Elsevier

Urology

Volume 84, Issue 5, November 2014, Pages 1249.e1-1249.e7
Urology

Basic and Translational Science
Effects of Ischemia and Oxidative Stress on Bladder Purinoceptors Expression

https://doi.org/10.1016/j.urology.2014.07.023Get rights and content

Objective

To study the effects of chronic ischemia on bladder purinoceptors. A close correlation between bladder ischemia and lower urinary tract symptoms has been reported. Purinoceptors contribute to important aspects of bladder function including sensation, neural signaling, and voiding contraction. Our goal was to examine purinoceptors expression in the ischemic overactive bladder.

Materials and Methods

Moderate bladder ischemia was produced in rabbits by creating bilateral iliac artery atherosclerosis. After 8 weeks, bladder blood flow was measured, and cystometrograms were obtained. Bladder tissues from 8-week ischemic and age-matched control bladders were processed for the analysis of oxidative stress markers, P2X and P2Y purinoceptors expression, and transmission electron microscopy.

Results

Arterial atherosclerosis significantly decreased bladder blood flow. Markers of oxidative stress characterized by increased levels of advanced oxidation protein products and malondialdehyde were evident in the ischemic bladder tissues. Chronic ischemia and oxidative stress decreased the bladder capacity and increased spontaneous bladder contractions. Bladder pressure at micturition and intravesical pressure rise during contractions tended to be greater in the ischemic bladder but did not reach significance. Transmission electron microscopy showed smooth muscle cell and microvasculature structural damage and diffuse fibrosis. These changes in the ischemic bladder were associated with significant increases in purinoceptors P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 expression. The P2Y isoforms were not expressed in the rabbit bladder.

Conclusion

Structural and functional changes in the chronically ischemic bladder were associated with upregulation of P2X receptor isoforms. Increased P2X expression may play a role in ischemia-induced bladder overactivity and noncompliance.

Section snippets

Animal Model of Chronic Bladder Ischemia

Animal care and experimental protocols were in accordance with the guidelines of our institutional animal care and use committee. New Zealand white male rabbits (3-3.5 kg) were anesthetized with continuous inhalation of 1%-2% isoflurane mixed with oxygen. Moderate arterial atherosclerosis and bladder ischemia were produced using bilateral iliac arteries balloon de-endothelialization. Arterial ballooning was repeated 3-4 times on each side while rotating the catheter. The animals received a

Cystometric Changes in Bladder Ischemia

Three of the 10 treated animals did not develop significant arterial atherosclerosis and were removed from the study. In the remaining 7 animals, atherosclerotic changes characterized by intimal thickening and significant luminal narrowing of the iliac arteries were present. The hemodynamic significance of arterial atherosclerosis was determined based on bladder blood flow measurements. Arterial atherosclerosis significantly decreased bladder blood flow of the 7 treated animals in comparison

Comment

Structural and functional consequences of chronic bladder ischemia depend on the severity and duration of arterial insufficiency.1, 2, 16 In moderate ischemia, the bladder coordinates a series of molecular responses to promote cell survival and preserve functional integrity of the nerves, smooth muscle cells, and microvasculature. These defensive reactions appear to augment neural reactivity and lead to differential receptor expression, smooth muscle hypersensitivity, and increased contractile

Conclusion

Upregulation of P2X purinergic receptor isoforms in bladder ischemia was associated with markers of oxidative stress, detrusor overactivity, and ultrastructural damage. P2X receptors, potential targets of oxidative radicals, could also mediate free radical formation and contribute to oxidative damage in the bladder. Differential P2X expression may be a disease-specific phenomenon in critical aspects of bladder dysfunction including overactivity, hypersensitivity, and pain. Despite the

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    Financial Disclosure: The authors declare that they have no relevant financial interests.

    Funding Support: This study was supported by grant BLR&D MERIT 1I01BX001428-01A1 from the U.S. Department of Veterans Affairs.

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