemicals have been isolated and identified. Until now, none of these herbal compounds have been further developed into clinical therapeutics for OAB. CONCLUSIONS This review provides the basis for discovering and designing new phytopharmaceutical candidates with effective and well-tolerated properties to treat OAB. Increasing evidences indicate new strategies with alternative herbal treatment for OAB have high efficacy and safety, showing great promise for their clinical use. Future studies in a rigorously designed controlled manner will be beneficial to further support the eligibility of herbal treatment as OAB therapeutics.
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Affiliation(s)
- Huanxian Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, University of Macau, Macao, China
| | - Maggie Pui Man Hoi
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, University of Macau, Macao, China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao, China
| | - Simon Ming Yuen Lee
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, University of Macau, Macao, China.
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao, China.
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, China.
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Jiang YH, Kuo HC. Current optimal pharmacologic therapies for overactive bladder. Expert Opin Pharmacother 2023; 24:2005-2019. [PMID: 37752121 DOI: 10.1080/14656566.2023.2264183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 09/25/2023] [Indexed: 09/28/2023]
Abstract
INTRODUCTION Overactive bladder (OAB) is a common syndrome in adults. Current pharmacologic treatment includes antimuscarinic agents and β-3 adrenoceptor agonists. For non-responders to oral medication, intravesical injection of botulinum toxin A (BoNT-A) is an effective option. However, these treatments have potential adverse events and should be cautiously selected for appropriate patients. This review presents the recently published results of clinical trials and studies for patients with OAB and the underlying pathophysiology of OAB. Appropriate medical therapy based on pathophysiology of OAB is also presented. AREAS COVERED Literature search from Pubmed from 2001 to 2023 including clinical background, pharmacology, and clinical studies for OAB medications. EXPERT OPINION Treatment of OAB syndrome with any antimuscarinic or β-3 adrenoceptor agonist is feasible as a first-line approach. For patients with suboptimal therapeutic effect to full-dose antimuscarinics or mirabegron, combination with both drugs can improve efficacy. Intravesical BoNT-A 100-U injection provides therapeutic effects for refractory OAB. Patients who are refractory to initial pharmacotherapies should be investigated for the underlying pathophysiology; then an appropriate medication can be added, such as an α1-blocker or anti-inflammatory agents. Patient education about behavioral modification and therapies should always be provided with oral medication or BoNT-A injection for OAB patients.
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Affiliation(s)
- Yuan-Hong Jiang
- Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Hann-Chorng Kuo
- Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
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Michel MC, Cardozo L, Chermansky CJ, Cruz F, Igawa Y, Lee KS, Sahai A, Wein AJ, Andersson KE. Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders. Pharmacol Rev 2023; 75:554-674. [PMID: 36918261 DOI: 10.1124/pharmrev.121.000523] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 03/16/2023] Open
Abstract
Overactive bladder syndrome with and without urinary incontinence and related conditions, signs, and disorders such as detrusor overactivity, neurogenic lower urinary tract dysfunction, underactive bladder, stress urinary incontinence, and nocturia are common in the general population and have a major impact on the quality of life of the affected patients and their partners. Based on the deliberations of the subcommittee on pharmacological treatments of the 7th International Consultation on Incontinence, we present a comprehensive review of established drug targets in the treatment of overactive bladder syndrome and the aforementioned related conditions and the approved drugs used in its treatment. Investigational drug targets and compounds are also reviewed. We conclude that, despite a range of available medical treatment options, a considerable medical need continues to exist. This is largely because the existing treatments are symptomatic and have limited efficacy and/or tolerability, which leads to poor long-term adherence. SIGNIFICANCE STATEMENT: Urinary incontinence and related disorders are prevalent in the general population. While many treatments have been approved, few patients stay on long-term treatment despite none of them being curative. This paper provides a comprehensive discussion of existing and emerging treatment options for various types of incontinence and related disorders.
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Affiliation(s)
- Martin C Michel
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Linda Cardozo
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Christopher J Chermansky
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Francisco Cruz
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Yasuhiko Igawa
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Kyu-Sung Lee
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Arun Sahai
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Alan J Wein
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Karl-Erik Andersson
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
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Hughes FM, Allkanjari A, Odom MR, Mulcrone JE, Jin H, Purves JT. Male Akita mice develop signs of bladder underactivity independent of NLRP3 as a result of a decrease in neurotransmitter release from efferent neurons. Am J Physiol Renal Physiol 2023; 325:F61-F72. [PMID: 37167271 PMCID: PMC10292983 DOI: 10.1152/ajprenal.00284.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 04/26/2023] [Accepted: 05/08/2023] [Indexed: 05/13/2023] Open
Abstract
Diabetic bladder dysfunction (DBD) is a prevalent diabetic complication that is recalcitrant to glucose control. Using the Akita mouse model (type 1) bred to be NLR family pyrin domain containing 3 (NLRP3)+/+ or NLRP3-/-, we have previously found that females (mild hyperglycemia) progress from an overactive to underactive bladder phenotype and that this progression was dependent on NLRP3-induced inflammation. Here, we examined DBD in the male Akita mouse (severe hyperglycemia) and found by urodynamics only a compensated underactive-like phenotype (increased void volume and decreased frequency but unchanged efficiency). Surprisingly, this phenotype was still present in the NLRP3-/- strain and so was not dependent on NLRP3 inflammasome-induced inflammation. To examine the cause of the compensated underactive-like phenotype, we assessed overall nerve bundle density and afferent nerve bundles (Aδ-fibers). Both were decreased in density during diabetes, but denervation was absent in the diabetic NLRP3-/- strain so it was deemed unlikely to cause the underactive-like symptoms. Changes in bladder smooth muscle contractility to cell depolarization and receptor activation were also not responsible as KCl (depolarizing agent), carbachol (muscarinic agonist), and α,β-methylene-ATP (purinergic agonist) elicited equivalent contractions in denuded bladder strips in all groups. However, electrical field stimulation revealed a diabetes-induced decrease in contractility that was not blocked in the NLRP3-/- strain, suggesting that the bladder compensated underactive-like phenotype in the male Akita mouse is likely through a decrease in efferent neurotransmitter release.NEW & NOTEWORTHY In this study, we show that diabetic bladder dysfunction (the most common diabetic complication) manifests through different mechanisms that may be related to severity of hyperglycemia and/or sex. Male Akita mice, which have severe hyperglycemia, develop bladder underactivity as a result of a decrease in efferent neurotransmitter release that is independent of inflammation. This contrasts with females, who have milder hyperglycemia, where diabetic bladder dysfunction progresses from overactivity to underactivity in an inflammation-dependent manner.
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Affiliation(s)
- Francis M Hughes
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Armand Allkanjari
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Michael R Odom
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Jack E Mulcrone
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - Huixia Jin
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
| | - J Todd Purves
- Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States
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7
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Son HS, Moon SY, Kwon J, Kim JH. Effect of β3-adrenoceptor agonist on the micromotion of bilateral major pelvic ganglion-excised rat bladder. Neurourol Urodyn 2023; 42:530-538. [PMID: 36633527 DOI: 10.1002/nau.25127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/14/2022] [Accepted: 12/20/2022] [Indexed: 01/13/2023]
Abstract
AIMS Micromotion is an autonomous intramural movement of the bladder, and is believed to be an initial step in the generation of urinary urgency. Therefore, controlling micromotion may be a novel target in overactive bladder (OAB) treatment. However, developing micromotion treatment has been limited by the absence of a standardized animal model. We attempted to create a micromotion animal model and investigated the effectiveness of a β3 -adrenoceptor agonist (CL316,243) on micromotion. METHODS Bilateral major pelvic ganglia (MPGs) were excised in 18 male Sprague-Dawley rats, resulting in an almost completely denervated bladder. On postoperative Day 7, cystometry was performed. Rats were divided into three treatment groups: CL316,243; β3- adrenoceptor antagonist (SR59230A) pretreated CL316,243; and a nonselective antimuscarinic agent (oxybutynin). Changes in micromotion were evaluated after the intra-arterial administration of each agent. RESULTS Low-amplitude oscillations in intravesical pressure (micromotion) were observed 1 week after MPGs excision. Micromotion frequency significantly (p = 0.003) decreased (2.17 ± 3.54 times/5 min) with CL316,243 compared with vehicle (6.33 ± 1.97 times/5 min). Micromotion amplitude also decreased with CL316,243 (1.15 ± 1.93 cmH2 O) compared with vehicle (5.96 ± 5.12 cmH2 O), approaching conventional significance (p = 0.090). No significant decreases in frequency or amplitude were observed with oxybutynin treatment. CONCLUSIONS Systemic administration of the β3 -adrenoceptor agonist CL316,243 effectively controlled micromotion in bilateral MPGs-excised, almost completely denervated rat bladders. This result indicates that β3 -adrenoceptor agonist may affect the bladder directly, suggesting that it might be effective for overall OAB, regardless of the presence or level of neurological deficits. Bilateral MPGs-excised rats are considered a plausible micromotion animal model suitable for future research.
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Affiliation(s)
- Hee Seo Son
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | - Soo Young Moon
- Biomedical Research Center, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - Joonbeom Kwon
- Department of Urology, Daegu Fatima Hospital, Daegu, Republic of Korea
| | - Jang Hwan Kim
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
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8
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Abe-Takahashi Y, Kitta T, Ouchi M, Chiba H, Higuchi M, Togo M, Shinohara N. Evaluation of pelvic floor muscle elasticity in patients with overactive bladder syndrome using real-time tissue elastography. Eur J Obstet Gynecol Reprod Biol 2022; 276:9-13. [DOI: 10.1016/j.ejogrb.2022.06.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 05/12/2022] [Accepted: 06/26/2022] [Indexed: 11/28/2022]
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9
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吉田 正. [Management for lower urinary tract dysfunction in the elderly according to guidelines]. Nihon Ronen Igakkai Zasshi 2022; 59:115-130. [PMID: 35650043 DOI: 10.3143/geriatrics.59.115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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10
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Maddra KM, Li R, Nagle AS, Klausner AP, Speich JE. Repeatability of Ultrasound-Defined Bladder Shape Metrics in Healthy Volunteers. Res Rep Urol 2022; 14:185-192. [PMID: 35572816 PMCID: PMC9091689 DOI: 10.2147/rru.s351347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 04/16/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Patients and Methods Results Conclusion
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Affiliation(s)
- Kaitlyn M Maddra
- Department of Surgery/Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Rui Li
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University College of Engineering, Richmond, VA, USA
| | - Anna S Nagle
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University College of Engineering, Richmond, VA, USA
| | - Adam P Klausner
- Department of Surgery/Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - John E Speich
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University College of Engineering, Richmond, VA, USA
- Correspondence: John E Speich, Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University College of Engineering, Richmond, VA, USA, Tel +1 804 827 7036, Fax +1 804 827 7030, Email
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11
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Huang R, Tamalunas A, Waidelich R, Strittmatter F, Stief CG, Hennenberg M. Inhibition of Full Smooth Muscle Contraction in Isolated Human Detrusor Tissues by Mirabegron Is Limited to Off-Target Inhibition of Neurogenic Contractions. J Pharmacol Exp Ther 2022; 381:176-187. [PMID: 35153197 DOI: 10.1124/jpet.121.001029] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/08/2022] [Indexed: 03/08/2025] Open
Abstract
Mirabegron is used for treatment of storage symptoms in overactive bladder (OAB) caused by spontaneous bladder smooth muscle contractions. However, owing to limitations in available studies using human tissues, central questions are still unresolved, including mechanisms underlying improvements by mirabegron and its anticontractile effects in the detrusor. Here, we assessed concentration-dependent mirabegron effects on contractions of human detrusor tissues in frequency-response curves and concentration-response curves for different cholinergic and noncholinergic agonists. Detrusor tissues were sampled from patients undergoing radical cystectomy. Contractions were induced by electric field stimulation (EFS) and by cumulative concentrations of cholinergic agonists, endothelin-1, and the thromboxane A2 analog U46619. EFS-induced contractions were inhibited using 10 µM mirabegron, but not using 1 µM. Inhibition by 10 µM mirabegron was resistant to the β 3-adrenergic antagonist L-748,337. Concentration-dependent contractions by carbachol were not inhibited by 1 µM or 10 µM mirabegron. Concentration-response curves for methacholine were slightly right-shifted by 10 µM, but not 1 µM mirabegron. Concentration-dependent contractions by endothelin-1 or U46619 were not changed by mirabegron. In contrast, the muscarinic antagonist tolterodine right-shifted concentration-response curves for carbachol and methacholine and inhibited EFS-induced contractions. In conclusion, inhibition of neurogenic contractions in isolated detrusor tissues by mirabegron requires concentrations highly exceeding known plasma levels during standard dosing and the known binding constant (Ki values) for β 3-adrenoceptors. Full contractions by cholinergic agonists, endothelin-1, and U46619 are not affected by therapeutic concentrations of mirabegron. Improvements of storage symptoms are most likely not imparted by inhibition of β 3-adrenoceptors in the bladder wall itself. SIGNIFICANCE STATEMENT: Mirabegron is used for overactive bladder (OAB) treatment, but the underlying mechanisms are unclear, and preclinical and clinical findings are controversial due to limitations in available studies. Our findings suggest that inhibition of detrusor contractions by mirabegron is limited to neurogenic contractions, which requires unphysiologic concentrations and does not involve β 3-adrenoceptors. Mechanisms accounting for improvements of OAB by mirabegron are located outside the urinary bladder.
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MESH Headings
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/metabolism
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/therapeutic use
- Acetanilides
- Carbachol/pharmacology
- Endothelin-1/pharmacology
- Female
- Humans
- Male
- Methacholine Chloride/metabolism
- Methacholine Chloride/pharmacology
- Methacholine Chloride/therapeutic use
- Muscle Contraction
- Muscle, Smooth
- Receptors, Adrenergic/metabolism
- Thiazoles
- Urinary Bladder, Overactive/drug therapy
- Urinary Bladder, Overactive/metabolism
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Affiliation(s)
- Ru Huang
- Department of Urology, University Hospital, LMU Munich, Munich, Germany
| | | | | | | | - Christian G Stief
- Department of Urology, University Hospital, LMU Munich, Munich, Germany
| | - Martin Hennenberg
- Department of Urology, University Hospital, LMU Munich, Munich, Germany
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12
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Aizawa N, Fujita T. The TRPM8 channel as a potential therapeutic target for bladder hypersensitive disorders. J Smooth Muscle Res 2022; 58:11-21. [PMID: 35354708 PMCID: PMC8961290 DOI: 10.1540/jsmr.58.11] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In the lower urinary tract, transient receptor potential (TRP) channels are primarily involved in physiological function, especially in cellular sensors responding to chemical and physical stimuli. Among TRP channels, TRP melastatin 8 (TRPM8) channels, responding to cold temperature and/or chemical agents, such as menthol or icilin, are mainly expressed in the nerve endings of the primary afferent neurons and in the cell bodies of dorsal root ganglia innervating the urinary bladder (via Aδ- and C-fibers); this suggests that TRPM8 channels primarily contribute to bladder sensory (afferent) function. Storage symptoms of overactive bladder, benign prostatic hyperplasia, and interstitial cystitis are commonly related to sensory function (bladder hypersensitivity); thus, TRPM8 channels may also contribute to the pathophysiology of bladder hypersensitivity. Indeed, it has been reported in a pharmacological investigation using rodents that TRPM8 channels contribute to the pathophysiological bladder afferent hypersensitivity of mechanosensitive C-fibers. Similar findings have also been reported in humans. Therefore, a TRPM8 antagonist would be a promising therapeutic target for bladder hypersensitive disorders, including urinary urgency or nociceptive pain. In this review article, the functional role of the TRPM8 channel in the lower urinary tract and the potential of its antagonist for the treatment of bladder disorders was described.
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Affiliation(s)
- Naoki Aizawa
- Department of Pharmacology and Toxicology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
| | - Tomoe Fujita
- Department of Pharmacology and Toxicology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
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13
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Zargham M, Hajian MR, Alizadeh F, Eslami MJ, Khalili Boroujeni N, Gholipour F. Hypothyroidism is prevalent among adult women with chronic lower urinary tract symptoms. Low Urin Tract Symptoms 2022; 14:248-254. [PMID: 35224856 DOI: 10.1111/luts.12428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/03/2022] [Accepted: 01/18/2022] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To define the prevalence of hypothyroidism in women with chronic lower urinary tract symptoms (LUTS) and to compare the severity of each symptom between patients with hypothyroidism and controls. SUBJECTS AND METHODS In this prospective observational study, we screened all adult women who came to the urology clinic between March 2017 and September 2020, and enrolled patients with chronic LUTS in the study. We assessed thyroid function. We evaluated the severity of voiding and storage urinary symptoms by the International Prostate Symptom Score. We also assessed the severity of urge urinary incontinence (UUI) and stress urinary incontinence (SUI). For between-group analysis, we selected age-matched cases and controls and compared them regarding the distribution and severity of urinary symptoms. RESULTS Seven hundred and twenty-five women with a mean age of 51.7 ± 14.0 years were included in the final analysis. Two hundred fifty-eight patients (35.6%) had hypothyroidism. Age-matched case and control groups consisting of 210 patients each were selected. There was no significant difference in the severity and distribution of voiding LUTS and UUI between the study groups (P values >0.05). The severity of storage symptoms was lower in patients with hypothyroidism (P = 0.04). Sixty-seven patients with hypothyroidism (31.9%) had SUI, which was significantly higher than controls (23.3%) (P = 0.03). CONCLUSION More than one-third of women with chronic LUTS have hypothyroidism which is much more frequent than in the general population. We also suggest a possible relationship between hypothyroidism and the severity of SUI and an inverse relationship between hypothyroidism and storage symptoms.
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Affiliation(s)
- Mahtab Zargham
- Department of Urology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Reza Hajian
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Alizadeh
- Department of Urology, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Noushin Khalili Boroujeni
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farshad Gholipour
- Isfahan Kidney Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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14
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Aizawa N. [Pathophysiology and pharmacotherapy of benign prostatic disorders]. Nihon Yakurigaku Zasshi 2022; 157:164-167. [PMID: 35491110 DOI: 10.1254/fpj.21103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Men with benign prostatic hyperplasia (BPH) often experience symptoms of overactive bladder (OAB), and bladder outlet obstruction (BOO) is one of cause of BPH. It has been suggested that bladder myogenic microcontractions or micromotions may partly contribute to the development of urgency (bladder sensory (afferent) hypersensitivity) in OAB related to BOO. We have investigated the direct effects of drugs (β3-adrenoceptor agonists, α1-adrenoceptor antagonists, PDE type5 inhibitors) on the bladder afferent function in BOO rats. In our results, almost all drugs may act on the bladder afferent function, and mirabegron inhibits the afferent activities through the suppression of the bladder myogenic microcontractions in BOO condition. Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) causes long-standing pain and/or storage symptoms including storage symptoms, such as urgency and frequency. We evaluated the likelihood of deterioration of bladder sensation in a carrageenan-induced CP/CPPS model. In results, the carrageenan-induced CP/CPPS rat model showed edema, ischemia, and inflammatory pain in the prostate, whereas a little change was detected in bladder sensation. These findings demonstrated that the bladder sensation is unlikely deteriorated in this model, suggesting CP/CPPS is possibly overlapping with symptoms in BPH.
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Affiliation(s)
- Naoki Aizawa
- Department of Pharmacology and Toxicology, Dokkyo medical university
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15
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Ravishankar B, Vasdev RMS, Timm GW, Nelson DE. Measurement and Quantification of Cystometric Bladder Pressure Spectra in an in-vivo Sheep Model: A Feasibility Study. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2021; 2021:5005-5010. [PMID: 34892331 DOI: 10.1109/embc46164.2021.9630641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Cystometry is a standard procedure for the clinical evaluation of lower urinary tract disorders such as detrusor overactivity (DO). The utility of this procedure for DO diagnosis, however, is limited by the use of physician observations of bladder contractions and patient reported filling sensations. Although a number of preclinical and clinical studies have observed and developed methods to characterize bladder pressure dynamics, these techniques have not been scaled for routine clinical application. The goal of this study was to evaluate the feasibility of using an awake large animal model to characterize bladder pressure signals from cystometry as bladder pressure spectra and quantify changes in spectra during bladder filling. Two adult female sheep were trained for quiet catheterization in a minimally supportive sling and underwent multiple awake and limited anesthetized cystometry tests. In each test, bladder pressure was measured during continuous filling or with filling that included periods of no filling (constant volume). A Fast-Fourier Transform (FFT)-based algorithm was then used to quantify changes in pre-voiding bladder pressure spectra. Changes in Spectral Power (SP) and Weighted Average Frequency (WAF) were calculated during filling. To visualize temporal changes in bladder pressure frequencies during filling, Continuous Wavelet Transform (CWT) was also applied to cystometry data. Results showed that a significant increase in SP and decrease in WAF were both associated with bladder filling. However, during awake constant volume tests, SP significantly increased while changes in WAF were nonsignificant. Anesthetized tests demonstrated comparable values to awake tests for WAF while SP was considerably reduced. CWT facilitated visualization of spectral changes associated with SP and WAF as well as apparent non-voiding contractions during awake and anesthetized volume tests.Clinical Relevance-Bladder pressure spectra during cystometry are detectable in sheep and the changes during filling are similar to those observed in human retrospective clinical data. Sheep cystometry may be a valuable testbed for establishing and testing quantitative pressure spectra for use as a clinical diagnostic tool.
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16
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Fry CH, Chakrabarty B, Hashitani H, Andersson KE, McCloskey K, Jabr RI, Drake MJ. New targets for overactive bladder-ICI-RS 2109. Neurourol Urodyn 2020; 39 Suppl 3:S113-S121. [PMID: 31737931 PMCID: PMC8114459 DOI: 10.1002/nau.24228] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 10/31/2019] [Indexed: 12/16/2022]
Abstract
AIM To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms. METHODS A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB. RESULTS Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide-dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for β3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1 , TRPV4 , TRPA1 , and TRPM4 ) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+ -activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-β pathway-the canonical fibrosis pathway. CONCLUSIONS The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor.
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Affiliation(s)
- Christopher Henry Fry
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Basu Chakrabarty
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Hikaru Hashitani
- Department of Cell Physiology, Nagoya City University, Nagoya, Japan
| | - Karl-Erik Andersson
- Institute of Laboratory Medicine, Lund University, Lund, Sweden
- Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Karen McCloskey
- School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Belfast, UK
| | - Rita I. Jabr
- Division of Biochemical Sciences, Faculty of Health and Biomedical Sciences, University of Surrey, Guildford, UK
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17
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Ke QS, Lee CL, Kuo HC. Recurrent urinary tract infection in women and overactive bladder - Is there a relationship? Tzu Chi Med J 2020; 33:13-21. [PMID: 33505873 PMCID: PMC7821830 DOI: 10.4103/tcmj.tcmj_38_20] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/02/2020] [Accepted: 04/08/2020] [Indexed: 02/06/2023] Open
Abstract
Overactive bladder (OAB) in women has similar symptomatology with other common urologic diseases such as recurrent urinary tract infection (UTI). Recent evidence showed that chronic low-grade bacterial bladder colonization might exacerbate OAB symptoms and could be the etiology of recurrent UTI. The high prevalence of lower urinary tract dysfunction is associated with OAB. Women with urgency urinary incontinence refractory to antimuscarinic therapy had more bacteria and a more diverse urinary microbiome. The bacterial reside in the superficial urothelial cells to form intracellular bacterial community and outbreak when the host innate immunity is low. Women with recurrent UTI are found to have highly prevalent voiding dysfunction and detrusor overactivity. These functional abnormalities will further damage the urothelial barrier integrity and create vulnerable to uropathogen invasion. The defective urinary microbiota is less common in women with recurrent UTI, suggesting that the normal flora in the urine might inhibit uropathogen growth and invasion. The defective urothelial barrier function, deficient basal proliferation, and deficient maturation might be owing to chronic suburothelial inflammation, resulting in activation of sensory nerves (causing OAB) and failure elimination of intracellular bacterial communities (causing recurrent UTI). Precision diagnosis and multidisciplinary treatment of the underlying pathophysiology of OAB and recurrent UTI is necessary.
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Affiliation(s)
- Qian-Sheng Ke
- Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Cheng-Ling Lee
- Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Hann-Chorng Kuo
- Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
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18
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Tantin A, Bou Assi E, van Asselt E, Hached S, Sawan M. Predicting urinary bladder voiding by means of a linear discriminant analysis: Validation in rats. Biomed Signal Process Control 2020. [DOI: 10.1016/j.bspc.2019.101667] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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19
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Cullingsworth ZE, Klausner AP, Li R, Nagle AS, Carroll AW, Roseman JT, Speich JE. Comparative-fill urodynamics in individuals with and without detrusor overactivity supports a conceptual model for dynamic elasticity regulation. Neurourol Urodyn 2019; 39:707-714. [PMID: 31856359 DOI: 10.1002/nau.24255] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 12/06/2019] [Indexed: 12/17/2022]
Abstract
AIMS Dynamic elasticity was previously identified in individuals with overactive bladder (OAB) using comparative-fill urodynamics (UD) and is a biomechanical mechanism for acutely regulating detrusor wall tension. On the basis of this data, a conceptual model of dynamic elasticity regulation mediated through a balance of passive mechanisms and active contractions was constructed. The present study tested this model by determining whether individuals with detrusor overactivity (DO) exhibit less dynamic elasticity than individuals without DO. METHODS Individuals with and without urgency based on International Consultation on Incontinence Questionnaire-OAB surveys were prospectively enrolled in a comparative-fill UD study. An initial fill defined the presence or absence of DO and determined cystometric capacity. Three additional fills were employed with either passive emptying via a catheter or active voiding. To identify dynamic elasticity, average filling pressures (Pves ) were compared for fill 1 (before strain softening), fill 2 (after strain softening), and fill 3 (after active void). A dynamic elasticity index was defined. RESULTS From 28 participants, those without DO showed decreased Pves during filling after strain softening and restored Pves during filling following active voiding, revealing dynamic elasticity. Participants with DO did not show dynamic elasticity. A dynamic elasticity index less than 1.0 cmH2 O/40% capacity was identified in 2 out of 13 participants without DO and 9 out of 15 with DO, revealing a significant association between DO and reduced/absent dynamic elasticity (P = .024). CONCLUSIONS This study supports a conceptual model for dynamic elasticity, a mechanism to acutely regulate detrusor wall tension through a balance of competing active contractile and passive strain mechanisms. Improved understanding of this mechanistic model may help us to identify novel treatment strategies for OAB.
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Affiliation(s)
- Zachary E Cullingsworth
- Department of Mechanical and Nuclear Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia
| | - Adam P Klausner
- Division of Urology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Rui Li
- Department of Mechanical and Nuclear Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia
| | - Anna S Nagle
- Department of Mechanical and Nuclear Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia
| | - Ashley W Carroll
- Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - John T Roseman
- Division of Urology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - John E Speich
- Department of Mechanical and Nuclear Engineering, College of Engineering, Virginia Commonwealth University, Richmond, Virginia
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20
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Aizawa N. [Afferent nerve activity in relation to bladder sensation]. Nihon Yakurigaku Zasshi 2019; 154:255-258. [PMID: 31735754 DOI: 10.1254/fpj.154.255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Bladder afferent nerves are composed by myelinated Aδ- and unmyelinated C-fibers. During the storage phase of urine, distention of the bladder has long been considered to evoke afferent activity via Aδ-fibers connected in series with the smooth muscle fibers. In contrast, a previous study in cats revealed that more than 90% of C-fibers do not respond to normal bladder distension, being so called 〝silent〟 fibers. However, at least in rats, C-fibers can respond to normal bladder distension like Aδ-fibers, although they may also fulfill a potentially different role in the bladder sensory function in response to abnormal stimuli. The symptoms of overactive bladder (OAB) or interstitial cystitis (IC) are believed to be commonly related to the sensory (afferent) function. In addition, it has been suggested that bladder myogenic microcontractions or micromotions may partly contribute to the development of urgency in OAB related to bladder outlet obstruction (BOO), which is one of cause of benign prostatic hyperplasia (BPH). We have investigated the direct effects of drugs (anticholinergics, β3-adrenoceptor agonists, α1-adrenoceptor antagonists, PDE type5 inhibitors, etc.) on the bladder afferent function in rodents. In our results, almost all drugs may act on the bladder afferent function, and some of drug (e.g. mirabegron) inhibits the afferent activities through the suppression of the bladder myogenic microcontractions in normal or pathophysiological conditions.
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Affiliation(s)
- Naoki Aizawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine.,Present address: Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine
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21
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Mitsui R, Lee K, Uchiyama A, Hayakawa S, Kinoshita F, Kajioka S, Eto M, Hashitani H. Contractile elements and their sympathetic regulations in the pig urinary bladder: a species and regional comparative study. Cell Tissue Res 2019; 379:373-387. [PMID: 31446446 DOI: 10.1007/s00441-019-03088-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 08/05/2019] [Indexed: 12/18/2022]
Abstract
Contractile behaviour of the urinary bladder and its sympathetic inhibition during storage phases are not well understood. Here, we explore muscularis mucosae (MM) as a predominant mucosal contractile element and the capability of sympathetic nerves to relax detrusor smooth muscle (DSM) or MM. Distribution of α-smooth muscle actin (α-SMA)-immunoreactive cells was compared in pig, human, guinea pig, rat and mouse bladders by immunohistochemistry, while contractility of the bladder mucosa was compared in these species by isometric tension recordings. In pig, human and guinea pig bladders, DSM and MM located in the lamina propria expressed α-SMA immunoreactivity, while both rat and mouse bladders lacked a MM. Consistent with this presence or absence of MM, bladder mucosa of pig, human and guinea pig but not rat and mouse developed spontaneous phasic contractions (SPCs). Distribution of tyrosine hydroxylase (TH)-immunoreactive sympathetic nerve fibres was compared in pig DSM, MM, trigone and urethra, as were their sympathetic nerve-evoked contractile/relaxing responses examined. In pig DSM or MM, where TH-immunoreactive sympathetic fibres exclusively projected to the vasculature, sympathetic relaxations were difficult to demonstrate. In contrast, sympathetic contractions were invariably evoked in pig trigone and urethra where the smooth muscle cells receive TH-immunoreactive sympathetic innervations. Thus, SPCs of bladder mucosa appear to predominantly arise from the MM displaying species differences. Despite the currently accepted concept of sympathetic nerve-mediated DSM relaxation during the storage phase, it is unlikely that neurally released noradrenaline acts on β-adrenoceptors to relax either DSM or MM due to the anatomical lack of sympathetic innervation.
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Affiliation(s)
- Retsu Mitsui
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan.
| | - Ken Lee
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Aoi Uchiyama
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan
| | - Shunta Hayakawa
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan
| | - Fumio Kinoshita
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shunichi Kajioka
- Department of Applied Urology and Molecular Medicine, Kyushu University, Fukuoka, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hikaru Hashitani
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan
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22
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Fry CH, McCloskey KD. Spontaneous Activity and the Urinary Bladder. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1124:121-147. [PMID: 31183825 DOI: 10.1007/978-981-13-5895-1_5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The urinary bladder has two functions: to store urine, when it is relaxed and highly compliant; and void its contents, when intravesical pressure rises due to co-ordinated contraction of detrusor smooth muscle in the bladder wall. Superimposed on this description are two observations: (1) the normal, relaxed bladder develops small transient increases of intravesical pressure, mirrored by local bladder wall movements; (2) pathological, larger pressure variations (detrusor overactivity) can occur that may cause involuntary urine loss and/or detrusor overactivity. Characterisation of these spontaneous contractions is important to understand: how normal bladder compliance is maintained during filling; and the pathophysiology of detrusor overactivity. Consideration of how spontaneous contractions originate should include the structural complexity of the bladder wall. Detrusor smooth muscle layer is overlain by a mucosa, itself a complex structure of urothelium and a lamina propria containing sensory nerves, micro-vasculature, interstitial cells and diffuse muscular elements.Several theories, not mutually exclusive, have been advanced for the origin of spontaneous contractions. These include intrinsic rhythmicity of detrusor muscle; modulation by non-muscular pacemaking cells in the bladder wall; motor input to detrusor by autonomic nerves; regulation of detrusor muscle excitability and contractility by the adjacent mucosa and spontaneous contraction of elements of the lamina propria. This chapter will consider evidence for each theory in both normal and overactive bladder and how their significance may vary during ageing and development. Further understanding of these mechanisms may also identify novel drug targets to ameliorate the clinical consequences of large contractions associated with detrusor overactivity.
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Affiliation(s)
- Christopher H Fry
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.
| | - Karen D McCloskey
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
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Swavely NR, Speich JE, Stothers L, Klausner AP. New Diagnostics for Male Lower Urinary Tract Symptoms. CURRENT BLADDER DYSFUNCTION REPORTS 2019; 14:90-97. [PMID: 31938079 PMCID: PMC6959483 DOI: 10.1007/s11884-019-00511-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Lower urinary tract symptoms (LUTS) is a common constellation of symptoms that affect the aging male population with an astonishing prevalence. New technology and new uses of established technology are being used to help further evaluate LUTS in the male population and help guide treatment options. This review focuses on the developments and future directions in diagnostic modalities for evaluation of male LUTS, focusing on evaluation of both the filling and voiding phases of micturition. RECENT FINDINGS New techniques in evaluating the voiding phase include penile cuff test, external pressure sensing condom catheter, ultrasound measurement of detrusor wall thickness, ultrasound measurement of intravesical prostatic protrusion, doppler ultrasound and NIRS technology. Evaluation of the filling phase is still undergoing much development and requires additional validation studies. The techniques undergoing evaluation include sensation meters during UDS, assessing bladder micromotion and wall rhythm, assessing detrusor wall biomechanics, ultrasound measurement of detrusor wall thickness, pelvic doppler ultrasound, as well as functional brain imaging including fNIRS and fMRI. SUMMARY The development of novel, non-invasive, diagnostic tools have the potential for better evaluation of LUTS with earlier and enhanced treatments. This will likely improve the quality of life for men with LUTS.
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Affiliation(s)
- Natalie R Swavely
- Department of Surgery/Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - John E Speich
- Department of Mechanical & Nuclear Engineering, Virginia Commonwealth University College of Engineering, Richmond, VA
| | - Lynn Stothers
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Adam P Klausner
- Department of Surgery/Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA
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Igawa Y, Aizawa N, Michel MC. β 3 -Adrenoceptors in the normal and diseased urinary bladder-What are the open questions? Br J Pharmacol 2019; 176:2525-2538. [PMID: 30868554 DOI: 10.1111/bph.14658] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/31/2018] [Accepted: 01/29/2019] [Indexed: 12/13/2022] Open
Abstract
β3 -Adrenoceptor agonists are used in the treatment of overactive bladder syndrome. Although the relaxant response to adrenergic stimulation in human detrusor smooth muscle cells is mediated mainly via β3 -adrenoceptors, the plasma concentrations of the therapeutic dose of mirabegron, the only clinically approved β3 -adrenoceptor agonist, are considerably lower than the EC50 for causing direct relaxation of human detrusor, suggesting a mechanism of action other than direct relaxation of detrusor smooth muscle. However, the site and mechanism of action of β3 -adrenoceptor agonists in the bladder have not been firmly established. Postulated mechanisms include prejunctional suppression of ACh release from the parasympathetic nerves during the storage phase and inhibition of micro-contractions through β3 -adrenoceptors on detrusor smooth muscle cells or suburothelial interstitial cells. Implications of possible desensitization of β3 -adrenoceptors in the bladder upon prolonged agonist exposure and possible causes of rarely observed cardiovascular effects of mirabegron are also discussed. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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Affiliation(s)
- Yasuhiko Igawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Naoki Aizawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Martin C Michel
- Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany
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Use of Ultrasound Urodynamics to Identify Differences in Bladder Shape Between Individuals With and Without Overactive Bladder. Female Pelvic Med Reconstr Surg 2018; 26:635-639. [PMID: 30256268 DOI: 10.1097/spv.0000000000000638] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVES The objective of this study was to identify differences in bladder shape changes between individuals with overactive bladder (OAB) and unaffected individuals during ultrasound urodynamics. METHODS A prospective urodynamic study was performed with concurrent transabdominal ultrasound (ultrasound urodynamics) on individuals with and without OAB based on validated International Consultation on Incontinence Questionnaire - OAB survey scores. Three-dimensional ultrasound images were acquired at 1-minute increments during filling and used to measure bladder diameters in the height, width, and depth orientations. The engineering strain for each diameter was compared between participants with OAB and controls during urodynamic filling. The height-to-width ratio at capacity was used to determine if individuals were shape outliers. RESULTS A total of 22 subjects were enrolled, including 11 with OAB and 11 without OAB. During urodynamic filling in both groups, the greatest degree of geometric strain was found in the height orientation, indicating that bladders generally fill in a craniocaudal shape. The mean ± SD height-to-width ratio of the control group was 1.06 ± 0.12 yielding a 95% confidence interval of 0.82 to 1.30. Five (45.5%) of 11 OAB subjects had height-to-width ratios outside this interval as compared with none of the control subjects, identifying a potential shape-mediated subgroup of OAB. CONCLUSIONS Three-dimensional ultrasound urodynamics can be used to identify differences in bladder shape comparing individuals with and without OAB. This method may be used to identify a subset of OAB patients with abnormal bladder shapes which may play a role in the pathophysiology of their OAB symptoms.
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Cullingsworth ZE, Kelly BB, Deebel NA, Colhoun AF, Nagle AS, Klausner AP, Speich JE. Automated quantification of low amplitude rhythmic contractions (LARC) during real-world urodynamics identifies a potential detrusor overactivity subgroup. PLoS One 2018; 13:e0201594. [PMID: 30110353 PMCID: PMC6093663 DOI: 10.1371/journal.pone.0201594] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 07/18/2018] [Indexed: 11/23/2022] Open
Abstract
Objectives Detrusor overactivity (DO) is characterized by non-voiding detrusor smooth muscle contractions during the bladder filling phase and often contributes to overactive bladder. In some patients DO is observed as isolated or sporadic contractions, while in others DO is manifested as low amplitude rhythmic contractions (LARC). The aim of this study was to develop an objective method to quantify LARC frequencies and amplitudes in urodynamic studies (UDS) and identify a subgroup DO of patients with LARC. Methods An automated Fast Fourier Transform (FFT) algorithm was developed to analyze a 205-second region of interest of retrospectively collected “real-world” UDS ending 30 seconds before voiding. The algorithm was designed to identify the three largest rhythmic amplitude peaks in vesical pressure (Pves) in the 1.75–6 cycle/minute frequency range. These peak Pves amplitudes were analyzed to determine whether they were 1) significant (above baseline Pves activity) and 2) independent (distinct from any in abdominal pressure (Pabd) rhythm). Results 95 UDS met criteria for inclusion and were analyzed with the FFT algorithm. During a blinded visual analysis, a neurourologist/urodynamicist identified 52/95 (55%) patients as having DO. The FFT algorithm identified significant and independent (S&I) LARC in 14/52 (27%) patients with DO and 0/43 patients (0%) without DO, resulting in 100% specificity and a significant association (Fischer’s exact test, p<0.0001). The average slowest S&I LARC frequency in this DO subgroup was 3.20±0.34 cycles/min with an amplitude of 8.40±1.30 cm-H2O. This algorithm can analyze individual UDS in under 5 seconds, allowing real-time interpretation. Conclusions An FFT algorithm can be applied to “real-world” UDS to automatically characterize the frequency and amplitude of underlying LARC. This algorithm identified a potential subgroup of DO patients with LARC.
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Affiliation(s)
- Zachary E. Cullingsworth
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University School of Engineering, Richmond, Virginia, United States of America
| | - Brooks B. Kelly
- Department of Surgery/Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Nicholas A. Deebel
- Department of Surgery/Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Andrew F. Colhoun
- Department of Surgery/Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
| | - Anna S. Nagle
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University School of Engineering, Richmond, Virginia, United States of America
| | - Adam P. Klausner
- Department of Surgery/Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
- Department of Surgery/Division of Urology Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States of America
| | - John E. Speich
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University School of Engineering, Richmond, Virginia, United States of America
- * E-mail:
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Malde S, Fry C, Schurch B, Marcelissen T, Averbeck M, Digesu A, Sahai A. What is the exact working mechanism of botulinum toxin A and sacral nerve stimulation in the treatment of overactive bladder/detrusor overactivity? ICI-RS 2017. Neurourol Urodyn 2018; 37:S108-S116. [DOI: 10.1002/nau.23552] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 02/19/2018] [Indexed: 11/09/2022]
Affiliation(s)
- Sachin Malde
- Department of Urology; Guy's Hospital; London United Kingdom
| | - Christopher Fry
- School of Physiology, Pharmacology & Neuroscience; University of Bristol; Bristol United Kingdom
| | - Brigitte Schurch
- Department of Clinical Neurosciences; Neuropsychology and Neurorehabilitation Service Vaudois University Hospital of Lausanne; Switzerland
| | - Tom Marcelissen
- Department of Urology; Maastricht University Medical Centre; Netherlands
| | | | - Alex Digesu
- Department of Urogynaecology; St. Mary's Hospital; United Kingdom
| | - Arun Sahai
- Department of Urology; Guy's Hospital; London United Kingdom
- King's College London; King's Health Partners; United Kingdom
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Muscarinic receptor-induced contractions of the detrusor are impaired in TRPC4 deficient mice. Sci Rep 2018; 8:9264. [PMID: 29915209 PMCID: PMC6006323 DOI: 10.1038/s41598-018-27617-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 06/06/2018] [Indexed: 01/25/2023] Open
Abstract
Acetylcholine contracts the bladder by binding to muscarinic M3 receptors on the detrusor, leading to Ca2+ influx via voltage-gated Ca2+ channels. The cellular mechanisms linking these events are poorly understood, but studies have suggested that activation of TRPC4 channels could be involved. The purpose of this study was to investigate if spontaneous and cholinergic-mediated contractions of the detrusor were impaired in TRPC4 deficient (TRPC4−/−) mice. Isometric tension recordings were made from strips of wild-type (WT) and TRPC4−/− detrusor. Spontaneous phasic detrusor contractions were significantly smaller in TRPC4−/− mice compared to wild-type, however no difference in response to exogenous application of 60 mM KCl was observed. Cholinergic responses, induced by electric-field stimulation (EFS), bath application of the cholinergic agonist carbachol, or the acetylcholinesterase inhibitor neostigmine were all significantly smaller in TRPC4−/− detrusor strips than wild-type. Surprisingly, the TRPC4/5 inhibitor ML204 reduced EFS and CCh-evoked contractions in TRPC4−/− detrusor strips. However, TRPC5 expression was up-regulated in these preparations and, in contrast to wild-type, EFS responses were reduced in amplitude by the TRPC5 channel inhibitor clemizole hydrochloride. This study demonstrates that TRPC4 channels are involved in spontaneous and cholinergic-mediated contractions of the murine detrusor. TRPC5 expression is up-regulated in TRPC4−/− detrusor strips, and may partially compensate for loss of TRPC4 channels.
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Grundy L, Chess-Williams R, Brierley SM, Mills K, Moore KH, Mansfield K, Rose'Meyer R, Sellers D, Grundy D. NKA enhances bladder-afferent mechanosensitivity via urothelial and detrusor activation. Am J Physiol Renal Physiol 2018; 315:F1174-F1185. [PMID: 29897284 DOI: 10.1152/ajprenal.00106.2018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Tachykinins are expressed within bladder-innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium or sensory afferents directly. Here, we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signaling from the bladder during distension, urothelial transmitter release ex vivo, and direct responses to neurokinin A (NKA) on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder-afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100 nM). Intravesical NKA significantly decreased bladder compliance but had no direct effect on mechanosensitivity to bladder distension (30 µl/min). GR159897 alone enhanced bladder compliance but had no effect on mechanosensation. Intravesical NKA enhanced both the amplitude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, whereas acetylcholine levels were reduced. NKA-mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.
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Affiliation(s)
- Luke Grundy
- Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University , Gold Coast, Queensland , Australia.,Visceral Pain Research Group, Human Physiology, Centre for Neuroscience, College of Medicine and Public Health, Flinders University , Bedford Park, South Australia , Australia.,Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Russ Chess-Williams
- Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University , Gold Coast, Queensland , Australia
| | - Stuart M Brierley
- Visceral Pain Research Group, Human Physiology, Centre for Neuroscience, College of Medicine and Public Health, Flinders University , Bedford Park, South Australia , Australia.,Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Kylie Mills
- Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University , Gold Coast, Queensland , Australia
| | - Kate H Moore
- Department of Urogynaecology, St. George Hospital, University of New South Wales , Sydney, New South Wales , Australia
| | - Kylie Mansfield
- Graduate School of Medicine, University of Wollongong , Wollongong, New South Wales , Australia
| | | | - Donna Sellers
- Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University , Gold Coast, Queensland , Australia
| | - David Grundy
- Department of Biomedical Science, University of Sheffield , Sheffield , United Kingdom
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Choudhary M, van Mastrigt R, van Asselt E. The frequency spectrum of bladder non-voiding activity as a trigger-event for conditional stimulation: Closed-loop inhibition of bladder contractions in rats. Neurourol Urodyn 2018; 37:1567-1573. [DOI: 10.1002/nau.23504] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 12/27/2017] [Indexed: 11/06/2022]
Affiliation(s)
- Mahipal Choudhary
- Department of Urology; Sector FURORE; Erasmus MC; Rotterdam The Netherlands
| | - Ron van Mastrigt
- Department of Urology; Sector FURORE; Erasmus MC; Rotterdam The Netherlands
| | - Els van Asselt
- Department of Urology; Sector FURORE; Erasmus MC; Rotterdam The Netherlands
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Aizawa N, Watanabe D, Fukuhara H, Fujimura T, Kume H, Homma Y, Igawa Y. Inhibitory effects of silodosin on the bladder mechanosensitive afferent activities and their relation with bladder myogenic contractions in male rats with bladder outlet obstruction. Neurourol Urodyn 2018; 37:1897-1903. [DOI: 10.1002/nau.23547] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 02/06/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Naoki Aizawa
- Department of Continence Medicine; The University of Tokyo Graduate School of Medicine; Tokyo Japan
| | - Daiji Watanabe
- Department of Continence Medicine; The University of Tokyo Graduate School of Medicine; Tokyo Japan
| | - Hiroshi Fukuhara
- Department of Urology; The University of Tokyo Graduate School of Medicine; Tokyo Japan
| | - Tetsuya Fujimura
- Department of Urology; The University of Tokyo Graduate School of Medicine; Tokyo Japan
| | - Haruki Kume
- Department of Urology; The University of Tokyo Graduate School of Medicine; Tokyo Japan
| | - Yukio Homma
- Department of Urology; The University of Tokyo Graduate School of Medicine; Tokyo Japan
| | - Yasuhiko Igawa
- Department of Continence Medicine; The University of Tokyo Graduate School of Medicine; Tokyo Japan
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Griffin CS, Bradley E, Hollywood MA, McHale NG, Thornbury KD, Sergeant GP. β3-adrenoceptor agonists inhibit carbachol-evoked Ca 2+ oscillations in murine detrusor myocytes. BJU Int 2018; 121:959-970. [PMID: 29211339 DOI: 10.1111/bju.14090] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To test if carbachol (CCh)-evoked Ca2+ oscillations in freshly isolated murine detrusor myocytes are affected by β3-adrenoceptor (β-AR) modulators. MATERIALS AND METHODS Isometric tension recordings were made from strips of murine detrusor, and intracellular Ca2+ measurements were made from isolated detrusor myocytes using confocal microscopy. Transcriptional expression of β-AR sub-types in detrusor strips and isolated detrusor myocytes was assessed using reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time quantitative PCR (qPCR). Immunocytochemistry experiments, using a β3-AR selective antibody, were performed to confirm that β3-ARs were present on detrusor myocytes. RESULTS The RT-PCR and qPCR experiments showed that β1-, β2- and β3-AR were expressed in murine detrusor, but that β3-ARs were the most abundant sub-type. The selective β3-AR agonist BRL37344 reduced the amplitude of CCh-induced contractions of detrusor smooth muscle. These responses were unaffected by addition of the BK channel blocker iberiotoxin. BRL37344 also reduced the amplitude of CCh-induced Ca2+ oscillations in freshly isolated murine detrusor myocytes. This effect was mimicked by CL316,243, another β3-AR agonist, and inhibited by the β3-AR antagonist L748,337, but not by propranolol, an antagonist of β1- and β2-ARs. BRL37344 did not affect caffeine-evoked Ca2+ transients or L-type Ca2+ current in isolated detrusor myocytes. CONCLUSION Inhibition of cholinergic-mediated contractions of the detrusor by β3-AR agonists was associated with a reduction in Ca2+ oscillations in detrusor myocytes.
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Affiliation(s)
- Caoimhin S Griffin
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Co Louth, Ireland
| | - Eamonn Bradley
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Co Louth, Ireland
| | - Mark A Hollywood
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Co Louth, Ireland
| | - Noel G McHale
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Co Louth, Ireland
| | - Keith D Thornbury
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Co Louth, Ireland
| | - Gerard P Sergeant
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Co Louth, Ireland
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Kuga N, Tanioka A, Hagihara K, Kawai T. Fiber type-specific afferent nerve activity induced by transient contractions of rat bladder smooth muscle in pathological states. PLoS One 2017; 12:e0189941. [PMID: 29267380 PMCID: PMC5739434 DOI: 10.1371/journal.pone.0189941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 11/18/2017] [Indexed: 11/20/2022] Open
Abstract
Bladder smooth muscle shows spontaneous phasic contractions, which undergo a variety of abnormal changes depending on pathological conditions. How abnormal contractions affect the activity of bladder afferent nerves remains to be fully tested. In this study, we examined the relationship between transient increases in bladder pressure, representing transient contraction of bladder smooth muscle, and spiking patterns of bladder afferent fibers of the L6 dorsal root, in rat pathological models. All recordings were performed at a bladder pressure of approximately 10 cmH2O by maintaining the degree of bladder filling. In the cyclophosphamide-induced model, both Aδ and C fibers showed increased sensitivity to transient bladder pressure increases. In the prostaglandin E2-induced model, Aδ fibers, but not C fibers, specifically showed overexcitation that was time-locked with transient bladder pressure increases. These fiber type-specific changes in nerve spike patterns may underlie the symptoms of urinary bladder diseases.
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Affiliation(s)
- Nahoko Kuga
- Pharmacology Research Laboratory, Watarase Research Center, Kyorin Pharmaceutical Company, Limited, Nogi, Tochigi, Japan
| | - Asao Tanioka
- Pharmacology Research Laboratory, Watarase Research Center, Kyorin Pharmaceutical Company, Limited, Nogi, Tochigi, Japan
| | - Koichiro Hagihara
- Pharmacology Research Laboratory, Watarase Research Center, Kyorin Pharmaceutical Company, Limited, Nogi, Tochigi, Japan
| | - Tomoyuki Kawai
- Pharmacology Research Laboratory, Watarase Research Center, Kyorin Pharmaceutical Company, Limited, Nogi, Tochigi, Japan
- * E-mail:
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Aizawa N, Igawa Y. Pathophysiology of the underactive bladder. Investig Clin Urol 2017; 58:S82-S89. [PMID: 29279880 PMCID: PMC5740034 DOI: 10.4111/icu.2017.58.s2.s82] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 08/22/2017] [Indexed: 01/05/2023] Open
Abstract
Underactive bladder (UAB), which has been described as a symptom complex suggestive of detrusor underactivity, is usually characterized by prolonged urination time with or without a sensation of incomplete bladder emptying, usually with hesitancy, reduced sensation on filling, and slow stream often with storage symptoms. Several causes such as aging, bladder outlet obstruction, diabetes mellitus, neurologic disorders, and nervous injury to the spinal cord, cauda equine, and peripheral pelvic nerve have been assumed to be responsible for the development of UAB. Several contributing factors have been suggested in the pathophysiology of UAB, including myogenic failure, efferent and/or afferent dysfunctions, and central nervous system dysfunction. In this review article, we have described relationships between individual contributing factors and the pathophysiology of UAB based on previous reports. However, many pathophysiological uncertainties still remain, which require more investigations using appropriate animal models.
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Affiliation(s)
- Naoki Aizawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Igawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Re: The Potential Role of Unregulated Autonomous Bladder Micromotions in Urinary Storage and Voiding Dysfunction; Overactive Bladder and Detrusor Underactivity. J Urol 2017; 198:490. [DOI: 10.1016/j.juro.2017.06.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Quantification of bladder wall biomechanics during urodynamics: A methodologic investigation using ultrasound. J Biomech 2017; 61:232-241. [PMID: 28835340 DOI: 10.1016/j.jbiomech.2017.07.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 06/20/2017] [Accepted: 07/22/2017] [Indexed: 01/22/2023]
Abstract
Overactive bladder is often characterized by biomechanical changes in the bladder wall, but there is no established method to measure these changes in vivo. The goal of this study was to develop a novel method to determine detrusor wall biomechanical parameters during urodynamics through the incorporation of transabdominal ultrasound imaging. Individuals with overactive bladder (OAB) underwent ultrasound imaging during filling. The fill rate was 10% of the cystometric capacity per minute as determined by an initial fill. Transabdominal ultrasound images were captured in the midsagittal and transverse planes at 1min intervals. Using image data and Pves, detrusor wall tension, stress, and compliance were calculated. From each cross-sectional image, luminal and wall areas along with inner perimeters were measured. In the sagittal and transverse planes, wall tension was calculated as Pves∗luminal area, wall stress as tension/wall area, and strain as the change in perimeter normalized to the perimeter at 10% capacity. Elastic modulus was calculated as stress/strain in the medial-lateral and cranial-caudal directions. Patient-reported fullness sensation was continuously recorded. Data from five individuals with OAB showed that detrusor wall tension, volume, and strain had the highest correlations to continuous bladder sensation of all quantities measured. This study demonstrates how detrusor wall tension, stress, strain, and elastic modulus can be quantified by adding ultrasound imaging to standard urodynamics. This technique may be useful in diagnosing and better understanding the biomechanics involved in OAB and other bladder disorders.
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Characteristics of the mechanosensitive bladder afferent activities in relation with microcontractions in male rats with bladder outlet obstruction. Sci Rep 2017; 7:7646. [PMID: 28794457 PMCID: PMC5550413 DOI: 10.1038/s41598-017-07898-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 07/03/2017] [Indexed: 11/15/2022] Open
Abstract
We investigated the characteristics of bladder mechanosensitive single-unit afferent activities (SAAs) in rats with a bladder outlet obstruction (BOO) and their relationship with bladder microcontractions. Male Wistar rats were divided into Sham and BOO groups. Four or 10 days after the surgery, rats were anesthetized with urethane. The SAAs of Aδ- or C-fibers from the L6 dorsal roots were recorded during bladder filling. The BOO group showed a higher number of microcontractions and lower SAAs of Aδ-fibers compared with those of the Sham group. These findings were significant at day 10 post-operatively. In contrast, SAAs of C-fibers were not significantly different between the groups at either day 4 or 10. In the BOO group at day 10, the SAAs of both Aδ- and C-fibers at the “ascending” phase of microcontractions were significantly higher than those at the other phases (descending or stationary), and a similar tendency was also observed at day 4. Taken together, during bladder filling, the bladder mechanosensitive SAAs of Aδ-fibers were attenuated, but SAAs of both Aδ- and C-fibers were intermittently enhanced by propagation of microcontractions.
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Iguchi N, Dönmez Mİ, Malykhina AP, Carrasco A, Wilcox DT. Preventative effects of a HIF inhibitor, 17-DMAG, on partial bladder outlet obstruction-induced bladder dysfunction. Am J Physiol Renal Physiol 2017; 313:F1149-F1160. [PMID: 28768664 DOI: 10.1152/ajprenal.00240.2017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 07/11/2017] [Accepted: 07/24/2017] [Indexed: 01/11/2023] Open
Abstract
Posterior urethral valves are the most common cause of partial bladder outlet obstruction (PBOO) in the pediatric population. Pathological changes in the bladder developed during PBOO are responsible for long-lasting voiding dysfunction in this population despite early surgical interventions. Increasing evidence showed PBOO induces an upregulation of hypoxia-inducible factors (HIFs) and their transcriptional target genes, and they play a role in pathophysiological changes in the obstructed bladders. We hypothesized that blocking HIF pathways can prevent PBOO-induced bladder dysfunction. PBOO was surgically created by ligation of the bladder neck in male C57BL/6J mice for 2 wk. PBOO mice received intraperitoneal injection of either saline or 17-DMAG (alvespimycin, 3 mg/kg) every 48 h starting from day 1 postsurgery. Sham-operated animals received injection of saline on the same schedule as PBOO mice and served as controls. The bladders were harvested after 2 wk, and basal activity and evoked contractility of the detrusor smooth muscle (DSM) were evaluated in vitro. Bladder function was assessed in vivo by void spot assay and cystometry in conscious, unrestrained mice. Results indicated the 17-DMAG treatment preserved DSM contractility and partially prevented the development of detrusor over activity in obstructed bladders. In addition, PBOO caused a significant increase in the frequency of micturition, which was significantly reduced by 17-DMAG treatment. The 17-DMAG treatment improved urodynamic parameters, including increases in the bladder pressure at micturition and nonvoid contractions observed in PBOO mice. These results demonstrate that treatment with 17-DMAG, a HIF inhibitor, significantly alleviated PBOO-induced bladder pathology in vivo.
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Affiliation(s)
- Nao Iguchi
- Division of Urology, Department of Surgery, University of Colorado Denver School of Medicine, Aurora, Colorado; and
| | - M İrfan Dönmez
- Division of Urology, Department of Surgery, University of Colorado Denver School of Medicine, Aurora, Colorado; and
| | - Anna P Malykhina
- Division of Urology, Department of Surgery, University of Colorado Denver School of Medicine, Aurora, Colorado; and
| | | | - Duncan T Wilcox
- Division of Urology, Department of Surgery, University of Colorado Denver School of Medicine, Aurora, Colorado; and .,Children's Hospital Colorado, Aurora, Colorado
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Niederhauser T, Gafner ES, Cantieni T, Grämiger M, Haeberlin A, Obrist D, Burkhard F, Clavica F. Detection and quantification of overactive bladder activity in patients: Can we make it better and automatic? Neurourol Urodyn 2017; 37:823-831. [DOI: 10.1002/nau.23357] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 06/19/2017] [Indexed: 12/21/2022]
Affiliation(s)
- Thomas Niederhauser
- Institute for Human Centered Engineering; Bern University of Applied Sciences; Biel Switzerland
| | - Elena S. Gafner
- Department of Urology; Bern University Hospital; Bern Switzerland
| | | | | | - Andreas Haeberlin
- ARTORG Center; University of Bern; Bern Switzerland
- Department of Cardiology; Bern University Hospital; Bern Switzerland
| | | | - Fiona Burkhard
- Department of Urology; Bern University Hospital; Bern Switzerland
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Neal CJ, Lin JB, Hurley T, Miner AS, Speich JE, Klausner AP, Ratz PH. Slowly cycling Rho kinase-dependent actomyosin cross-bridge "slippage" explains intrinsic high compliance of detrusor smooth muscle. Am J Physiol Renal Physiol 2017; 313:F126-F134. [PMID: 28356291 DOI: 10.1152/ajprenal.00633.2016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 01/12/2023] Open
Abstract
Biological soft tissues are viscoelastic because they display time-independent pseudoelasticity and time-dependent viscosity. However, there is evidence that the bladder may also display plasticity, defined as an increase in strain that is unrecoverable unless work is done by the muscle. In the present study, an electronic lever was used to induce controlled changes in stress and strain to determine whether rabbit detrusor smooth muscle (rDSM) is best described as viscoelastic or viscoelastic plastic. Using sequential ramp loading and unloading cycles, stress-strain and stiffness-stress analyses revealed that rDSM displayed reversible viscoelasticity, and that the viscous component was responsible for establishing a high stiffness at low stresses that increased only modestly with increasing stress compared with the large increase produced when the viscosity was absent and only pseudoelasticity governed tissue behavior. The study also revealed that rDSM underwent softening correlating with plastic deformation and creep that was reversed slowly when tissues were incubated in a Ca2+-containing solution. Together, the data support a model of DSM as a viscoelastic-plastic material, with the plasticity resulting from motor protein activation. This model explains the mechanism of intrinsic bladder compliance as "slipping" cross bridges, predicts that wall tension is dependent not only on vesicle pressure and radius but also on actomyosin cross-bridge activity, and identifies a novel molecular target for compliance regulation, both physiologically and therapeutically.
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Affiliation(s)
- Christopher J Neal
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, Virginia; and
| | - Jia B Lin
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia
| | - Tanner Hurley
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia
| | - Amy S Miner
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia
| | - John E Speich
- Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, Virginia; and
| | - Adam P Klausner
- Department of Surgery, Virginia Commonwealth University, Richmond, Virginia
| | - Paul H Ratz
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia;
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Igawa Y, Aizawa N. Incontinence: How do β 3-adrenoceptor agonists work in the bladder? Nat Rev Urol 2017; 14:330-332. [PMID: 28322259 DOI: 10.1038/nrurol.2017.43] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Yasuhiko Igawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Naoki Aizawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Palmer CJ, Choi JM. Pathophysiology of Overactive Bladder: Current Understanding. CURRENT BLADDER DYSFUNCTION REPORTS 2017. [DOI: 10.1007/s11884-017-0402-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Low amplitude rhythmic contraction frequency in human detrusor strips correlates with phasic intravesical pressure waves. World J Urol 2016; 35:1255-1260. [PMID: 28025660 DOI: 10.1007/s00345-016-1994-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 12/16/2016] [Indexed: 10/24/2022] Open
Abstract
PURPOSE Low amplitude rhythmic contractions (LARC) occur in detrusor smooth muscle and may play a role in storage disorders such as overactive bladder and detrusor overactivity. The purpose of this study was to determine whether LARC frequencies identified in vitro from strips of human urinary bladder tissue correlate with in vivo LARC frequencies, visualized as phasic intravesical pressure (p ves) waves during urodynamics (UD). METHODS After IRB approval, fresh strips of human urinary bladder were obtained from patients. LARC was recorded with tissue strips at low tension (<2 g) and analyzed by fast Fourier transform (FFT) to identify LARC signal frequencies. Blinded UD tracings were retrospectively reviewed for signs of LARC on the p ves tracing during filling and were analyzed via FFT. RESULTS Distinct LARC frequencies were identified in 100% of tissue strips (n = 9) obtained with a mean frequency of 1.97 ± 0.47 cycles/min (33 ± 8 mHz). Out of 100 consecutive UD studies reviewed, 35 visually displayed phasic p ves waves. In 12/35 (34%), real p ves signals were present that were independent of abdominal activity. Average UD LARC frequency was 2.34 ± 0.36 cycles/min (39 ± 6 mHz) which was similar to tissue LARC frequencies (p = 0.50). A majority (83%) of the UD cohort with LARC signals also demonstrated detrusor overactivity. CONCLUSIONS During UD, a subset of patients displayed phasic p ves waves with a distinct rhythmic frequency similar to the in vitro LARC frequency quantified in human urinary bladder tissue strips. Further refinements of this technique may help identify subsets of individuals with LARC-mediated storage disorders.
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[S2e guideline of the German urologists: Conservative and pharmacologic treatment of benign prostatic hyperplasia]. Urologe A 2016; 55:184-94. [PMID: 26518303 DOI: 10.1007/s00120-015-3984-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
This report summarizes the relevant aspects of the S2e guideline of the German Urologists for the conservative and pharmacological treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. Recommendations are given regarding watchful waiting, behavioral therapy, phytotherapy and pharmacological mono- and combination therapy. The influence of the different therapeutic options on bladder outlet obstruction (BOO) is described in detail.
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Albisinni S, Biaou I, Marcelis Q, Aoun F, De Nunzio C, Roumeguère T. New medical treatments for lower urinary tract symptoms due to benign prostatic hyperplasia and future perspectives. BMC Urol 2016; 16:58. [PMID: 27629059 PMCID: PMC5024450 DOI: 10.1186/s12894-016-0176-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lower Urinary Tract Symptoms (LUTS) in men are a common clinical problem in urology and have been historically strictly linked to benign prostatic hyperplasia (BPH), which may lead to bladder outlet obstruction (BOO). New molecules have been approved and have entered the urologists' armamentarium, targeting new signaling pathways and tackling specific aspects of LUTS. Objective of this review is to summarize the evidence regarding the new medical therapies currently available for male non-neurogenic LUTS, including superselective α1-antagonists, PDE-5 inhibitors, anticholinergic drugs and intraprostatic onabotulinum toxin injections. METHODS The National Library of Medicine Database was searched for relevant articles published between January 2006 and December 2015, including the combination of "BPH", "LUTS", "medical" and "new". Each article's title, abstract and text were reviewed for their appropriateness and their relevance. One hundred forty eight articles were reviewed. RESULTS Of the 148 articles reviewed, 92 were excluded. Silodosin may be considered a valid alternative to non-selective α1-antagonists, especially in the older patients where blood pressure alterations may determine major clinical problems and ejaculatory alterations may be not truly bothersome. Tadalafil 5 mg causes a significant decrease of IPSS score with an amelioration of patients' QoL, although with no significant increase in Qmax. Antimuscarinic drugs are effective on storage symptoms but should be used with caution in patients with elevated post-void residual. Intraprostatic injections of botulinum toxin are well-tolerated and effective, with a low rate of adverse events; however profound ameliorations were seen also in the sham arms of RCTs evaluating intraprostatic injections. CONCLUSION New drugs have been approved in the last years in the medical treatment of BPH-related LUTS. Practicing urologists should be familair with their pharmacodynamics and pharmacokinetics.
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Affiliation(s)
- Simone Albisinni
- Urology Department, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium.
| | - Ibrahim Biaou
- Urology Department, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Quentin Marcelis
- Urology Department, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Fouad Aoun
- Urology Department, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Cosimo De Nunzio
- Department of Urology, Ospedale Sant'Andrea, University "La Sapienza", Roma, Italy
| | - Thierry Roumeguère
- Urology Department, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
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Drake MJ, Kanai A, Bijos DA, Ikeda Y, Zabbarova I, Vahabi B, Fry CH. The potential role of unregulated autonomous bladder micromotions in urinary storage and voiding dysfunction; overactive bladder and detrusor underactivity. BJU Int 2016; 119:22-29. [PMID: 27444952 DOI: 10.1111/bju.13598] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The isolated bladder shows autonomous micromotions, which increase with bladder distension, generate sensory nerve activity, and are altered in models of urinary dysfunction. Intravesical pressure resulting from autonomous activity putatively reflects three key variables; the extent of micromotion initiation, distances over which micromotions propagate, and overall bladder tone. In vivo, these variables are subordinate to the efferent drive of the central nervous system. In the micturition cycle storage phase, efferent inhibition keeps autonomous activity generally at a low level, where it may signal 'state of fullness', whilst maintaining compliance. In the voiding phase, mass efferent excitation elicits generalised contraction (global motility initiation). In lower urinary tract dysfunction, efferent control of the bladder can be impaired, for example due to peripheral 'patchy' denervation. In this case, loss of efferent inhibition may enable unregulated micromotility, and afferent stimulation, predisposing to urinary urgency. If denervation is relatively slight, the detrimental impact on voiding may be low, as the adjacent innervated areas may be able to initiate micromotility synchronous with the efferent nerve drive, so that even denervated areas can contribute to the voiding contraction. This would become increasingly inefficient the more severe the denervation, such that ability of triggered micromotility to propagate sufficiently to engage the denervated areas in voiding declines, so the voiding contraction increasingly develops the characteristics of underactivity. In summary, reduced peripheral coverage by the dual efferent innervation (inhibitory and excitatory) impairs regulation of micromotility initiation and propagation, potentially allowing emergence of overactive bladder and, with progression, detrusor underactivity.
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Affiliation(s)
- Marcus J Drake
- School of Clinical Sciences, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.,Bristol Urological Institute, Southmead Hospital, University of West of England, Bristol, UK
| | | | - Dominika A Bijos
- Bristol Urological Institute, Southmead Hospital, University of West of England, Bristol, UK
| | - Youko Ikeda
- University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Bahareh Vahabi
- Bristol Urological Institute, Southmead Hospital, University of West of England, Bristol, UK.,School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
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47
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Juszczak K, Drewa T. Pharmacotherapy in detrusor underactivity: A new challenge for urologists and pharmacologists (from lab to clinic). Pharmacol Rep 2016; 68:703-6. [DOI: 10.1016/j.pharep.2016.03.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 03/01/2016] [Accepted: 03/09/2016] [Indexed: 12/17/2022]
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Effects of K(+) channel openers on spontaneous action potentials in detrusor smooth muscle of the guinea-pig urinary bladder. Eur J Pharmacol 2016; 789:179-186. [PMID: 27455901 DOI: 10.1016/j.ejphar.2016.07.041] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 07/22/2016] [Accepted: 07/22/2016] [Indexed: 12/18/2022]
Abstract
The modulation of spontaneous excitability in detrusor smooth muscle (DSM) upon the pharmacological activation of different populations of K(+) channels was investigated. Effects of distinct K(+) channel openers on spontaneous action potentials in DSM of the guinea-pig bladder were examined using intracellular microelectrode techniques. NS1619 (10μM), a large conductance Ca(2+)-activated K(+) (BK) channel opener, transiently increased action potential frequency and then prevented their generation without hyperpolarizing the membrane in a manner sensitive to iberiotoxin (IbTX, 100nM). A higher concentration of NS1619 (30μM) hyperpolarized the membrane and abolished action potential firing. NS309 (10μM) and SKA31 (100μM), small conductance Ca(2+)-activated K(+) (SK) channel openers, dramatically increased the duration of the after-hyperpolarization and then abolished action potential firing in an apamin (100nM)-sensitive manner. Flupirtine (10μM), a Kv7 channel opener, inhibited action potential firing without hyperpolarizing the membrane in a manner sensitive to XE991 (10μM), a Kv7 channel blocker. BRL37344 (10μM), a β3-adrenceptor agonist, or rolipram (10nM), a phosphodiesterase 4 inhibitor, also inhibited action potential firing. A higher concentration of rolipram (100nM) hyperpolarized the DSM and abolished the action potentials. IbTX (100nM) prevented the rolipram-induced blockade of action potentials but not the hyperpolarization. BK and Kv7 channels appear to predominantly contribute to the stabilization of DSM excitability. Spare SK channels could be pharmacologically activated to suppress DSM excitability. BK channels appear to be involved in the cyclic AMP-induced inhibition of action potentials but not the membrane hyperpolarization.
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Heppner TJ, Tykocki NR, Hill-Eubanks D, Nelson MT. Transient contractions of urinary bladder smooth muscle are drivers of afferent nerve activity during filling. ACTA ACUST UNITED AC 2016; 147:323-35. [PMID: 26976828 PMCID: PMC4810069 DOI: 10.1085/jgp.201511550] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 02/12/2016] [Indexed: 01/23/2023]
Abstract
Activation of afferent nerves during urinary bladder (UB) filling conveys the sensation of UB fullness to the central nervous system (CNS). Although this sensory outflow is presumed to reflect graded increases in pressure associated with filling, UBs also exhibit nonvoiding, transient contractions (TCs) that cause small, rapid increases in intravesical pressure. Here, using an ex vivo mouse bladder preparation, we explored the relative contributions of filling pressure and TC-induced pressure transients to sensory nerve stimulation. Continuous UB filling caused an increase in afferent nerve activity composed of a graded increase in baseline activity and activity associated with increases in intravesical pressure produced by TCs. For each ∼4-mmHg pressure increase, filling pressure increased baseline afferent activity by ∼60 action potentials per second. In contrast, a similar pressure elevation induced by a TC evoked an ∼10-fold greater increase in afferent activity. Filling pressure did not affect TC frequency but did increase the TC rate of rise, reflecting a change in the length-tension relationship of detrusor smooth muscle. The frequency of afferent bursts depended on the TC rate of rise and peaked before maximum pressure. Inhibition of small- and large-conductance Ca(2+)-activated K(+) (SK and BK) channels increased TC amplitude and afferent nerve activity. After inhibiting detrusor muscle contractility, simulating the waveform of a TC by gently compressing the bladder evoked similar increases in afferent activity. Notably, afferent activity elicited by simulated TCs was augmented by SK channel inhibition. Our results show that afferent nerve activity evoked by TCs represents the majority of afferent outflow conveyed to the CNS during UB filling and suggest that the maximum TC rate of rise corresponds to an optimal length-tension relationship for efficient UB contraction. Furthermore, our findings implicate SK channels in controlling the gain of sensory outflow independent of UB contractility.
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Affiliation(s)
- Thomas J Heppner
- Department of Pharmacology, University of Vermont, Burlington, VT 05405
| | - Nathan R Tykocki
- Department of Pharmacology, University of Vermont, Burlington, VT 05405
| | | | - Mark T Nelson
- Department of Pharmacology, University of Vermont, Burlington, VT 05405 Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, England, UK
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50
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Furuta A, Suzuki Y, Kimura S, Koike Y, Egawa S, Yoshimura N. Combination therapy with β3 -adrenoceptor agonists and muscarinic acetylcholine receptor antagonists: Efficacy in rats with bladder overactivity. Int J Urol 2016; 23:425-30. [PMID: 26890938 DOI: 10.1111/iju.13066] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 01/13/2016] [Indexed: 12/13/2022]
Abstract
OBJECTIVE 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. METHODS Cystometry was carried out in conscious female rats with intravesical instillation of oxotremorine methiodide (200 μmol/L). Either mirabegron (0.3-3 mg/kg), methoctramine (0.1-1 mg/kg) or 4-DAMP (0.03-0.3 mg/kg) was cumulatively applied intravenously. Also, the effects of combined application of mirabegron (3 mg/kg) plus methoctramine (1 mg/kg) or 4-DAMP (0.3 mg/kg) on cystometric parameters were compared with those of single-agent monotherapy. RESULTS Intravesical instillation of oxotremorine methiodide induced bladder overactivity, as evidenced by decreases in threshold pressure and bladder capacity. In oxotremorine methiodide-treated rats, single application of mirabegron (1, 3 mg/kg), methoctramine (0.3, 1 mg/kg) or 4-DAMP (0.1, 0.3 mg/kg) decreased baseline pressure and increased bladder capacity. In addition, reductions in threshold pressure and maximal voiding pressure were also seen after the administration of 4-DAMP (0.3 mg/kg). The combined treatment of mirabegron plus 4-DAMP induced a larger increase in bladder capacity compared with monotherapy of either drug, whereas there were no significant changes in cystometric parameters between the combination therapy of mirabegron plus methoctramine and monotherapy of either drug. CONCLUSION These results suggest that the combination therapy of β3 -adrenoceptor agonists plus muscarinic acetylcholine receptor3 antagonists is more effective compared with monotherapy for the treatment of bladder overactivity. In contrast, the efficacy of β3 -adrenoceptor agonists might not be increased by the addition of muscarinic acetylcholine receptor2 antagonists.
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Affiliation(s)
- Akira Furuta
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Yasuyuki Suzuki
- Department of Urology, Tokyo Metropolitan Rehabilitation Hospital, Tokyo, Japan
| | - Shoji Kimura
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Yusuke Koike
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Shin Egawa
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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