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. Author manuscript; available in PMC: 2022 Dec 27.
Published in final edited form as: Neurourol Urodyn. 2020 Feb 14;39(Suppl 3):S16–S22. doi: 10.1002/nau.24313

Are oxidative stress and ischemia significant causes of bladder damage leading to lower urinary tract dysfunction? Report from the ICI-RS 2019

John E Speich 1, Tufan Tarcan 2,3, Hikaru Hashitani 4, Bahareh Vahabi 5,6, Karen D McCloskey 7, Karl-Erik Andersson 8,9, Alan J Wein 10, Lori A Birder 11,12
PMCID: PMC9794413  NIHMSID: NIHMS1860850  PMID: 32056281

Abstract

Several studies indicate that pelvic ischemia and oxidative stress may play a significant role in lower urinary tract dysfunction (LUTD), including detrusor overactivity (DO)/overactive bladder (OAB) and detrusor underactivity (DU)/underactive bladder (UAB). The present article addresses Proposal 1: “Are oxidative stress and ischemia significant causes of bladder damage leading to LUTD?” from the 2019 International Consultation on Incontinence – Research Society (ICI-RS) meeting. Bladder ischemia in animals and humans is briefly described, along with the proposed progression from ischemia to LUTD. Bladder ischemia is compared to ischemia other organs, and the ongoing development of pelvic ischemia animal models is discussed. In addition, the distribution of blood within the bladder during filling and voiding and the challenges of quantification of blood flow in vivo are described. Furthermore, oxidative stress, including potential biomarkers and treatments, and challenges regarding antioxidant therapy for the treatment of LUTD are discussed. Finally, seven critical research questions and proposed studies to answer those questions were identified as priorities that would lead to major advances in the understanding and treatment of LUTS/LUTD associated with pelvic ischemia and oxidative stress.

INTRODUCTION

Recent reviews have summarized the evidence supporting roles that pelvic ischemia and oxidative stress may play in LUTD, including DO/OAB and DU/UAB.1–3 In addition, studies have shown that intermittent oxygen desaturations in individuals with sleep-disordered breathing are associated with nocturia,4 and oxidative stress due to sleep apnea has been linked with nocturia.5 Furthermore, bladder blood flow has been demonstrated to be reduced in patients with bladder pain syndrome,6 and oxidative stress is reportedly associated with interstitial cystitis,7 Thus, pelvic ischemia and oxidative stress have putative links to a broad range of LUTD.

The present article addresses Proposal 1: “Are oxidative stress and ischemia significant causes of bladder damage leading to LUTD?” from the 2019 ICI-RS meeting which took place June 6–8, 2019 in Bristol, UK. The objective was to propose studies that are needed (a) to determine the mechanisms underpinning how ischemia and/or oxidative stress lead to LUTD and (b) pre-clinical studies for the development of treatments to prevent/alleviate LUTD arising from ischemia/oxidative stress.

PELVIC ISCHEMIA

Chronic pelvic ischemia has previously been proposed to cause different types of LUTD including OAB/DO and UAB/DU even as a common etiological factor to explain the co-existence of the aforementioned conditions.8,9 The main evidence originates from animal models since human correlates are challenging to establish due to difficulties in investigating long-term moderate bladder ischemia in humans.

Bladder ischemia: Evidence from animal models

According to animal studies, it is important to differentiate between moderate and severe ischemia which lead to contradictory findings in terms of bladder function and morphology. In the rabbit model, severe ischemia has been defined as a reduction in the bladder wall blood flow more than 60% whereas moderate ischemia was characterized with a decrease between 40 and 60%.10

For example, chronic moderate bladder ischemia in the rabbit was shown to cause increased contractile responses to pharmacological and electrical stimulation in isometric tension studies and DO in cystometry.10 On the contrary, chronic severe bladder ischemia impaired detrusor contractility and lead to decreased contractile responses to pharmacological and electrical stimulation.10 The latter intervention was also associated with marked histological changes such as loss of smooth muscle and increased collagen in the bladder tissue.

The effect of ischemia on bladder function and structure is complicated and involves several mechanisms including redox-mediated cellular stress, differential translocation of transcription factors, mitochondrial dysfunction, activation of cell survival pathways, sensitization of smooth muscle cells to contractile stimuli, neural ultrastructural damage, a shift in the regulation of smooth muscle contractility from M3 to M2 and upregulated purinergic receptor expression.11,12 Overall, early or moderate stages of ischemia may lead to mild pathophysiological changes whereas late or severe stages may cause more significant alterations in the bladder. This phenomenon is markedly associated with a shift from DO to DU,2,12 as described below.

Bladder ischemia: The human data

The most likely factors that may cause chronic bladder ischemia in neurologically intact humans are suggested to be atherosclerosis-induced arterial insufficiency, bladder outlet obstruction (BOO) or undesirable bladder habits such as infrequent voiding.8,9 In Particular, their coexistence may expose the bladder to a more severe insult. Indeed, decreased bladder blood flow is significantly correlated with lower urinary tract symptoms (LUTS) in both men and women. For example, the degrees of pelvic atherosclerosis significantly correlated with the severity of LUTS in elderly patients.13 Human bladder blood flow decreases with aging and decreased bladder blood flow significantly correlates with reduced compliance.14–17 Likewise, it is shown that severe chronic pelvic ischemia caused by significant aortoiliac disease in elderly men is associated with a significant increase in LUTS and bladder neurogenic inflammation, as suggested by the increase of NGF release in urine, sensitizing bladder afferents.18 In men, LUTS improvement with alpha adrenoceptor blockers is associated with significant increase in bladder blood flow.19 Regulation of TNF-like ligand 1a (TL1A) and its receptor DR3 by bladder ischemia and potential roles TL1A and DR3 in bladder inflammation are documented in the elderly patients.20 Dutasteride (5α-reductase inhibitor, anti-androgen) is suggested to reduce OAB symptoms by increasing blood flow and improving bladder ischemia.21

Recently, a study of women consisting of 74 OAB patients and 73 controls showed that all atherosclerosis indicators were significantly associated with OAB and that there was a significant relationship between OAB and decreased bladder neck perfusion. It was also found that OAB correlated with severity of systemic atherosclerosis and with impaired vascular perfusion of the bladder. These results suggested that OAB-related microvascular disease may be a component of systemic atherosclerosis rather than a separate process.22

Despite the aforementioned research, further evidence in humans is needed. However, investigating bladder ischemia in humans presents a number of challenges. For example, the pathophysiological mechanism may be influenced by behavioral factors because the human bladder blood wall undergoes physiological cycles of ischemia and reperfusion with filling and emptying and this is also related to intravesical pressure changes.14,15 Therefore, bladder habits including infrequent voiding will likely affect bladder blood flow in the long term. The consequences of bladder ischemia may also change depending on existing co-morbidities and host factors including diabetes, other vascular risk factors, fluid intake, genetic factors and medications (Ca2+ channel blockers, antioxidants, statins etc.).

Bladder ischemia to understand the progression of LUTD:

Bladder ischemia also enables us to understand and study the possible transition of OAB/DO to UAB/DU and their co-existence with each other. It was previously hypothesized that, at least in some patients, OAB/DO can progress to UAB/DU.23 The long-term effect of ischemia originating from OAB and/or dysfunctional voiding may play a role in this transition. Supporting this, Zhao et al showed that bladder responses to an ischemic insult depended on the duration of ischemia in a rat model of atherosclerosis-induced ischemia.12 They reported that micturition patterns and cystometric changes at 8-weeks ischemia was associated with DO, while voiding behavior and cystometrograms at 16-weeks ischemia demonstrated abnormal detrusor function, mimicking underactivity. In parallel to these findings, upregulation of M2 receptors was found after 8- and 16 weeks of ischemia. Downregulation of M3 and upregulation of M1 were detected at 16-week ischemia. Neural structural damage and marked neurodegeneration were found after 8 and 16 weeks of ischemia, respectively.12

Large animal bladder ischemia models:

Much of our knowledge of the effect of oxidative stress and ischemia on LUT function has come from research using small rodents24–27, and the in vivo models have often been developed using an endothelial injury coupled with a high cholesterol diet10,12 or BOO.28 Extrapolating findings generated using small laboratory animals to the physiology of urine storage and voiding in large animals is difficult, and requires further validation. Studies have evaluated the urodynamic properties of pigs in vivo, demonstrating comparable urodynamic and structural characteristics to humans, and potential clinical relevance.29 Recognizing this similarity, researchers have utilized miniature and domestic pigs as research models for various urological functional studies.

In order to study the effect of hypoxia and oxidative stress on pig urinary bladder function, various methods and models have been used. Pigs with chronic BOO have been utilized to study the in vivo and in vitro effects of hypoxia.28 In addition, bladder strips from normal pigs have been used in organ bath experiments whereby oxidative stress was mimicked by the addition of various compounds such as cumene hydroperoxide, hypochlorous acid etc. to the organ baths.30,31 In order to effectively analyze the relationship between perfusion and function of the bladder, models in which both can be monitored and manipulated quantitatively are required. Isolated perfused pig bladder models allowing this have been reported.29,32

Ischemia in the bladder compared to other organs:

LUTS induced by bladder ischemia is considered a manifestation of systemic atherosclerosis similar to ischemic diseases in the brain, heart or lower limbs. Indeed, atherosclerosis preferentially affects certain regions of the circulation including the bifurcation of the iliac artery supplying blood to the bladder.33 As detrusor smooth muscles vigorously contract for only several minutes a day to eliminate urine, the energetic requirements of the bladder are much lower than the organs that have a high prevalence of ischemic dysfunction. In addition, organs susceptible to ischemia have circulatory vulnerabilities; the brain has very limited energetic reserves, and thus the cerebral circulation must be maintained within a narrow range. Myocardial perfusion predominately occurs during diastole due to the high extravascular compressive forces during systole. In contrast, the bladder circulation appears to have a reserved capacity, and also its extravascular pressure, namely intravesical pressure, does not readily exceed even capillary pressure.34 Therefore, it may not be appropriate to explain a large number of patients worldwide with ischemic bladder dysfunction simply by a reduction in the blood supply due to narrowing of the feeding arteries.

Distribution of blood within the bladder layers during filling and voiding:

The most significant characteristic of the bladder circulation is its adaptation to normal physiological distension due to substantial volume changes (400mL/0mL, cf. heart 120mL/50mL). The tortuous arrangement of intramural blood vessels prevents longitudinal stretching and resultant increases in vascular resistance. Spontaneous contractions in muscularis mucosae35 or blood vessels themselves26 may also function to protect the vasculature from over-stretching. The extensive mucosal vascular plexus indicates that the bladder circulation is predominant in the mucosa during the storage phase34 as is the case of the gastrointestinal tract.36 Thus, there must be a prompt yet dramatic switching of blood flow distribution to a detrusor dominant pattern upon micturition.

Quantification of bladder blood flow:

Because of the mucosa dominant circulation during the storage phase, precise measurements of the mucosal blood flow are fundamental for the diagnosis of bladder ischemia. This can be achieved using a cyctoscopic laser Doppler flow probe, but non-invasive imaging examinations are more desirable. Functional MRI, high resolution PET or optical coherence tomography may have potential. Since laser Doppler flow probes are usually applied from the outer surface of the bladder in animal models, caution should be exercised when interpreting blood flow changes, particularly in animals that have a thicker, non-translucent bladder wall. Since intramural blood vessels could be the site of action of β3 agonists or PDE5 inhibitors, the properties of different intramural vascular segments require further exploration for a complete understanding of the pathophysiology of bladder ischemia, as well as the development of novel therapeutic strategies.

OXIDATIVE STRESS

Oxidative Stress

Oxidative stress is broadly defined as a disturbance in a pro oxidant-antioxidant balance (i.e., uncontrolled increases in the production of reactive oxygen (or nitrogen) species or deficiencies in antioxidant defense mechanisms) which can lead to potential damage. Oxidative metabolism can yield free radicals and other unstable oxygen- and nitrogen-containing molecules.37–40 When produced at low or physiological levels, reactive oxygen species (ROS) can regulate a number of processes including maintenance of vascular tone and signal transduction. However, at higher levels, excessive ROS can result in oxidative damage to lipids, proteins, carbohydrates and DNA, leading to the generation of secondary reactive species and finally loss of function and cell death.37–40 ROS (and reactive nitrogen species, RNS) are also generated during radiation therapy and in the bladder, radiation toxicity generates LUTD 41,42. Sources of ROS can include nitric oxide synthase, xanthine oxidase as well as the mitochondria, an essential supplier of energy. Mitochondria have been described as both a primary source and also target of ROS. ROS is a general term that includes a number of species such as the superoxide anion, which is often increased in conditions of ischemia or hypoxia. Excessive amounts of superoxide can interact with nitric oxide to form peroxynitrite which is a pro-oxidant capable of rapidly diffusing to nearby cells inducing damage. The highly reactive hydroxyl radical is thought to mediate most free radical induced tissue damage.37–40

Mitochondrial DNA (mtDNA) is more susceptible to oxidative damage than nuclear DNA due in part to proximity of mtDNA to the respiratory chain and decreased availability of repair mechanisms.43 Damage to mtDNA can not only result in mitochondrial dysfunction but can trigger inflammatory and innate immune responses.44,45 Studies suggest that oxidative stress also plays a role in fibrotic diseases by augmenting the production of various regulators of fibrosis such as growth factors, angiogenic factors and cytokines. In the airways, augmented ROS is involved in increased vascular permeability and bronchial hyper-responsiveness, characteristic features of asthma.46,47 Because mitochondria are the major consumers of cellular oxygen, it is not surprising that these organelles are significantly impacted by hypoxia and ischemia. Reduced levels of oxygen result in augmented ROS production, decreases energy production and changes in mitochondrial morphology.

Oxidative stress: potential biomarkers and treatments

A number of studies have reported potential biomarkers as a surrogate for oxidative/nitrosative stress/damage in human disease. Measurement of ROS/RNS are generally not feasible due mainly to their short half-life that would limit the ability to measure in tissues or fluids. Instead, measurement of stable metabolites or concentration of their oxidation target products such as lipid peroxidation have been used. For example, secondary products of lipid peroxidation include malondialdehyde (MDA), 4-hydroxynonenal/4-hydroxy-2-nonenal (HNE) and 2-propenal (acrolein).48 However, depending upon the severity and duration exposure, and the type and level of ROS and RNS, oxidative stress can yield a vast range of cellular responses in different diseases.

Given the evidence supporting a role for oxidative stress in the pathogenesis of a number of disorders, antioxidant therapy seems an obvious course for minimizing symptoms and even reversing the course of the disease. There are a number of substances that are thought to act as potential ‘anti-oxidants’ which exhibit the ability to act as an electron donor. Most agents to date including antioxidant supplements show limited if any benefit on the prevention of chronic diseases in a number of randomized controlled trials.49 The failure of these agents may be due to the inability to cross the relevant cellular or mitochondrial barrier or that many of the agents were given when the condition has already been established which may involve a number of other factors. It is also important to note that homeostatic mechanisms are important and excessive intake of antioxidant supplements can upset the balance of vital signaling responses with adverse consequences increasing the risk of chronic disease.50

Current challenges regarding antioxidant therapy:

There is substantive evidence that oxidative/nitrosative stress is involved in a large number of both acute and chronic human conditions. Many current antioxidant therapies lack specificity and are unable to mediate a response against a specific target. Increasing cellular levels of antioxidants by targeting the mitochondria may be an effective approach in the prevention or treatment of chronic diseases. Though there are clear advances in the field, a number of challenges exist which include validation of available biomarkers for oxidative damage in both human and animal studies and relation to disease. A better understanding of the pathogenesis of oxidative stress and the effects of ROS-induced mitochondrial dysfunction in chronic LUT disorders is needed in order to develop new pharmacological approaches (i.e., antioxidants with dual antioxidant/anti-inflammatory activities) to treat these conditions.

RESEARCH QUESTIONS AND PROPOSALS

The following research questions and proposed studies have been identified as priorities that would lead to major advances in the understanding and treatment of LUTS/LUTD associated with pelvic ischemia and oxidative stress.

Question 1: How can we measure and monitor human bladder wall blood flow with accurate, reproducible and preferably non-invasive tools and utilize them for human research?

Proposal 1: Design multidisciplinary research studies in collaboration with engineers and physicists to invent a measurement method that fulfills the above criteria.

Question 2: How can we measure oxidative stress in the bladder?

Proposal 2: Identify and validate new and available biomarkers for oxidative damage in both human and animal studies and their relation to specific LUTD.

Question 3: What are the best experimental models for ischemia/oxidative stress?

Proposal 3: Integrate mechanistic and physiological data from cellular, tissue and in vivo animal studies from a panel of experimental ischemic/oxidative stress models including hypoxia chambers, irradiation, chemical-induced oxidative stress and surgical interventions.

Question 4: How can we determine precisely how ischemia/oxidative stress lead to LUTD and directly or indirectly confirm experimental results from animal models in humans?

Proposal 4: Design studies using biomarkers and non-invasive functional monitoring in significant numbers of patients to more precisely understand the vicious cascade of membrane depolarization, calcium overload, increased ROS, mitochondrial dysfunction and the release of mitochondrial contents to induce apoptosis.

Question 5: Can we treat ischemia-related LUTD or prevent their progression by improving bladder wall blood flow by behavioral, pharmacological or surgical methods?

Proposal 5: Plan prospective studies to assess the effect of specified treatment modalities and their outcome on bladder wall blood flow changes and LUTD.

Question 6: What studies are needed for the development of treatments for mechanisms of LUTD involving oxidative stress?

Proposal 6: Design studies to measure biomarkers of oxidative damage (such as DNA, lipids and proteins) or free radical production and their response to potential antioxidant treatments in animal models, including antioxidant deficient mouse models, and in humans.

Question 7: Can we decrease the burden of LUTD by creating preventive and/or therapeutic measures for vascular risk factors aiming to improve bladder blood flow?

Proposal 7: Design longitudinal studies to assess how early detection and treatment of vascular risk factors in selected groups affect bladder blood flow and consequently the incidence and progression of different types LUTD.

CONCLUSION

Key research questions and proposed studies have been identified that could lead to the next major advances in the understanding and treatment of LUTD associated with bladder ischemia and oxidative stress.

REFERENCES

  • 1.Andersson KE. Oxidative stress and lower urinary tract symptoms: cause or consequence? BJU Int. 2019;123(5):749–750. [DOI] [PubMed] [Google Scholar]
  • 2.Andersson KE, Boedtkjer DB, Forman A. The link between vascular dysfunction, bladder ischemia, and aging bladder dysfunction. Ther Adv Urol. 2017;9(1):11–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Nomiya M, Andersson KE, Yamaguchi O. Chronic bladder ischemia and oxidative stress: new pharmacotherapeutic targets for lower urinary tract symptoms. Int J Urol. 2015;22(1):40–46. [DOI] [PubMed] [Google Scholar]
  • 4.Finamore P, Scarlata S, Laudisio A, et al. Occurrence of nocturia is not mediated by nocturnal hypoxia length and severity in patients with sleep-disordered breathing. Sleep Medicine. 2018;45:69–73. [DOI] [PubMed] [Google Scholar]
  • 5.Witthaus MW, Nipa F, Yang JH, Li Y, Lerner LB, Azadzoi KM. Bladder oxidative stress in sleep apnea contributes to detrusor instability and nocturia. J Urol. 2015;193(5):1692–1699. [DOI] [PubMed] [Google Scholar]
  • 6.Ozcaglayan O, Akgul M, Yazici C, Ozcaglayan TI, Malak A, Dogru Md M. Is bladder blood flow an etiologic factor for the bladder pain syndrome? Neurourol Urodyn. 2019;38(4):1135–1141. [DOI] [PubMed] [Google Scholar]
  • 7.Ener K, Keske M, Aldemir M, et al. Evaluation of oxidative stress status and antioxidant capacity in patients with painful bladder syndrome/interstitial cystitis: preliminary results of a randomised study. Int Urol Nephrol. 2015;47(8):1297–1302. [DOI] [PubMed] [Google Scholar]
  • 8.Tarcan T, Rademakers K, Arlandis S, von Gontard A, van Koeveringe GA, Abrams P. Do the definitions of the underactive bladder and detrusor underactivity help in managing patients: International Consultation on Incontinence Research Society (ICI-RS) Think Tank 2017? Neurourol Urodyn. 2018;37(S4):S60–S68. [DOI] [PubMed] [Google Scholar]
  • 9.Tarcan T, Azadzoi KM, Siroky MB, Goldstein I, Krane RJ. Age-related erectile and voiding dysfunction: the role of arterial insufficiency. Br J Urol. 1998;82 Suppl 1:26–33. [DOI] [PubMed] [Google Scholar]
  • 10.Azadzoi KM, Tarcan T, Kozlowski R, Krane RJ, Siroky MB. Overactivity and structural changes in the chronically ischemic bladder. J Urol. 1999;162(5):1768–1778. [PubMed] [Google Scholar]
  • 11.Yang JH, Siroky MB, Yalla SV, Azadzoi KM. Mitochondrial stress and activation of PI3K and Akt survival pathway in bladder ischemia. Res Rep Urol. 2017;9:93–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Zhao Z, Azad R, Yang JH, Siroky MB, Azadzoi KM. Progressive changes in detrusor function and micturition patterns with chroinc bladder ischemia. Investig Clin Urol. 2016;57(4):249–259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Takahashi N, Shishido K, Sato Y, et al. The Association between Severity of Atherosclerosis and Lower Urinary Tract Function in Male Patients with Lower Urinary Tract Symptoms. Low Urin Tract Symptoms. 2012;4(1):9–13. [DOI] [PubMed] [Google Scholar]
  • 14.Batista JE, Wagner JR, Azadzoi KM, Krane RJ, Siroky MB. Direct measurement of blood flow in the human bladder. J Urol. 1996;155(2):630–633. [PubMed] [Google Scholar]
  • 15.Kershen RT, Azadzoi KM, Siroky MB. Blood flow, pressure and compliance in the male human bladder. J Urol. 2002;168(1):121–125. [PubMed] [Google Scholar]
  • 16.Pinggera G-M, Mitterberger M, Steiner E, et al. Association of lower urinary tract symptoms and chronic ischaemia of the lower urinary tract in elderly women and men: assessment using colour Doppler ultrasonography. BJU International. 2008;102(4):470–474. [DOI] [PubMed] [Google Scholar]
  • 17.De EJ, Hou P, Estrera AL, et al. Pelvic ischemia is measurable and symptomatic in patients with coronary artery disease: a novel application of dynamic contrast-enhanced magnetic resonance imaging. J Sex Med. 2008;5(11):2635–2645. [DOI] [PubMed] [Google Scholar]
  • 18.Antunes-Lopes T, Vasconcelos A, Costa D, et al. The Impact of Chronic Pelvic Ischemia on LUTS and Urinary Levels of Neuroinflammatory, Inflammatory, and Oxidative Stress Markers in Elderly Men: A Case-control Study. Urology. 2019;123:230–234. [DOI] [PubMed] [Google Scholar]
  • 19.Pinggera GM, Mitterberger M, Pallwein L, et al. alpha-Blockers improve chronic ischaemia of the lower urinary tract in patients with lower urinary tract symptoms. BJU Int. 2008;101(3):319–324. [DOI] [PubMed] [Google Scholar]
  • 20.Wang W, Zhang N, Zhu XH, et al. Involvement of TL1A and DR3 in induction of ischaemia and inflammation in urinary bladder dysfunction in the elderly. Mol Med Rep. 2012;6(2):434–438. [DOI] [PubMed] [Google Scholar]
  • 21.Wada N, Matsumoto S, Kita M, Hashizume K, Kakizaki H. Improvement of Overactive Bladder Symptoms and Bladder Ischemia with Dutasteride in Patients with Benign Prostatic Enlargement. Low Urin Tract Symptoms. 2015;7(1):37–41. [DOI] [PubMed] [Google Scholar]
  • 22.Yeniel AO, Ergenoglu AM, Meseri R, et al. Is overactive bladder microvasculature disease a component of systemic atheroscleorosis? Neurourol Urodyn. 2018;37(4):1372–1379. [DOI] [PubMed] [Google Scholar]
  • 23.Tarcan T, von Gontard A, Apostolidis A, Mosiello G, Abrams P. Can we improve our management of dysfunctional voiding in children and adults: International Consultation on Incontinence Research Society; ICI-RS2018? Neurourology and Urodynamics. 2019;In Press. [DOI] [PubMed] [Google Scholar]
  • 24.Saito M, Ohmura M, Kondo A. Effect of ageing on blood flow to the bladder and bladder function. Urol Int. 1999;62(2):93–98. [DOI] [PubMed] [Google Scholar]
  • 25.Azadzoi KM, Radisavljevic ZM, Siroky MB. Effects of ischemia on tachykinin-containing nerves and neurokinin receptors in the rabbit bladder. Urology. 2008;71(5):979–983. [DOI] [PubMed] [Google Scholar]
  • 26.Hashitani H, Takano H, Fujita K, Mitsui R, Suzuki H. Functional properties of suburothelial microvessels in the rat bladder. J Urol. 2011;185(6):2382–2391. [DOI] [PubMed] [Google Scholar]
  • 27.Nomiya M, Yamaguchi O, Andersson KE, et al. The effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat. Neurourol Urodyn. 2012;31(1):195–200. [DOI] [PubMed] [Google Scholar]
  • 28.Greenland JE, Hvistendahl JJ, Andersen H, et al. The effect of bladder outlet obstruction on tissue oxygen tension and blood flow in the pig bladder. BJU Int. 2000;85(9):1109–1114. [DOI] [PubMed] [Google Scholar]
  • 29.Parsons BA, Drake MJ, Gammie A, Fry CH, Vahabi B. The validation of a functional, isolated pig bladder model for physiological experimentation. Front Pharmacol. 2012;3:52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.de Jongh R, Haenen GR, van Koeveringe GA, Dambros M, De Mey JG, van Kerrebroeck PE. Oxidative stress reduces the muscarinic receptor function in the urinary bladder. Neurourol Urodyn. 2007;26(2):302–308. [DOI] [PubMed] [Google Scholar]
  • 31.Dambros M, Dambros MC, Lorenzetti F, Dassen EL, van Koeveringe GA. The use of hypochlorous acid as a model for investigating bladder overactivity. Int Braz J Urol. 2014;40(3):408–413. [DOI] [PubMed] [Google Scholar]
  • 32.Anele UA, Ratz PH, Colhoun AF, et al. Potential vascular mechanisms in an ex vivo functional pig bladder model. Neurourol Urodyn. 2018;37(8):2425–2433. [DOI] [PubMed] [Google Scholar]
  • 33.VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb Vasc Biol. 2004;24(1):12–22. [DOI] [PubMed] [Google Scholar]
  • 34.Brading AF, Greenland JE, Mills IW, McMurray G, Symes S. Blood supply to the bladder during filling. Scand J Urol Nephrol Suppl. 1999;201:25–31. [PubMed] [Google Scholar]
  • 35.Lee K, Mitsui R, Kajioka S, Naito S, Hashitani H. Role of PTHrP and Sensory Nerve Peptides in Regulating Contractility of Muscularis Mucosae and Detrusor Smooth Muscle in the Guinea Pig Bladder. J Urol. 2016;196(4):1287–1294. [DOI] [PubMed] [Google Scholar]
  • 36.Matheson PJ, Wilson MA, Garrison RN. Regulation of intestinal blood flow. J Surg Res. 2000;93(1):182–196. [DOI] [PubMed] [Google Scholar]
  • 37.Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 5 ed. Oxford: Oxford University Press; 2015. [Google Scholar]
  • 38.Cadenas E, Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000;29(3–4):222–230. [DOI] [PubMed] [Google Scholar]
  • 39.Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87(1):315–424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A. 1988;85(17):6465–6467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Marks LB, Carroll PR, Dugan TC, Anscher MS. The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. International journal of radiation oncology, biology, physics. 1995;31(5):1257–1280. [DOI] [PubMed] [Google Scholar]
  • 42.Ozyurt H, Cevik O, Ozgen Z, et al. Quercetin protects radiation-induced DNA damage and apoptosis in kidney and bladder tissues of rats. Free Radic Res. 2014;48(10):1247–1255. [DOI] [PubMed] [Google Scholar]
  • 43.Herrero A, Barja G. Effect of aging on mitochondrial and nuclear DNA oxidative damage in the heart and brain throughout the life-span of the rat. J Am Aging Assoc. 2001;24(2):45–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Chen Y, Zhou Z, Min W. Mitochondria, Oxidative Stress and Innate Immunity. Front Physiol. 2018;9:1487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Krysko DV, Agostinis P, Krysko O, et al. Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol. 2011;32(4):157–164. [DOI] [PubMed] [Google Scholar]
  • 46.Riedl MA, Nel AE. Importance of oxidative stress in the pathogenesis and treatment of asthma. Curr Opin Allergy Clin Immunol. 2008;8(1):49–56. [DOI] [PubMed] [Google Scholar]
  • 47.Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81–128. [DOI] [PubMed] [Google Scholar]
  • 49.Ghezzi P, Jaquet V, Marcucci F, Schmidt H. The oxidative stress theory of disease: levels of evidence and epistemological aspects. Br J Pharmacol. 2017;174(12):1784–1796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Hercberg S, Ezzedine K, Guinot C, et al. Antioxidant supplementation increases the risk of skin cancers in women but not in men. J Nutr. 2007;137(9):2098–2105. [DOI] [PubMed] [Google Scholar]

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