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戴槐青 1 , 鄭劍廷 2 , 余宏政 1 1 台大醫院泌尿部 2 師大生命科學系

J12. The Pathophysiological Mechanisms for Triggering Detrusor Overactivity in Chronic Ischemic Urinary Bladder. 戴槐青 1 , 鄭劍廷 2 , 余宏政 1 1 台大醫院泌尿部 2 師大生命科學系. Introduction.

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戴槐青 1 , 鄭劍廷 2 , 余宏政 1 1 台大醫院泌尿部 2 師大生命科學系

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  1. J12 The PathophysiologicalMechanisms for Triggering Detrusor Overactivity in Chronic Ischemic Urinary Bladder 戴槐青1,鄭劍廷2,余宏政1 1台大醫院泌尿部 2師大生命科學系

  2. Introduction • Lower urinary tract symptoms (LUTS), including overactive bladder (OAB), occur commonly in both men and women, with an age-related increase in both sexes. (Irwin DE et al., 2006) • Epidemiological and clinical studies have demonstrated that arterial occlusive disease (atherosclerosis), a common aging-associated disorder, has a role in the pathogenesis of lower urinary tract dysfunction, such as detrusor overactivity (DO). (Ponholzer A et al., 2006; Pinggera GM et al., 2008)

  3. Introduction • Azadzoi et al. were the first to create a rabbit model of chronic bladder ischemia and showed ischemia was associated with DO (moderate) and impaired detrusor contraction (severe). (Azadzoi et al. 1999 and 2001) • We developed bilaterally partial femoral arterial obstruction and evaluated the responses and possible mechanisms in chronic bladder ischemia-induced bladder dysfunction. ? ? ? ? Chronic bladder ischemia Bladder dysfunction

  4. Materials and Methods • Bilateral partial femoral arterial occlusion was performed in Avertin-anesthetized Female Wistarrats (250g) for 2 or 4 weeks.

  5. Exp groups Ischemia 2 weeks (N=6) Ischemia 4 weeks (N=6) Control (N=5) In Vivo Experiment -Bladder blood flow -Cystometry* -Bladder reactive oxygen species (ROS)* -Urinary ROS* In Vitro Experiment -Bladder ATP and ACh -Immunocytochemistry and Western blot Oxidative stress, Inflammation, Autophagy, ER stress, Apoptosis, Purinergicand muscarinic receptor expression *Normal saline Carbachol 3µM Oxom 40µM

  6. Results

  7. Bladder blood flow BP IVP Bloodflow

  8. Bladder function (Cystometry) Ischemia Frequency↑, Amplitude↓

  9. Bladder ROS

  10. Urinary ROS

  11. Bladder ATP and ACh ACh ATP

  12. HE Stain

  13. Macrophage Stain

  14. 3NT Stain Nitric Oxide

  15. Beclin 1: Autophagy

  16. TUNEL: Apoptosis

  17. GRP 78: ER stress

  18. Masson stain Hydroxyproline

  19. Expression of Bladder M2/3 receptor

  20. Expression of Bladder purinergic receptor

  21. Summary • Compared to control rats, partially vascular occlusion decreased bladder blood flow,increased frequency and suppressed voiding contractile amplitude in the chronic bladder ischemia rats. • Increased bladder and urinary ROS production, macrophages infiltration, expression in 3NT, GRP78, Beclin-1 and TUNEL stain were all identified in the chronic ischemic bladders in a time-dependent manner.

  22. Summary • Chronic bladder ischemia time-dependently reduced ATP andACh content and up-regulated protein expression of postsynaptic purinergic receptors (P2X1, P2X2,P2X3) and muscarinic ACh receptors (M2,M3) in smooth muscles of urinary bladder.

  23. Conclusions-our hypothesis Oxidative stress LUTS! ER stress Chronic bladder ischemia Inflammation Autophagy Apoptosis Bladder dysfunction (DO) ATP ↓ ACh↓ P2X ↑ M2/3 ↑

  24. 謝謝大家!

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