Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
PLoS One. 2024 Sep 18;19(9):e0301883. doi: 10.1371/journal.pone.0301883. eCollection 2024.
Bladder dysfunction associated with type 2 diabetes mellitus (T2DM) includes urine storage and voiding disorders. We examined pathological conditions of the bladder wall in a rat T2DM model and evaluated the effects of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil.
Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats were used as the T2DM and control groups, respectively. Tadalafil was orally administered for 12 weeks. Micturition behavior was monitored using metabolic cages, and bladder function was evaluated by cystometry. Bladder blood flow was evaluated by laser speckle imaging, and an organ bath bladder distention test was used to measure adenosine triphosphate (ATP) release from the bladder urothelium. The expression levels of vesicular nucleotide transporter (VNUT), hypoxia markers, pro-inflammatory cytokines and growth factors in the bladder wall were measured using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Bladder wall contractions in response to KCl and carbachol were monitored using bladder-strip tests.
With aging, OLETF rats had higher micturition frequency and greater urine volume than LETO rats. Although bladder capacity was not significantly different, non-voiding bladder contraction occurred more frequently in OLETF rats than in LETO rats. Bladder blood flow was decreased and ATP release was increased with higher VNUT expression in OLETF rats than in LETO rats. These effects were suppressed by tadalafil administration, with accompanying decreased HIF-1α, 8-OHdG, IL-6, TNF-α, IGF-1, and bFGF expression. The impaired contractile responses of bladder strips to KCl and carbachol in OLETF rats with aging were restored by tadalafil administration.
The T2DM rats had polyuria, increased ATP release induced by decreased bladder blood flow and impaired contractile function. PDE5 inhibition improved these changes and may prevent T2DM-associated urinary frequency and bladder storage and voiding dysfunctions.
与 2 型糖尿病（T2DM）相关的膀胱功能障碍包括尿液储存和排空障碍。我们在 2 型糖尿病大鼠模型中检查了膀胱壁的病理状况，并评估了磷酸二酯酶-5（PDE-5）抑制剂他达拉非的作用。
雄性 Otsuka Long-Evans Tokushima Fatty（OLETF）大鼠和 Long-Evans Tokushima Otsuka（LETO）大鼠分别作为 2 型糖尿病组和对照组。他达拉非经口给药 12 周。使用代谢笼监测排尿行为，通过膀胱测压评估膀胱功能。通过激光散斑成像评估膀胱血流，使用器官浴膀胱扩张试验测量膀胱尿路上皮释放的三磷酸腺苷（ATP）。使用实时聚合酶链反应和酶联免疫吸附试验测量膀胱壁中囊泡核苷酸转运体（VNUT）、缺氧标志物、促炎细胞因子和生长因子的表达水平。使用膀胱条测试监测对 KCl 和卡巴胆碱的膀胱壁收缩反应。
随着年龄的增长，OLETF 大鼠的排尿频率高于 LETO 大鼠，尿量也多于 LETO 大鼠。尽管膀胱容量没有显著差异，但 OLETF 大鼠的非排尿性膀胱收缩比 LETO 大鼠更频繁。与 LETO 大鼠相比，OLETF 大鼠的膀胱血流减少，ATP 释放增加，VNUT 表达增加。给予他达拉非可抑制这些作用，同时降低 HIF-1α、8-OHdG、IL-6、TNF-α、IGF-1 和 bFGF 的表达。随着年龄的增长，OLETF 大鼠膀胱条对 KCl 和卡巴胆碱的收缩反应受损，给予他达拉非后得到恢复。
2 型糖尿病大鼠出现多尿、膀胱血流减少导致的 ATP 释放增加以及收缩功能障碍。PDE5 抑制可改善这些变化，并可能预防 2 型糖尿病相关的尿频和膀胱储存及排空障碍。
