Impaired Detrusor Contractility in a Rat Model of Chronic Bladder Ischemia

Sagawa, Koji; Aikawa, Kohsuke; Nomiya, Masanori; Ogawa, Soichiro; Akaihata, Hidenori; Takahashi, Norio; Yamaguchi, Osamu; Kojima, Yoshiyuki

doi:10.1016/j.urology.2013.02.013

Cited by 22 publications

(29 citation statements)

References 13 publications

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“…Interestingly, chronic ischemia, as studied in the same rat model, decreased bladder contractility [17,33]. Also in the bladder, chronic ischemia induces oxidative stress and elevation of proinflammatory cytokines and other inflammatory mediators [31,34].…”

Section: Discussionmentioning

confidence: 99%

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia

et al. 2014

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BackgroundThe etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action.MethodsAdult male Sprague-Dawley rats were divided into control, arterial endothelial injury (AI), and AI with tadalafil treatment (AI-tadalafil) groups. AI and AI-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-tadalafil rats were treated with tadalafil (2 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, animals were sacrificed, and pharmacological and morphological studies on prostate tissues were performed.ResultsIliac arteries from AI rats displayed neo-intimal formation and luminal occlusion, an effect that was not prevented by tadalafil treatment. In the AI group, there was an obvious epithelial atrophy and a statistically significant increase in collagen fibers compared with the controls. Immunohistochemically, there was an up-regulation of smooth muscle α-actin (SMA). Contractile responses of prostate strips to KCl, electrical field stimulation (EFS), and phenylephrine (PE) were significantly higher after AI than in controls. Chronic treatment with tadalafil prevented the increase in contractile responses in ischemic tissue, and decreased the collagen deposition compared with the AI group.ConclusionsIn this rat model, chronic pelvic ischemia caused distinct functional and morphological changes in the prostate. Prostatic tissue from ischemic animals showed an increased contractile response to electrical and pharmacological stimulation, an increase in SMA, and an increased deposition of collagen. All these changes could be prevented by treatment with the PDE5 inhibitor, tadalafil, suggesting an involvement of cyclic guanosine monophosphate (cGMP). Prostate 75:233–241, 2015. © 2014 The Authors. The Prostate Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia

et al. 2014

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“…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 . 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.…”

Section: Rat Modelsmentioning

confidence: 99%

Chronic bladder ischemia and oxidative stress: New pharmacotherapeutic targets for lower urinary tract symptoms

2014

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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.

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“…Previous studies indicated that CBI did not affect maximum pressure in conscious, freely moving rats despite impaired detrusor contractility in vitro [21,22] . Generally, the levels of neurotransmitters released from nerve terminals are high compared with the drug concentrations in an organ bath.…”

Section: Discussionmentioning

confidence: 95%

“…Animal models of CBI were reported to exhibit decreased BBF, decreased nerve fibers in the bladder, and reduced detrusor function [6,21,22] . Therefore, we evaluated the effects of silodosin on denervation and detrusor dysfunction using a rat model of CBI.…”

Section: Introductionmentioning

confidence: 99%

Silodosin, an α<sub>1A</sub>-Adrenoceptor Antagonist, May Ameliorate Ischemia-Induced Bladder Denervation and Detrusor Dysfunction by Improving Bladder Blood Flow

Goi

Tomiyama²,

Maruyama³

et al. 2016

Pharmacology

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Background/Aims: This study was performed to investigate the detailed mechanism underlying the effects of the selective α_1A-adrenoceptor antagonist, silodosin, on bladder function in a rat model of atherosclerosis-induced chronic bladder ischemia (CBI). Methods: The CBI model was prepared by balloon endothelial injury of the bilateral iliac arteries in male rats. Using an osmotic pump, the CBI rats received either silodosin or vehicle alone subcutaneously for 8 weeks. Rats received a 2% cholesterol diet throughout the experiment. Bladder blood flow (BBF) was measured. Immunohistochemical staining was performed to determine the nerve distribution and nerve growth factor expression in the bladder. Bladders were used for muscle strip contraction analysis. The expression levels of muscarinic M2 and M3 receptors were measured. Results: Silodosin abrogated the decrease in BBF in CBI rats. Silodosin prevented the decrease in nerve distribution and increase in nerve growth factor expression in the CBI model. Bladder contractile response was reduced in the CBI group. Silodosin ameliorated the effect on the bladder contractile response. The level of muscarinic M3 receptor mRNA present in the bladder of CBI rats was increased by silodosin. Conclusion: The results of this study suggest that silodosin ameliorates the denervation of the bladder and effects on detrusor contractile function under ischemic conditions by restoring BBF.

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Impaired Detrusor Contractility in a Rat Model of Chronic Bladder Ischemia

Cited by 22 publications

References 13 publications

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia

Chronic bladder ischemia and oxidative stress: New pharmacotherapeutic targets for lower urinary tract symptoms

Silodosin, an α<sub>1A</sub>-Adrenoceptor Antagonist, May Ameliorate Ischemia-Induced Bladder Denervation and Detrusor Dysfunction by Improving Bladder Blood Flow

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