Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.
J Sex Med. 2014 Nov;11(11):2661-70. doi: 10.1111/jsm.12682. Epub 2014 Sep 5.
Cardiovascular and endocrine-metabolic diseases associated with increased oxidative stress such as obesity lead to erectile dysfunction (ED). Activators of soluble guanylyl cyclase (sGC) such as BAY 60-2770 reactivate the heme-oxidized sGC in vascular diseases.
This study aimed to evaluate the effects of 2-week oral intake with BAY 60-2270 on a murine model of obesity-associated ED.
C57BL/6 male mice were fed for 12 weeks with standard chow or high-fat diet. Lean and obese mice were treated with BAY 60-2770 (1 mg/kg/day, 2 weeks).
Measurements of intracavernosal pressure (ICP), along with acetylcholine (10(-9) to 10(-5) M) and electrical field stimulation (EFS; 4-10 Hz)-induced corpus cavernosum relaxations in vitro, were obtained. Levels of cyclic guanosine monophosphate (cGMP), reactive oxygen species (ROS), and sGC protein expressions in cavernosal tissues were measured.
Cavernous nerve stimulation caused frequency-dependent ICP increases, which were significantly lower in obese compared with lean mice (P < 0.05). Two-week therapy with BAY 60-2770 fully reversed the decreased ICP in obese group. Acetylcholine-induced cavernosal relaxations were 45% lower (P < 0.001) in obese mice, which were fully restored by BAY 60-2770 treatment. Likewise, the EFS-induced relaxations in obese mice were restored by BAY 60-2770. Basal cGMP content in erectile tissue was 68% lower (P < 0.05) in obese mice, an effect normalized by BAY 60-2770. Levels of ROS were 52% higher (P < 0.05) whereas protein expression of α1 sGC subunit was reduced in cavernosal tissue of obese mice, both of which were normalized by BAY 60-2770. In lean group, BAY 60-2770 did not significantly affect any functional, biochemical, or molecular parameter analyzed.
Two-week therapy with BAY 60-2770 restores the erectile function in obese mice that is associated with reduced ROS levels, up-regulation of α1 sGC subunit, and increased cGMP levels in the erectile tissue.
与肥胖等导致氧化应激增加相关的心血管和内分泌代谢疾病会导致勃起功能障碍（ED）。可溶性鸟苷酸环化酶（sGC）的激活剂，如 BAY 60-2770，可使血管疾病中的血红素氧化 sGC 重新活化。
本研究旨在评估口服 BAY 60-2270 对肥胖相关 ED 小鼠模型的 2 周作用。
C57BL/6 雄性小鼠用标准饲料或高脂肪饮食喂养 12 周。瘦鼠和肥胖鼠用 BAY 60-2770（1mg/kg/天，2 周）治疗。
测量海绵体内压（ICP），以及乙酰胆碱（10(-9) 到 10(-5) M）和电刺激（4-10 Hz）诱导的体外海绵体松弛。测量海绵体组织中环鸟苷单磷酸（cGMP）、活性氧（ROS）和 sGC 蛋白表达水平。
海绵体神经刺激引起的 ICP 随频率增加而增加，肥胖鼠的 ICP 明显低于瘦鼠（P < 0.05）。BAY 60-2770 治疗 2 周可完全逆转肥胖组 ICP 的降低。肥胖鼠的乙酰胆碱诱导的海绵体松弛降低了 45%（P < 0.001），BAY 60-2770 治疗完全恢复。同样，肥胖鼠的 EFS 诱导松弛也被 BAY 60-2770 恢复。勃起组织中 cGMP 含量在肥胖鼠中降低了 68%（P < 0.05），BAY 60-2770 治疗可使其正常化。肥胖鼠海绵体组织中的 ROS 水平升高 52%（P < 0.05），α1 sGC 亚基蛋白表达降低，BAY 60-2770 可使这两种情况正常化。在瘦鼠组中，BAY 60-2770 对分析的任何功能、生化或分子参数均无显著影响。
BAY 60-2770 治疗 2 周可恢复肥胖鼠的勃起功能，这与 ROS 水平降低、α1 sGC 亚基上调和勃起组织中 cGMP 水平升高有关。
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