The pathophysiology of lower urinary tract symptoms (LUTS), particularly in the elderly, seems to be multifactorial. One of the factors involved may be chronic ischemia of the bladder caused by bladder outflow obstruction (male) or atherosclerosis (male/female). The mechanisms by which chronic ischemia initiates and causes LUTS and progressive bladder dysfunction, and the time course of the effects, are incompletely known. Bladder ischemia and repeated ischemia/reperfusion during a micturition cycle may produce oxidative stress, leading to denervation of the bladder and the expression of tissue damaging molecules in the bladder wall. This may be responsible for the development of detrusor overactivity progressing to detrusor underactivity and inability to empty the bladder. The extent of bladder dysfunction in chronic bladder ischemia may depend on the degree and duration of ischemia. To prevent chronic bladder ischemia caused by atherosclerosis and to treat its consequences, more pathophysiological knowledge is needed. Several animal models of atherosclerosis-induced chronic bladder ischemia are available and should be useful tools for further research. Neurourol. Urodynam. 33:54–58, 2014. © 2013 Wiley Periodicals, Inc.
Aging-related bladder dysfunction and associated lower urinary tract symptoms (LUTS) have been well documented in both male and female patients. LUTS are divided into storage, voiding and postmicturition symptoms. Overactive bladder, the storage subset of LUTS, is a symptom syndrome defined as urgency, with or without urgency incontinence, usually with frequency and nocturia.
In males, benign prostatic enlargement (BPE) and consequent bladder outflow obstruction (BOO) have been believed to be the basis for LUTS. However, LUTS may occur independently of BOO because men with LUTS do not necessarily have BOO. Thus, male LUTS may result from BOO or a primary bladder abnormality. Recent epidemiological studies have demonstrated that LUTS, including OAB, occur commonly in both men and women, with an age-related increase seen in both sexes.[4, 5] It is likely that LUTS is a gender-independent, age-related multifactorial process encompassing functional changes of the bladder and systemic medical comorbidity. However, the specific mechanisms behind the different types of LUTS remain to be established.
Recently, attention has been focused on bladder ischemia as a common pathophysiologic mechanism for LUTS. In male patients, LUTS are often associated with BOO, and BOO is known to cause a reduction in bladder blood flow (bladder ischemia).[6, 7] In addition, recent epidemiologic studies[8-11] have suggested that in both men and women, arterial obstructive disease, such as atherosclerosis, eventually results in chronic bladder ischemia, which may play a key role in the development of LUTS. Supporting this view, transrectal color Doppler ultrasonography of elderly patients with LUTS also showed a significant decrease in blood flow of the lower urinary tract in comparison with asymptomatic younger controls.[12, 13] The mechanisms underlying the changes in bladder function caused by chronic bladder ischemia, and the time course of the progression of these changes, are incompletely known.
In this review, based on evidence from available literature, we discuss the effects of chronic ischemia on bladder function, with particular emphasis on chronic ischemia associated with BOO and atherosclerosis, and suggest some directions for future research.
BLADDER BLOOD FLOW
The vascular supply to the human bladder is derived mainly from the superior and inferior vesical arteries, the latter being directly connected to the internal iliac artery. This means atherosclerotic obstructive changes distal to the aortic bifurcation will have consequences for the distal vasculature and for bladder blood flow. Miodoński and Litwin, performing a corrosion casting study on the human bladder wall, identified two major vascular plexuses (adventitial/serosal and mucosal) and distinguished two distinct capillary networks (muscular and subepithelial) in the successive layers of the wall. The barrier function of the urothelium and contractile functions of the detrusor depend on adequate supply of oxygen and nutrients from the blood. The blood vessels in the bladder wall must be capable of adapting to the spatial changes that result from the filling/voiding cycle without compromising the bloodstriking feature of almost all bladder vessels, except the capillaries—tortuosity ranging from waviness to tight coiling. The mucosal plexus consisted of some capillaries, thin arteries (50–100 µm) and more numerous thicker veins (80–250 µm), showing a tortuous appearance and frequent interlacements. The rich mucosal plexus formed a distinct vascular layer that followed the mucosal folds parallel to their surface and gave off short, straight, mostly perpendicular twigs communicating with the subepithelial capillary network. The subepithelial capillary network showed extreme density and uneven contours of the capillaries. The network was looser and the capillaries thinner only in less folded areas of the trigone and urethral orifice. In contrast, the capillary system of the muscularis was poorly developed.
It is reasonable to assume that the arrangement of the bladder wall vessels should make it possible to maintain blood flow during normal filling. However, measurements of bladder blood flow during filling, using different methodologies, have shown divergent results with both increased and decreased flow. A drop in vascular resistance and an increase in blood flow during filling in spite of increasing intravesical pressure was seen in the cat when blood flow was measured. In human bladders without obstruction, there was a twofold increase in bladder blood flow associated with filling, compared to the empty state, as measured with laser Doppler in the posterior wall. Blood flow did not start to decrease until 75% of maximum capacity was reached. Several studies have shown a decreased blood flow in both the mucosa and the detrusor muscle. Nemeth et al., using a microsphere technique in dogs, found a greater fall in the mucosal than in the muscularis blood flow. This would mean that the mucosa, which has a metabolic rate three times higher than that of the detrusor, should be the most vulnerable part of the bladder wall. Since a large part of afferent nerves are located within the lamina propria, they may be activated to signal ischemic insult. Indeed, this seems to be the case. Azadzoi et al. showed that in the rabbit bladder, atherosclerosis-induced ischemia caused alterations of neurokinin 2 receptor reactivity and gene expression, an increased number of tachykinin immunopositive nerves and greater immunoreactivity of epithelial tachykinin.
BOO AND BLADDER ISCHEMIA
OAB symptoms and detrusor overactivity (DO) are often associated with BPE and BOO. In obstructed bladder, there is a reduction of blood flow due to the effect of raised intravesical pressure during voiding or the increased tissue pressure in the bladder wall during filling. Such hemodynamic change has been demonstrated in a canine model of outlet obstruction. Greenland and Brading also showed that BOO is associated with repeated episodes of prolonged detrusor ischemia in pigs. Results from another study using inducible form of nitric oxide synthase knockout mice suggest that the generation of nitric oxide (NO) soon after obstruction is necessary to prevent detrusor dysfunction, since NO produces vasodilatation and decreases platelet aggregation.
Gosling et al. demonstrated a reduction in acetylcholine esterase staining nerves in detrusor muscle from patients with BOO, suggesting that partial denervation of the detrusor muscle occurs in obstructed human bladder. This would mean that bladder blood flow decreases (bladder ischemia) in this condition, since nerves are highly sensitive to ischemia or hypoxia. Koritsiadis et al. investigated the expression of hypoxia-inducible factor (HIF-1α), a cellular marker of hypoxia, in the detrusor of patients with BOO, and demonstrated that the number of HIF-1α-immunoreactive cells, mainly in stromal cells, significantly increased in obstructed human bladder. Thus, these clinical studies suggest that chronic bladder ischemia secondary to BOO may be responsible for obstruction-induced male LUTS.
In this context, the therapeutic effect of an α-adrenergic receptor (AR) blocker on male LUTS would be due to the improvement of bladder ischemia. Using transrectal color Doppler ultrasound, Pinggera et al. reported significantly lower maximum filling capacity and reduced change in perfusion during filling in 19 men with LUTS compared to 4 healthy age-matched controls. Following 5 weeks of α-AR blocker therapy, bladder capacity increased substantially, the change in perfusion reached essentially normal levels, and substantial improvements were seen in LUTS. In apparent disagreement with the view that α-AR blocker therapy improves bladder ischemia, Koritsiadis et al. did not find that treatment with tamsulosin in patients with BOO resulted in down-regulation of HIF-1α: They speculated that “it is likely that once obstruction has settled, [α-AR blocker treatment] does not change bladder metabolism, which continues to be under chronic stress.”
As described, BOO can cause bladder ischemia which leads to partial denervation of the detrusor muscle.[7, 25] A study in pigs and mini-pigs of experimental outflow obstruction showed consistent increases in voiding pressure and reduced flow rates in all obstructed animals, evidence of bladder instability in 77%, and an increased sensitivity to agonists applied exogenously. Pharmacologic studies performed on detrusor muscle biopsies from patients with BOO showed that detrusor strips from DO patients exhibited denervation supersensitivity.[22, 27] A postjunctional supersensitivity, secondary to partial denervation of the obstructed bladder, may contribute to DO and OAB symptoms. In addition, increased outflow resistance may result in changes in the electrical properties of the detrusor smooth muscle, and reorganization of C-fiber-mediated micturition reflexes,[29, 30] both of which are associated with the development of DO in animal models.
In animal model studies of obstructed bladder, chronic BOO progresses from a compensated state, where emptying remains normal, to a decompensated state characterized by reduced flow, interrupted urination and finally an elevated postvoid residual volume. Levin et al. suggested that the important characteristics of animal bladder response to partial outlet obstruction are progressive increase in bladder mass and progressive denervation.
ATHEROSCLEROSIS AND CHRONIC BLADDER ISCHEMIA
LUTS, a gender-independent and multifactorial process, show an age-related increase in both sexes.[4, 5, 32] BOO is known to cause male LUTS, but many men with LUTS do not have BOO.[2, 8, 33, 34] Thus, there may be common causes for the development of LUTS affecting both men and women.
A number of cardiovascular, metabolic, and endocrine factors may be associated with the development of LUTS.[9, 10] Vascular endothelial dysfunction also occurs during the human aging process and is an independent risk factor for the development of atherosclerosis and hypertension. Ponholzer et al. have investigated the association between LUTS and vascular risk factors (hypertension, hyperlipemia, diabetes mellitus, nicotine use). They reported that the international prostate symptom score increased significantly in both men and women with two or more risk factors, suggesting the potential role of atherosclerosis in the development of LUTS in both sexes. Atherosclerosis-induced arterial insufficiency is a common clinical problem in the elderly. Moreover, the abdominal aorta and its branches, especially the bifurcation of the iliac arteries, are particularly vulnerable to atherosclerotic lesion, suggesting that atherosclerotic obstructive changes distal to the aortic bifurcation will have consequences for the distal vasculature and for bladder blood flow. Atherosclerosis potentially causes a reduction of bladder blood flow, leading to chronic bladder ischemia in both men and women. In this respect, men are more vulnerable to its consequences, since BOO by itself may reduce bladder blood flow. Thus, men may develop LUTS due to both atherosclerosis and BOO, which could act simultaneously and perhaps synergistically to increase consequences of bladder ischemia.
However, the impact of atherosclerosis-induced chronic bladder ischemia alone on bladder function is not easily studied directly in humans. More detailed studies have been carried out in animal models. Recently, several animal models of chronic bladder ischemia in the absence of BOO have been described which should serve as useful tools for further research.
Animal Models of Chronic Bladder Ischemia
Previous rabbit model studies[37, 38] 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 damage to the bladder. To develop a useful rabbit model of chronic bladder ischemia, Azadzoi et al.[39, 40] utilized arterial balloon endothelial injury techniques with a 0.5% cholesterol diet to produce iliac artery occlusive disease. This model showed that moderate ischemia caused: frequent voiding; DO defined as a significant increase in the frequency of spontaneous bladder contractions and increased contractile responses to carbachol and electrical field stimulation (EFS) with moderate fibrosis in the bladder wall. Severe ischemia caused very weak bladder contraction and decreased contractile responses to various stimuli with severe fibrosis. The authors also examined markers of oxidative injury and neural density in the ischemic bladder, and demonstrated that bladder hyperactivity under ischemic conditions involved noxious oxidative products and denervation. The mechanisms by which chronic bladder ischemia induces DO appeared to involve upregulation of stimulatory molecules, oxidative stress-sensitive genes, ultrastructural damage and neurodegeneration.[20, 41-46]
To evaluate bladder function with gradual development of atherosclerosis and ischemia in a rabbit model, Yoshida et al. examined the functional and histological bladder changes in the myocardial infarction-prone Watanabe Heritable Hyperlipidemia (WHHLMI) rabbit, widely used as a model of hyperlipidemia, atherosclerosis, and related ischemic diseases. Their study demonstrated that WHHLMI rabbits showed: atherosclerotic changes in the iliac arteries; an increase in connective tissues in the bladder wall; frequent voiding and DO (non-voiding contractions) with decreased detrusor contraction and decreased contractile responses to carbachol and EFS with denervation. The authors suggested that the bladder dysfunction observed in WHHLMI rabbits might be a state of detrusor hyperactivity with impaired contraction which can be clinically observed in human elderly patients.
To evaluate urodynamic characteristics in an awake animal with chronic bladder ischemia, Nomiya et al. developed a rat model using techniques similar to those Azadzoi et al.[39, 40] had applied to rabbits. The authors 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, carbachol stimulation and nerve stimulation. In addition, the animals exhibited increased collagen ratio in the muscle layer, elevated oxidative stress markers, upregulation of proinflammatory cytokines and decreased constitutive nitric oxide synthase (NOS) expression. These changes were associated with bladder hyperactivity defined as a significant increase in voiding frequency without effect on maximum pressure or residual volume. The functional and morphological changes were prevented by prophylactic treatment with tadalafil or melatonin,[49, 50] suggesting that the voiding reflex facilitated by chronic ischemia, oxidative stress and inflammatory processes might be suppressed by phosphodiesterase 5 inhibitors via the NO/cyclic guanosine monophosphate signaling pathway, or by melatonin through its free radical scavenging and antioxidative properties.[48-51]
Son and coworkers evaluated voiding function in a rat model of vasculogenic erectile dysfunction (ED) previously described by Park and coworkers. Rats fed a 1% cholesterol diet for 8 weeks, together with 2 weeks of NG-nitro-L-arginine methyl ester given to induce intimal changes, showed atherosclerotic changes in the iliac arteries and urodynamic bladder hyperactivity with increases in the proportions of purinergic contractions.
Rahman et al. also examined bladder function in a rat model of ED. Rats fed a 2% cholesterol and 10% lard diet alone for 6 months showed bladder hyperactivity with non-voiding contractions. They found hypertrophy of the detrusor muscle and upregulation of P2X3, P2X1 and vanilloid receptor 1 expression in the hyperlipidemic bladders, and suggested that these changes might contribute to bladder hyperactivity. However, in this model results such as bladder weight, vascular changes and cystometric parameters were not reported.
Shenfeld et al. examined contractility of bladder muscle strips from Apolipoprotein E gene knockout (APOEKO) mice known to spontaneously develop atherosclerosis. The authors concluded that 70-week-old APOEKO mice did not show statistically significant differences in in vitro detrusor function compared with control C57BI/6 mice, although APOEKO mice exhibited massive atherosclerosis of the abdominal aortas and iliac arteries. The authors suggested that gradual development of atherosclerosis and the presumed chronic bladder ischemia associated with it probably do not significantly change the contractile responses of the detrusor muscle to bethanechol and potassium chloride, or the resting tone. However, information such as bladder weight and cystometric parameters was not reported.
POSSIBLE MECHANISMS FOR BLADDER ISCHEMIA-INDUCED LUTS
Evidence from clinical and basic research suggests that BOO in men and atherosclerosis in both genders induce a reduction of bladder blood flow, leading to chronic ischemia of the bladder (Fig. 1). 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). Thus, chronic bladder ischemia and repeated ischemia/reperfusion during a micturition cycle may produce oxidative stress, leading to denervation of the bladder and the expression of tissue damaging molecules (nerve growth factor, prostaglandins) in the bladder wall.[43, 44, 51] This appears to be responsible for the development of DO progressing to detrusor underactivity and inability to empty the bladder. Studies in animal models[39, 40] suggest that the extent of bladder dysfunction in chronic bladder ischemia depends on the degree and duration of ischemia. Moderate ischemia may cause DO and storage symptoms via sensitization of afferent pathways as well as via a postjunctional supersensitivity due to partial denervation of the detrusor muscle (Fig. 1). When bladder ischemia becomes severe, progression of denervation and damage to detrusor muscle may cause detrusor underactivity and voiding symptoms.
Histopathophysiologic changes observed in these animal models of chronic bladder ischemia appear to be similar in many ways to those reported in BOO models. This would suggest that chronic bladder ischemia might be a common cause in the development of bladder dysfunction in both conditions; however, the BOO models show higher maximum pressure during the voiding phase and bladder weight changes that are quite different from those caused by chronic bladder ischemia in the absence of BOO. There seems to be no published experience on the changes in electrophysiologic properties of the smooth muscle in atherosclerosis-induced chronically ischemic bladders.
The increased bladder activity under ischemic/hypoxic conditions might be a defensive mechanism, because continued urine storage and distension will induce vessel compression, which in turn will worsen the ischemia/hypoxia by consuming more energy during the voiding phase. However, lack of perfusion, repeated ischemia/reperfusion during the micturition cycle, and accumulation of noxious oxidative elements in the bladder might eventually lead to the failure of defensive mechanisms, inducing a decompensated state (bladder underactivity) with a postvoid residual volume. Thus, whether chronic medical treatment for OAB has a positive or negative impact on bladder hyperactivity under ischemic/hypoxic conditions would be a target for future research.
LUTS occur commonly in both men and women, and show an increasing prevalence with age. Recent studies suggest that arterial occlusive disease (atherosclerosis), a common aging-associated disorder, has a role in the pathogenesis of lower urinary tract dysfunction, such as DO. Chronic ischemia secondary to BOO and atherosclerosis-induced chronic ischemia share common pathophysiological mechanisms. A better understanding of the similarities and differences in both conditions may lead to more accurate assessments of LUTS, and to better treatments of the condition.
Editorial support was provided by Christina Sarabhai and Gregory Bezkorovainy of Adelphi Communications New York and was funded by Astellas.