Jesmin Subrina, Zaedi Sohel, Yamaguchi Naoto, Maeda Seiji, Yamaguchi Iwao, Goto Katsutoshi, Miyauchi Takashi
Department of Cardiovascular Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
Exp Biol Med (Maywood). 2006 Jun;231(6):1034-9.
Erectile dysfunction (ED) affects approximately 50% of male patients with diabetes mellitus (DM) and is possibly due to the vascular and neuropathic complications of DM. Recently, apoptosis has been regarded as a downstream event in ED. More recently, the importance of alterations in apoptosis-related molecules in the mechanism of DM-induced ED has begun to be appreciated. Endothelin-1 (ET-1) plays a role via ET(A) and ET(B) receptors in the regulation of cavernosal smooth-muscle tone in penile tissues. We found that the ET-1 level in the penis of rats with DM was higher than that in the penis of control animals. The present study investigated a rat model in which DM was induced by a 3-week regimen of streptozotocin (STZ) to assess the expression of several apoptosis-related molecules in penile tissue and, concomitantly, the effects of ET antagonism on these changes. Male Sprague-Dawley rats (weight [+/-SD], 450 +/- 26 g) received a citrate saline vehicle or STZ (65 mg/kg ip). DM was confirmed by the presence of hyperglycemia. Diabetic animals were further separated into two treatment groups 1 week after onset of disease: one group received ET(A/B) dual receptor antagonist (SB209670) by means of osmotic minipump at a dosage of 1 mg/day, and the other group received saline. Rats in both groups were treated for 2 weeks and then sacrificed. Plasma glucose levels (+/-SD) in rats with DM were significantly higher than those in rats without DM (506 +/- 70 vs. 111 +/- 11 mg/dl). In the penile tissue of rats with DM, a 35% decrease in the expression of Bcl-2 protein (an important antiapoptotic marker detectable by immunoblotting) was seen, and ET(A/B) dual antagonist was observed to significantly counteract this decrease. Real-time polymerase chain reaction revealed that the expression of Bcl-2 mRNA was consistent with Bcl-2 protein expression. Levels of Bax and caspase-3, two important proapoptotic markers, were not significantly altered in the present study. Thus, we conclude that, in the penis of rats with early stage DM, the protection against apoptosis has decreased but can be improved by ET antagonism.
勃起功能障碍（ED）影响约50%的糖尿病（DM）男性患者，这可能归因于DM的血管和神经病变并发症。最近，细胞凋亡被视为ED的下游事件。更近一些时候，细胞凋亡相关分子改变在DM诱导的ED机制中的重要性已开始得到认识。内皮素-1（ET-1）通过ET(A)和ET(B)受体在调节阴茎组织海绵体平滑肌张力中发挥作用。我们发现DM大鼠阴茎中的ET-1水平高于对照动物阴茎中的水平。本研究调查了一种通过3周链脲佐菌素（STZ）给药方案诱导DM的大鼠模型，以评估阴茎组织中几种细胞凋亡相关分子的表达，并同时评估ET拮抗对这些变化的影响。雄性Sprague-Dawley大鼠（体重[±标准差]，450±26 g）接受柠檬酸盐生理盐水载体或STZ（65 mg/kg腹腔注射）。通过高血糖的存在确认DM。糖尿病动物在疾病发作1周后进一步分为两个治疗组：一组通过渗透微型泵以1 mg/天的剂量接受ET(A/B)双受体拮抗剂（SB209670），另一组接受生理盐水。两组大鼠均治疗2周，然后处死。DM大鼠的血浆葡萄糖水平（±标准差）显著高于无DM大鼠（506±70 vs. 111±11 mg/dl）。在DM大鼠的阴茎组织中，观察到Bcl-2蛋白（一种可通过免疫印迹检测到的重要抗凋亡标志物）的表达下降了35%，并且观察到ET(A/B)双拮抗剂可显著抵消这种下降。实时聚合酶链反应显示Bcl-2 mRNA的表达与Bcl-2蛋白表达一致。在本研究中，两种重要的促凋亡标志物Bax和caspase-3的水平没有显著改变。因此，我们得出结论，在早期DM大鼠的阴茎中，抗细胞凋亡能力下降，但可通过ET拮抗得到改善。
