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International Journal of Urology (2015) 22, 40–46

doi: 10.1111/iju.12652

Review Article

Chronic bladder ischemia and oxidative stress: New pharmacotherapeutic targets for lower urinary tract symptoms Masanori Nomiya,1 Karl-Erik Andersson2,3 and Osamu Yamaguchi1 1

Division of Bioengineering and LUTD Research, Nihon University School of Engineering, Koriyama, Japan; 2Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; and 3Aarhus Institute for Advanced Studies, Aarhus University, Aarhus, Denmark

Abbreviations & Acronyms AR = adrenoceptor BKCa = large conductance calcium-activated potassium BOO = bladder outlet obstruction BPE = benign prostatic enlargement cAMP = cyclic adenosine monophosphate DO = detrusor overactivity ED = erectile dysfunction IPSS = international prostate symptom score LUT = lower urinary tract LUTS = lower urinary tract symptoms NGF = nerve growth factor OAB = overactive bladder PDE = phosphodiesterase PDE5 = phosphodiesterase type 5 PG = prostaglandin ROS = reactive oxygen species UAB = underactive bladder Correspondence: Masanori Nomiya M.D., Division of Bioengineering and LUTD Research, Nihon University School of Engineering, 1 Nakagawara, Tamuramachi, Koriyama 963-8642, Japan. Email: [email protected] Received 18 July 2014; accepted 15 September 2014. Online publication 22 October 2014

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Abstract: Chronic bladder ischemia is potentially a common cause of lower urinary tract symptoms in the elderly. Epidemiological studies have shown a close association between lower urinary tract symptoms and vascular risk factors for atherosclerosis, and investigations using transrectal color Doppler ultrasonography have shown a negative correlation between decreased lower urinary tract perfusion and International Prostate Symptom Score in elderly patients with lower urinary tract symptoms. Bladder blood flow is also known to decrease in men with bladder outlet obstruction as a result of benign prostatic hyperplasia. Studies in animal models suggest that chronic bladder ischemia and repeated ischemia/reperfusion during a micturition cycle might produce oxidative stress, leading to denervation of the bladder and the expression of tissue-damaging molecules in the bladder wall, which could be responsible for the development of bladder hyperactivity progressing to bladder underactivity. The effects of drugs with different mechanisms of action; for example, α1-adrenoceptor antagonists, phosphodiesterase type 5 inhibitors, free radical scavengers and β3-adrenoceptor agonist, have been studied in animal models of chronic bladder ischemia. The drugs, representing different treatment principles for increasing blood flow and decreasing oxidative stress, showed protective effects not only on urodynamic parameters, but also on negative effects on muscle contractility and on detrimental structural bladder wall changes. Improvement of lower urinary tract perfusion and control of oxidative stress can be considered new therapeutic strategies for treatment of bladder dysfunction induced by chronic ischemia.

Key words: atherosclerosis, bladder outlet obstruction, chronic bladder ischemia, oxidative stress, pharmacotherapy.

Introduction LUTS, including the OAB syndrome, occur commonly in both men and women, with an age-related increase in both sexes.1–3 Recently, attention has been focused on bladder ischemia as a common cause for LUTS in the elderly.4 A number of studies have suggested that in both men and women, arterial obstructive disease, such as atherosclerosis, eventually results in chronic bladder ischemia, which might play a key role in the development of LUTS.3,5–7 Supporting this view, transrectal color Doppler ultrasonography of elderly patients with LUTS also showed a significant decrease in blood flow of the LUT in comparison with asymptomatic younger controls.6 In addition, several studies have suggested that BOO causes a reduction of bladder blood flow.8–10 Chronic bladder ischemia and repeated ischemia/reperfusion during a micturition cycle might produce oxidative stress from the generation of ROS, and contribute to the development of LUTS and bladder dysfunction.3,8,9,11–17 Vascular endothelial dysfunction also occurs during the human aging process, and is an independent risk factor for the development of atherosclerosis and hypertension.18 It has been proposed that the cellular, tissue and organ damage associated with aging is caused by an increase in the content of ROS and a decrease in natural anti-oxidant mechanisms.19 Thus, improvement of LUT perfusion and control of oxidative stress might be therapeutic strategies in the management of aging-related bladder dysfunction. In the present review, based on evidence from available literature, we discuss chronic bladder ischemia associated with BOO as a result of BPE or atherosclerosis, animal models of bladder ischemia and the possible mechanisms for chronic ischemia-induced LUTS. We also suggest bladder ischemia and oxidative stress as therapeutic targets for drugs aimed for LUTS treatment. © 2014 The Japanese Urological Association

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BOO and chronic bladder ischemia OAB symptoms, with and without associated DO, are often associated with BOO and BPE. In obstructed bladders, there is a reduction of blood flow due to the effect of raised intravesical pressure during voiding and/or the increased tissue pressure in the bladder wall during filling.8,9 Koritsiadis et al. investigated that the expression of hypoxia-inducible factor-1α, a cellular marker of hypoxia, in the detrusor of patients with BOO, and showed that the number of hypoxia-inducible factor-1α immunoreactive cells significantly increased in the obstructed human bladder.10 These findings suggest that BOO can cause a reduction of bladder blood flow (ischemia) and hypoxia in the bladder. Gosling et al. showed a reduction in acetylcholine esterase staining (cholinergic) nerves in the obstructed human bladder, and pharmacological studies carried out on detrusor biopsies from patients with BOO showed that detrusor muscle strips from patients with DO exhibited denervation supersensitivity.20,21 As nerves are highly sensitive to ischemia and hypoxia, chronic bladder ischemia secondary to BOO could lead to partial denervation, which might be responsible for obstruction-induced male LUTS.

Atherosclerosis and chronic bladder ischemia Chronic bladder ischemia can occur independently of BOO in the elderly. The abdominal aorta and its branches, especially the bifurcation of the iliac arteries, are particularly vulnerable to atherosclerotic lesions.22 The vascular supply to the human genitourinary tract, including the bladder, prostate, uterus, urethra and penis, is primarily derived from the iliac arteries. Atherosclerotic obstructive changes distal to the aortic bifurcation will have consequences for the distal vasculature and LUT blood flow.4 Epidemiological studies have investigated the association between LUTS and vascular risk factors for atherosclerosis (hypertension, hyperlipidemia, diabetes mellitus and nicotine use).7,23 Ponholzer et al. reported that IPSS increased significantly in both men and women with two or more risk factors, suggesting a potential role of atherosclerosis in the development of LUTS in both sexes.7 Takahashi et al. also showed the association between severity of atherosclerosis and male LUTS.24 Using transrectal color Doppler ultrasonography, Pinggera et al. showed that elderly patients with LUTS had a significant decrease in bladder blood flow compared with asymptomatic young individuals. They also found a negative correlation between decreased LUT perfusion and IPSS in these elderly patients.6 Berger et al. found that in BPH patients with severe vascular damage (type 2 diabetes), LUT perfusion and IPSS were significantly worse compared with BPH patients without type 2 diabetes and healthy controls.25 This implies that coexisting vascular disease-related chronic ischemia might be more detrimental for bladder function than BPH alone. Histological studies have shown fibrosis formation or denervation in bladder samples from elderly male and female patients without BOO.26–28 These observations are supported by the study of Kershen et al., which showed that decreased bladder blood flow and decreased bladder wall compliance correlated strongly, suggesting structural changes in the bladder wall induced by ischemia.29 Furthermore, pelvic arterial insufficiency, such as © 2014 The Japanese Urological Association

Chronic bladder ischemia and oxidative stress

atherosclerosis, is also strongly associated with ED.30,31 The close association between LUTS and ED has been well documented in elderly men.32–34 Thus, these clinical studies suggest aging-associated alterations of the pelvic vasculature as a common etiology in the development of both conditions.5,35,36

Animal models of chronic bladder ischemia Despite intensive clinical studies, the mechanisms underlying the changes in bladder function caused by chronic ischemia, and the time course of the progression of these changes, are incompletely known. The impact of atherosclerosis-induced chronic ischemia alone on bladder function is not easily studied directly in humans because of issues relating to, for example, reproducible unified measurement of bladder blood flow and lack of convenience biomarkers that reflect the severity of LUTS induced by chronic ischemia. Thus, the concept of LUTS induced by aging-associated alterations of the pelvic vasculature does not seem to have been established clinically, and there is no generally accepted treatment. More detailed studies have been carried out in animal models.4 Recently, several animal models of chronic bladder ischemia in the absence of BOO have been described, and they might increase our understanding of the pathophysiology of bladder dysfunction induced by chronic ischemia and oxidative stress.4

Rabbit models Previous studies in rabbits showed that unilateral ligation of the vesical arteries failed to produce long-term bladder ischemia and bladder dysfunction. In contrast, bilateral ligation of the vesical arteries led to extremely severe structural and functional damage, causing permanent bladder injury.37,38 To develop a useful rabbit model of chronic bladder ischemia, Azadzoi et al. utilized arterial balloon-induced endothelial injury techniques together with a 0.5 % cholesterol diet to produce arterial occlusive disease in the iliac arteries.13,14 Studies in this model showed that moderate ischemia caused moderate fibrosis in the bladder wall, frequent voiding, bladder hyperactivity (defined as a significant increase in the frequency of spontaneous bladder contractions) and increased contractile responses to carbachol and electrical field stimulation. In contrast, severe ischemia caused severe fibrosis with weak bladder contraction and decreased contractile responses to various stimuli. In addition, markers of oxidative injury and neural density showed that bladder hyperactivity under ischemic conditions involved noxious oxidative products and denervation.13,14 The mechanisms by which chronic bladder ischemia induces bladder hyperactivity appeared to involve upregulation of stimulatory molecules, oxidative stress sensitive genes, ultrastructural damage and neurodegeneration.11,12,39–43 To evaluate bladder function in a rabbit model of gradual development of atherosclerosis and ischemia, Yoshida et al. examined the functional and histological bladder changes in the myocardial infarction-prone Watanabe heritable hyperlipidemia rabbit, widely used as a model of hyperlipidemia, atherosclerosis and related ischemic diseases. Their study showed that Watanabe heritable hyperlipidemia rabbits showed atherosclerotic changes in the iliac arteries, increased connective tissues 41

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in the bladder wall, denervation, frequent voiding and bladder hyperactivity (non-voiding contractions) with decreased detrusor contraction, and decreased contractile responses to carbachol and electrical field stimulation. They suggested that the bladder dysfunction observed in Watanabe heritable hyperlipidemia rabbits might be a state of detrusor hyperactivity with impaired contraction, which can be clinically observed in human older adults.44

Rat models To evaluate urodynamic characteristics in an awake animal with chronic bladder ischemia, Nomiya et al. developed a rat model using techniques similar to those used by Azadzoi et al. in rabbits.17 They found that endothelial injury of the iliac arteries combined with a 2% cholesterol diet for 8 weeks induced arterial occlusive disease and consequent bladder ischemia. Decreased contractile responses to various stimuli were observed, such as membrane depolarization (KCl), carbachol stimulation and electrical field stimulation. In addition, there were changes in mucosal proteins involved in remodeling, repair and intercellular communication, increased collagen ratio, decreased protein gene product 9.5 positive nerve fibers in the muscle layer, elevated oxidative stress markers, upregulation of pro-inflammatory cytokines and decreased constitutive nitric oxide synthase expression. These changes were associated with bladder hyperactivity defined as a significant increase in voiding frequency without an effect on maximum pressure or residual volume.15–17,45–49 Furthermore, they found that arterial occlusive disease plus endothelial dysfunction induced by the addition of NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, caused progressive vascular damage, resulting in more severe impaired detrusor contractility (in vitro) and bladder underactivity with increased post-void residual volume. These findings suggest that in rats progressive vascular damage causes bladder dysfunction, which develops from bladder hyperactivity to bladder underactivity.50 Son et al. evaluated voiding function in a previously described rat model of vasculogenic ED. Rats fed a 1% cholesterol diet for 8 weeks together with NG-nitro-L-arginine methyl ester (2 weeks) to induce vascular intimal changes showed atherosclerotic changes in the iliac arteries and urodynamical bladder hyperactivity with an increase in the proportions of purinergic contractions.51,52 Rahman et al. also examined bladder function in a rat model of ED. Rats fed 2% cholesterol and 10% lard diet alone for 6 months showed bladder hyperactivity with non-voiding contraction. They found hypertrophy of the detrusor muscle and upregulation of P2X3, P2X1 (adenosine triphosphate-receptor subunits) and vanilloid receptor 1 expression in the hyperlipidemic bladders, and suggested that these changes might contribute to bladder hyperactivity.53 However, in this model the results of, for example, bladder weight, vascular changes and cystometric parameters, were not reported.

Mouse model Shenfeld et al. examined the contractility of bladder muscle strips from apolipoprotein E gene knockout mice, which are known to develop atherosclerosis spontaneously. They showed 42

that 70-week-old apolipoprotein E gene knockout mice did not show statistically significant differences in in vitro detrusor function compared with control C57BI/6 mice, although apolipoprotein E gene knockout mice had massive atherosclerosis of the abdominal aortas and iliac arteries. They suggested that gradually developing atherosclerosis and the presumed chronic bladder ischemia associated with it probably do not significantly change the detrusor’s contractile responses to bethanechol and KCl or the resting tone.54 However, information on, for example, bladder weight and cystometric parameters, was not reported.

Possible mechanisms for LUTS induced by chronic ischemia and oxidative stress Evidence from clinical and basic research suggests that atherosclerosis in both sexes can induce a reduction of bladder blood flow, leading to chronic ischemia of the bladder. A decrease in blood flow (ischemia phase) resulting in a decrease in oxygen tension (hypoxia) in the bladder, is followed by an increase in blood flow and oxygen tension after micturition (reperfusion phase).13,14,17 Chronic bladder ischemia and repeated ischemia/ reperfusion during a micturition cycle might produce oxidative stress, leading to denervation of the bladder and the expression of tissue damaging molecules, such as NGF and PG, in the bladder wall.16,41,42 Masuda et al. have suggested that oxidative stress mediates bladder hyperactivity through sensitization of afferent pathways in the bladder of rats.55 Azadzoi et al. also showed that atherosclerosis-induced chronic ischemia caused increased tachykinin-containing nerves and upregulation of neurokinin-2 receptor gene expression in the epithelium, and suggested that chronic ischemia-related bladder hyperactivity might be involved in activation of afferent signaling through tachykinin-containing nerves and neurokinin receptors.12 Studies in animal models suggest that the extent of bladder dysfunction in chronic ischemia depends on the degree and duration of ischemia.13,14,50 This appears to be responsible for the development of DO progressing to detrusor underactivity and inability to empty the bladder (Fig. 1).4,50 Thus, moderate ischemia might cause DO and storage symptoms through sensitization of afferent pathways,12–14,55 as well as through a postjunctional supersensitivity as a result of partial denervation of the detrusor muscle.28,56 When bladder ischemia becomes severe and prolonged, progression of denervation and damage to the detrusor muscle with fibrosis formation might cause detrusor underactivity and voiding symptoms (Fig. 2).4,13,14,42,50

Therapeutic targets for chronic ischemia-related LUTS As aforementioned, chronic ischemia secondary to atherosclerosis and vascular dysfunction can cause structural and functional changes in the bladder, and might eventually lead to progression of these changes. If chronic ischemia is a common factor contributing to age-related structural and functional changes of the bladder, therapeutic strategies for LUTS in the elderly population would be not only “to treat LUTS”, but also “to have an inhibiting effect on the progression of ischemiarelated structural and functional bladder changes.”57 © 2014 The Japanese Urological Association

Chronic bladder ischemia and oxidative stress

Vascular dysfunction/atherosclerosis Chronic bladder ischemia/repeated ischemia reperfusion Oxidative stress Proinflammatory cytokines in the bladder Severe and prolonged ischemia PGs, NGF and other stimulatory molecules in the urothelium and sub-urothelium

Afferent activation

Denervation Partial denervation supersensitivity Localized contraction

Detrusor overactivity/OAB

Moderate

Decreased muscle contractility Decreased sensory input

Detrusor underactivity/UAB

Chronic bladder ischemia (oxidative stress)

Detrusor overactivity

Progression of denervation (motor and sensory) Collagen deposition

PDE5 inhibition Severe

Detrusor underactivity

Fig. 2 Chronic bladder ischemia as a cause of detrusor overactivity and detrusor underactivity.

α1-AR blockade In patients with LUTS/BPH, α1-AR antagonists are still the mainstay of medical treatment.58,59 Such antagonists were developed based on the hypothesis that these drugs improve voiding dysfunction in LUTS by relieving BOO, as they were shown to relax prostatic smooth muscle and decrease urethral pressure in animal models. However, there are reports showing little association between LUTS improvement by α1-AR antagonist treatment and changes in bladder outlet resistance.60,61 In addition, these drugs improve LUTS in the absence of BOO. This shows that their therapeutic effects might occur independently of prostatic relaxation.59 Pinggera et al. reported that α1-AR antagonists improve bladder blood flow and symptoms in patients with LUTS, and suggested that these drugs might ameliorate LUTS by increasing bladder blood flow.62 Goi et al. investigated the effects of the selective α1-AR antagonist, silodosin, on bladder blood flow and bladder function using the rat model of chronic bladder ischemia described by Nomiya et al.16,17,45 In rats with chronic bladder ischemia, silodosin abrogated the decreased bladder blood flow in the empty bladder and during bladder distention, and prevented oxidative damage, resulting in elimination of bladder hyperactivity.45 These observations were supported by several studies in other rat models of ischemia/reperfusion or overdistention/emptyinginduced bladder hyperactivity showing that the α1-AR antagonist, tamsulosin, improved bladder hyperactivity through improvement of bladder blood flow as compared with the untreated group.63,64 © 2014 The Japanese Urological Association

Fig. 1 Possible mechanisms for LUTS induced by chronic ischemia and oxidative stress.

A current area of interest in male LUTS centers around a role for the nitric oxide/cyclic guanosine monophosphate signaling in the prostate and urinary bladder. Recent studies suggest that similar mechanisms might underlie the generation of male LUTS and ED.5,36,65–67 Based on this suggestion, it has been proposed that PDE5 inhibitors might target this signaling pathway to relax the bladder, urethra and prostate smooth muscle, thereby alleviating LUTS.68–70 However, the precise mechanisms of action of PDE5 inhibitors on LUTS remain to be elucidated. Recent evidence also suggests that bladder ischemia could play a role in the pathogenesis of male DO and OAB symptoms. In this respect, PDE5 inhibitors might produce vasodilation in the bladder, leading to an improvement of bladder ischemia and subsequent amelioration of LUTS.3,5,58 However, in a randomized controlled trial, Pinggera et al., using transrectal ultrasonography, compared the effects of tadalafil 5 mg/day and placebo given for 8 weeks to men with moderate to severe LUTS/BPH. They found no differences between the treatments, but did not exclude that changes in blood flow might have occurred, which for several reasons could not be detected.71 Interestingly, as mentioned previously, Pinggera et al., also using transrectal color Doppler ultrasound, quite convincingly showed that tamsulosin could increase perfusion to the LUT.62 Nomiya et al. investigated prophylactic effects of tadalafil on bladder function in a rat model of chronic bladder ischemia, and showed that chronic treatment with tadalafil protects bladder function and morphology, resulting in decreased bladder hyperactivity.47 Although the precise mechanisms of positive action of tadalafil were not established, these findings suggest that PDE5 inhibitors might not only be able to reduce LUTS, but also have an inhibitory effect on the progression of the underlying disorder.57

Anti-oxidant and free radical scavenging It has been proposed that the cellular, tissue and organ damage associated with aging is caused by an increase in the content of 43

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ROS and a decrease in natural anti-oxidant mechanisms.19 Atherosclerosis is also well known to be an inflammatory process involving a number of pro-inflammatory cytokines, and it is considered a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall.72,73 Studies in an experimental model in rabbits suggested that lack of perfusion and subsequent accumulation of oxidative stress and nitrosative elements in atherosclerosis-induced chronic bladder ischemia might contribute to the deterioration of microvasculature, nerve fibers, epithelium and smooth muscle cells by lipid peroxidation, protein oxidation and DNA damage.43 It is reasonable to assume that bladder hyperactivity, such as frequent bladder contractions under ischemic conditions, could involve accumulation of oxidative stress molecules, which in turn might lead to further impairment of bladder microcirculation resulting in a vicious cycle of tissue damage. There are many agents showing protective effects against oxidative stress induced by ischemia-reperfusion bladder injuries; for example, melatonin, co-enzyme Q10, eviprostat, vitamin E and edaravone.74–80 The effects of melatonin, eviprostat and co-enzyme Q10 have been investigated in the rat model of chronic bladder ischemia described by Nomiya et al., and the functional and morphological changes caused by chronic ischemia-related oxidative stress were protected by chronic treatment with these agents, resulting in improvement of bladder hyperactivity.15,46,81 Thus, control of oxidative stress as a therapeutic strategy could have beneficial effects on chronic ischemia-related bladder dysfunction.

bladder ischemia.17,91 However, they found that chronic treatment of mirabegron protected functional and morphological changes, resulting in reduced bladder hyperactivity without affecting post-void residual volume or micturition pressure, and suggested that mirabegron stimulation of BKCa channels in the bladder could well have a protective action. Supporting this, there is evidence that in the bladder, K+ channels mediating hyperpolarization, particularly BKCa channels, might be more important in β3-AR mediated relaxation than cAMP,92,93 and stimulation of BKCa channels could have cytoprotective effects.94–96 In conclusion, chronic bladder ischemia and oxidative stress might be important factors contributing to the development of LUTS in the elderly. Drugs with different mechanisms of action, such as α1-AR antagonists, PDE5 inhibitors, free radical scavengers and β3-AR agonists, have been tested in animal models of chronic bladder ischemia, and shown not only to protect against urodynamic changes (hyperactivity), but also to prevent the decrease in bladder muscle contractility and the detrimental structural changes induced by chronic ischemia and oxidative stress. Currently, several of the drugs discussed are being used in clinical practice, and some of them might be able not only to relieve symptoms, but also to have an inhibiting effect on the progression of chronic ischemia-related structural and functional bladder changes. Thus, improvement of LUT perfusion and control of oxidative stress can be considered new therapeutic strategies for treatment of bladder dysfunction induced by chronic ischemia.

β3-AR agonists

KE Andersson is a consultant/advisor to Allagan, Astellas and Ferring. O Yamaguchi is a consultant/advisor to Astellas and Ferring.

The β3-AR agonist, mirabegron, was recently introduced as an alternative to antimuscarinics in the treatment of OAB, and approved for use in Japan, the USA and the European Union.58,82 The efficacy of this drug was well documented in randomized controlled clinical trials.83–85 Stimulation of β3-AR relaxes detrusor smooth muscle, and consequently decreases afferent signaling from the bladder, improves bladder compliance on filling and increases bladder capacity.86,87 In hypoxic endothelial cells in culture, the concentration of cAMP was shown to decrease through a reduction of adenylyl cyclase activity. Warm ischemia is known to decrease the cAMP concentration in the liver, heart and kidney.88–90 Therefore, it might be reasonable to assume that a reduction of cAMP concentration also occurs in bladder tissue in chronic ischemia. Because urine storage and distension might induce vessel compression and in turn worsen ischemia/hypoxia by consuming more energy during the voiding phase, a cAMP-decreasing effect can be thought of as a defensive mechanism under ischemic conditions.8,9 If mirabegron mediates bladder relaxation and increases bladder capacity in the chronically ischemic bladder, this can be expected to affect the restrained cell metabolism under ischemic conditions, and raises the question of whether mirabegron treatment might have a negative impact, such as increased residual urine, on the chronically ischemic bladder. To test this question Sawada et al. investigated the effect of mirabegron in the previously described rat model of chronic 44

Conflict of interest

References 1 Chapple CR, Wein AJ, Abrams P et al. Lower urinary tract symptoms revisited: a broader clinical perspective. Eur. Urol. 2008; 54: 563–9. 2 Irwin DE, Milsom I, Hunskaar S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur. Urol. 2006; 50: 1306–14. 3 Yamaguchi O, Aikawa K, Shishido K, Nomiya M. Place of overactive bladder in male lower urinary tract symptoms. World J. Urol. 2009; 27: 723–8. 4 Yamaguchi O, Nomiya M, Andersson KE. Functional consequences of chronic bladder ischemia. Neurourol. Urodyn. 2014; 33: 54–8. 5 Andersson KE, de Groat WC, McVary KT et al. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action. Neurourol. Urodyn. 2011; 30: 292–301. 6 Pinggera GM, 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 Int. 2008; 102: 470–4. 7 Ponholzer A, Temml C, Wehrberger C, Marszalek M, Madersbacher S. The association between vascular risk factors and lower urinary tract symptoms in both sexes. Eur. Urol. 2006; 50: 581–6. 8 Greenland JE, Brading AF. The effect of bladder outflow obstruction on detrusor blood flow changes during the voiding cycle in conscious pigs. J. Urol. 2001; 165: 245–8. 9 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: 1109–14. 10 Koritsiadis G, Stravodimos K, Koutalellis G et al. Immunohistochemical estimation of hypoxia in human obstructed bladder and correlation with clinical variables. BJU Int. 2008; 102: 328–32. © 2014 The Japanese Urological Association

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11 Azadzoi KM, Radisavljevic ZM, Golabek T, Yalla SV, Siroky MB. Oxidative modification of mitochondrial integrity and nerve fiber density in the ischemic overactive bladder. J. Urol. 2010; 183: 362–9. 12 Azadzoi KM, Radisavljevic ZM, Siroky MB. Effects of ischemia on tachykinin-containing nerves and neurokinin receptors in the rabbit bladder. Urology 2008; 71: 979–83. 13 Azadzoi KM, Tarcan T, Kozlowski R, Krane RJ, Siroky MB. Overactivity and structural changes in the chronically ischemic bladder. J. Urol. 1999; 162: 1768–78. 14 Azadzoi KM, Tarcan T, Siroky MB, Krane RJ. Atherosclerosis-induced chronic ischemia causes bladder fibrosis and non-compliance in the rabbit. J. Urol. 1999; 161: 1626–35. 15 Nomiya M, Burmeister DM, Sawada N et al. Effect of melatonin on chronic bladder-ischaemia-associated changes in rat bladder function. BJU Int. 2013; 112: E221–30. 16 Nomiya M, Sagawa K, Yazaki J et al. Increased bladder activity is associated with elevated oxidative stress markers and proinflammatory cytokines in a rat model of atherosclerosis-induced chronic bladder ischemia. Neurourol. Urodyn. 2012; 31: 185–9. 17 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: 195–200. 18 Herrera MD, Mingorance C, Rodriguez-Rodriguez R, Alvarez de Sotomayor M. Endothelial dysfunction and aging: an update. Ageing Res. Rev. 2010; 9: 142–52. 19 Harman D. Free radical theory of aging. Mutat. Res. 1992; 275: 257–66. 20 Gosling JA, Gilpin SA, Dixon JS, Gilpin CJ. Decrease in the autonomic innervation of human detrusor muscle in outflow obstruction. J. Urol. 1986; 136: 501–4. 21 Harrison SC, Hunnam GR, Farman P, Ferguson DR, Doyle PT. Bladder instability and denervation in patients with bladder outflow obstruction. Br. J. Urol. 1987; 60: 519–22. 22 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. 23 Seyung Kim JYJ, Yong Jun C, Dong Hyun K, Won Ki L, Seong Ho L. Association between lower urinary tract symptoms and vascular risk factors in aging men: the hallym aging study. Korean J. Urol. 2010; 51: 477–82. 24 Takahashi N, Shishido K, Ogawa S et al. The association between severity of atherosclerosis and lower urinary tract function in male patients with lower urinary tract symptoms. LUTS 2012; 4: 9–13. 25 Berger AP, Horninger W, Bektic J et al. Vascular resistance in the prostate evaluated by colour Doppler ultrasonography: is benign prostatic hyperplasia a vascular disease? BJU Int. 2006; 98: 587–90. 26 Holm NR, Horn T, Hald T. Detrusor in ageing and obstruction. Scand. J. Urol. Nephrol. 1995; 29: 45–9. 27 Lepor H, Sunaryadi I, Hartanto V, Shapiro E. Quantitative morphometry of the adult human bladder. J. Urol. 1992; 148: 414–7. 28 Mills IW, Greenland JE, McMurray G et al. Studies of the pathophysiology of idiopathic detrusor instability: the physiological properties of the detrusor smooth muscle and its pattern of innervation. J. Urol. 2000; 163: 646–51. 29 Kershen RT, Azadzoi KM, Siroky MB. Blood flow, pressure and compliance in the male human bladder. J. Urol. 2002; 168: 121–5. 30 Kostis JB, Jackson G, Rosen R et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am. J. Cardiol. 2005; 96: 85M–93M. 31 Montorsi P, Ravagnani PM, Galli S et al. Association between erectile dysfunction and coronary artery disease: matching the right target with the right test in the right patient. Eur. Urol. 2006; 50: 721–31. 32 Braun MH, Sommer F, Haupt G, Mathers MJ, Reifenrath B, Engelmann UH. Lower urinary tract symptoms and erectile dysfunction: co-morbidity or typical “Aging Male” symptoms? Results of the “Cologne Male Survey”. Eur. Urol. 2003; 44: 588–94. 33 Kohler TS, McVary KT. The relationship between erectile dysfunction and lower urinary tract symptoms and the role of phosphodiesterase type 5 inhibitors. Eur. Urol. 2009; 55: 38–48. 34 Ponholzer A, Temml C, Obermayr R, Madersbacher S. Association between lower urinary tract symptoms and erectile dysfunction. Urology 2004; 64: 772–6.

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35 Coyne KS, Kaplan SA, Chapple CR et al. Risk factors and comorbid conditions associated with lower urinary tract symptoms: EpiLUTS. BJU Int. 2009; 103 (Suppl 3): 24–32. 36 McVary K. Lower urinary tract symptoms and sexual dysfunction: epidemiology and pathophysiology. BJU Int. 2006; 97 (Suppl 2): 23–8; discussion 44-5. 37 Gill HS, Monson FC, Wein AJ, Ruggieri MR, Levin RM. The effects of short-term in-vivo ischemia on the contractile function of the rabbit urinary bladder. J. Urol. 1988; 139: 1350–4. 38 Tong-Long Lin A, Gill HS, Wein AJ, Levin RM. Functional effect of chronic ischemia on the rabbit urinary bladder. Neurourol. Urodyn. 1988; 7: 1–12. 39 Azadzoi KM. Effect of chronic ischemia on bladder structure and function. Adv. Exp. Med. Biol. 2003; 539: 271–80. 40 Azadzoi KM, Heim VK, Tarcan T, Siroky MB. Alteration of urothelial-mediated tone in the ischemic bladder: role of eicosanoids. Neurourol. Urodyn. 2004; 23: 258–64. 41 Azadzoi KM, Shinde VM, Tarcan T, Kozlowski R, Siroky MB. Increased leukotriene and prostaglandin release, and overactivity in the chronically ischemic bladder. J. Urol. 2003; 169: 1885–91. 42 Azadzoi KM, Yalla SV, Siroky MB. Oxidative stress and neurodegeneration in the ischemic overactive bladder. J. Urol. 2007; 178: 710–5. 43 Azadzoi KM, Chen BG, Radisavljevic ZM, Siroky MB. Molecular reactions and ultrastructural damage in the chronically ischemic bladder. J. Urol. 2011; 186: 2115–22. 44 Yoshida M, Masunaga K, Nagata T, Satoji Y, Shiomi M. The effects of chronic hyperlipidemia on bladder function in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. Neurourol. Urodyn. 2010; 29: 1350–4. 45 Goi Y, Tomiyama Y, Nomiya M, Sagawa K, Aikawa K, Yamaguchi O. Effects of Silodosin, a Selective alpha1A-Adrenoceptor Antagonist, on Bladder Blood Flow and Bladder Function in a Rat Model of Atherosclerosis Induced Chronic Bladder Ischemia without Bladder Outlet Obstruction. J. Urol. 2013; 190: 1116–22. 46 Matsui T, Oka M, Fukui T et al. Suppression of bladder overactivity and oxidative stress by the phytotherapeutic agent, Eviprostat, in a rat model of atherosclerosis-induced chronic bladder ischemia. Int. J. Urol. 2012; 19: 669–75. 47 Nomiya M, Burmeister DM, Sawada N et al. Prophylactic effect of tadalafil on bladder function in a rat model of chronic bladder ischemia. J. Urol. 2013; 189: 754–61. 48 Sagawa K, Aikawa K, Nomiya M et al. Impaired detrusor contractility in a rat model of chronic bladder ischemia. Urology 2013; 81: 1379 e9–14. 49 Sunagawa M, Wolf-Johnston A, Nomiya M et al. Urinary bladder mucosal responses to ischemia. World J. Urol. 2014. doi: 10.1007/s00345-01401298-1 50 Nomiya M, Yamaguchi O, Akaihata H et al. Progressive vascular damage may lead to bladder underactivity in rats. J. Urol. 2014; 191: 1462–9. 51 Park K, Son H, Kim SW, Paick JS. Initial validation of a novel rat model of vasculogenic erectile dysfunction with generalized atherosclerosis. Int. J. Impot. Res. 2005; 17: 424–30. 52 Son H, Lee SL, Park WH et al. New unstable bladder model in hypercholesterolemia rats. Urology 2007; 69: 186–90. 53 Rahman NU, Phonsombat S, Bochinski D, Carrion RE, Nunes L, Lue TF. An animal model to study lower urinary tract symptoms and erectile dysfunction: the hyperlipidaemic rat. BJU Int. 2007; 100: 658–63. 54 Shenfeld OZ, Meir KS, Yutkin V, Gofrit ON, Landau EH, Pode D. Do atherosclerosis and chronic bladder ischemia really play a role in detrusor dysfunction of old age? Urology 2005; 65: 181–4. 55 Masuda H, Kihara K, Saito K et al. Reactive oxygen species mediate detrusor overactivity via sensitization of afferent pathway in the bladder of anaesthetized rats. BJU Int. 2008; 101: 775–80. 56 Brading AF, Turner WH. The unstable bladder: towards a common mechanism. Br. J. Urol. 1994; 73: 3–8. 57 Andersson KE, Nomiya M, Sawada N, Yamaguchi O. Pharmacological treatment of chronic pelvic ischemia. Ther. Adv. Urol. 2014; 6: 105–14. 58 Yamaguchi O. Latest treatment for lower urinary tract dysfunction: therapeutic agents and mechanism of action. Int. J. Urol. 2013; 20: 28–39. 59 Michel MC. The forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction: alpha-blockers in the treatment of male voiding dysfunction – how do they work and why do they differ in tolerability? J. Pharmacol. Sci. 2010; 112: 151–7.

45

M NOMIYA ET AL.

60 Barendrecht MM, Abrams P, Schumacher H, de la Rosette JJ, Michel MC. Do alpha1-adrenoceptor antagonists improve lower urinary tract symptoms by reducing bladder outlet resistance? Neurourol. Urodyn. 2008; 27: 226–30. 61 Kortmann BB, Floratos DL, Kiemeney LA, Wijkstra H, de la Rosette JJ. Urodynamic effects of alpha-adrenoceptor blockers: a review of clinical trials. Urology 2003; 62: 1–9. 62 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: 319–24. 63 Mizuno H, Yamamoto T, Okutsu H et al. Effect of tamsulosin on bladder microcirculation in a rat ischemia-reperfusion model, evaluated by pencil lens charge-coupled device microscopy system. Urology 2010; 76: 1266. e1–5. 64 Okutsu H, Matsumoto S, Ohtake A et al. Effect of tamsulosin on bladder blood flow and bladder function in a rat model of bladder over distention/emptying induced bladder overactivity. J. Urol. 2011; 186: 2470–7. 65 McVary KT. Erectile dysfunction and lower urinary tract symptoms secondary to BPH. Eur. Urol. 2005; 47: 838–45. 66 Rosen R, Altwein J, Boyle P et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur. Urol. 2003; 44: 637–49. 67 Rosen RC, Giuliano F, Carson CC. Sexual dysfunction and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Eur. Urol. 2005; 47: 824–37. 68 Gillespie JI, Markerink-van Ittersum M, De Vente J. Endogenous nitric oxide/cGMP signalling in the guinea pig bladder: evidence for distinct populations of sub-urothelial interstitial cells. Cell Tissue Res. 2006; 325: 325–32. 69 Truss MC, Stief CG, Uckert S et al. Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside. World J. Urol. 2001; 19: 344–50. 70 Uckert S, Kuthe A, Jonas U, Stief CG. Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J. Urol. 2001; 166: 2484–90. 71 Pinggera GM, Frauscher F, Paduch DA et al. Effect of tadalafil once daily on prostate blood flow and perfusion in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: a randomized, double-blind, multicenter, placebo-controlled trial. Urology 2014; 84: 412–9. 72 Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ. Res. 2004; 95: 764–72. 73 Ross R. Atherosclerosis–an inflammatory disease. N. Engl. J. Med. 1999; 340: 115–26. 74 Matsumoto S, Hanai T, Shimizu N, Sugimoto K, Uemura H. Effect of edaravone on ischemia/reperfusion injury in rat urinary bladder–changes in smooth muscle cell phenotype and contractile function. Aktuelle Urol. 2010; 41 (Suppl 1): S46–9. 75 Juan YS, Chuang SM, Mannikarottu A et al. Coenzyme Q10 diminishes ischemia-reperfusion induced apoptosis and nerve injury in rabbit urinary bladder. Neurourol. Urodyn. 2009; 28: 339–42. 76 Kawai Y, Oka M, Kyotani J, Oyama T, Matsumoto S, Kakizaki H. Effect of the phytotherapeutic agent eviprostat on the bladder in a rat model of bladder overdistension/emptying. Neurourol. Urodyn. 2013; 32: 1031–7. 77 Oka M, Fukui T, Ueda M, Tagaya M, Oyama T, Tanaka M. Suppression of bladder oxidative stress and inflammation by a phytotherapeutic agent in a rat model of partial bladder outlet obstruction. J. Urol. 2009; 182: 382–90. 78 Sener G, Sehirli AO, Paskaloglu K, Dulger GA, Alican I. Melatonin treatment protects against ischemia/reperfusion-induced functional and biochemical changes in rat urinary bladder. J. Pineal Res. 2003; 34: 226–30. 79 Shimizu S, Saito M, Kinoshita Y et al. Acute urinary retention and subsequent catheterization cause lipid peroxidation and oxidative DNA

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81

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84

85

86

87

88

89

90

91

92

93

94

95

96

damage in the bladder: preventive effect of edaravone, a free-radical scavenger. BJU Int. 2009; 104: 713–7. Parekh MH, Lobel R, O’Connor LJ, Leggett RE, Levin RM. Protective effect of vitamin E on the response of the rabbit bladder to partial outlet obstruction. J. Urol. 2001; 166: 341–6. Kim JW, Jang HA, Bae JH, Lee JG. Effects of coenzyme Q10 on bladder dysfunction induced by chronic bladder ischemia in a rat model. J. Urol. 2013; 189: 2371–6. Andersson KE, Martin N, Nitti V. Selective beta(3)-adrenoceptor agonists for the treatment of overactive bladder. J. Urol. 2013; 190: 1173–80. Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J. Urol. 2013; 189: 1388–95. Chapple CR, Dvorak V, Radziszewski P et al. A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int. Urogynecol. J. 2013; 24: 1447–58. Yamaguchi O, Marui E, Kakizaki H et al. Phase III, randomised, double-blind, placebo-controlled study of the beta -adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int. 2014; 113: 951–60. Aizawa N, Homma Y, Igawa Y. Effects of mirabegron, a novel beta3-adrenoceptor agonist, on primary bladder afferent activity and bladder microcontractions in rats compared with the effects of oxybutynin. Eur. Urol. 2012; 62: 1165–73. Gillespie JI, Palea S, Guilloteau V, Guerard M, Lluel P, Korstanje C. Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the beta(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int. 2012; 110: E132–42. Minor T, Akbar S, Tolba R. Preservation of livers from non-heart-beating donors: modulation of cAMP signal and organ viability by glucagon. Transplant. Proc. 1999; 31: 1068. Pinsky D, Oz M, Liao H et al. Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model. J. Clin. Invest. 1993; 92: 2994–3002. Riera M, Torras J, Cruzado JM et al. The enhancement of endogenous cAMP with pituitary adenylate cyclase-activating polypeptide protects rat kidney against ischemia through the modulation of inflammatory response. Transplantation 2001; 72: 1217–23. Sawada N, Nomiya M, Hood B, Koslov D, Zarifpour M, Andersson KE. Protective Effect of a beta3-Adrenoceptor Agonist on Bladder Function in a Rat Model of Chronic Bladder Ischemia. Eur. Urol. 2013; 64: 664–71. Frazier EP, Peters SL, Braverman AS, Ruggieri MR, Sr, Michel MC. Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors. Naunyn Schmiedebergs Arch. Pharmacol. 2008; 377: 449–62. Uchida H, Shishido K, Nomiya M, Yamaguchi O. Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors. Eur. J. Pharmacol. 2005; 518: 195–202. Chmielewska L, Malinska D. Cytoprotective action of the potassium channel opener NS1619 under conditions of disrupted calcium homeostasis. Pharmacol. Rep. 2011; 63: 176–83. Cole WC, McPherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. Circ. Res. 1991; 69: 571–81. Xu W, Liu Y, Wang S et al. Cytoprotective role of Ca2+- activated K+ channels in the cardiac inner mitochondrial membrane. Science 2002; 298: 1029–33.

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