西地那非对糖尿病兔海绵体平滑肌舒张及环磷酸鸟苷生成的影响。
The effect of sildenafil on corpus cavernosal smooth muscle relaxation and cyclic GMP formation in the diabetic rabbit.
作者信息
Thompson C S, Mumtaz F H, Khan M A, Wallis R M, Mikhailidis D P, Morgan R J, Angelini G D, Jeremy J Y
机构信息
Department of Molecular Pathology and Clinical Biochemistry, Royal Free Hospital and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
出版信息
Eur J Pharmacol. 2001 Aug 3;425(1):57-64. doi: 10.1016/s0014-2999(01)01077-9.
Sildenafil, a type V phosphodiesterase inhibitor, enhances smooth muscle relaxation in normal human and rabbit corpus cavernosum. We investigated the in vitro effects of sildenafil on non-adrenergic, non-cholinergic and nitric oxide (NO)-mediated cavernosal smooth muscle relaxation in diabetic rabbits, since alterations in this pathway are recognised in diabetic erectile dysfunction. Diabetes mellitus was induced in male New Zealand White rabbits with alloxan. Cavernosal strips from age-matched control, 3- and 6-month diabetic animals were mounted in organ baths. Relaxation responses to electrical field stimulation (1-20 Hz) or sodium nitroprusside (10(-8)-10(-4) M) were assessed in the absence and presence of sildenafil (10(-8) and 10(-7) M). The effect of sildenafil on cGMP formation by the corpus cavernosum was also assessed following stimulation with sodium nitroprusside, A23187 and acetylcholine. Sodium nitroprusside-stimulated relaxations were significantly (P<0.03) impaired in the corpus cavernosum from both diabetic groups, (IC(50)=4.6 x 10(-6) M following 3 months of diabetes mellitus and 4.0 x 10(-6) M following 6 months of diabetes mellitus; compared to 7.5 x 10(-7) M for pooled age-matched controls). Sildenafil (10(-7) M) significantly enhanced sodium nitroprusside-stimulated relaxation in control (P<0.05) and diabetic groups (P<0.03). Electrical field stimulation-mediated relaxations of the corpus cavernosum were significantly impaired after 6-month diabetes mellitus and enhanced by sildenafil (10(-8) M). cGMP formation by the diabetic corpus cavernosum was impaired significantly, but restored towards normal by sildenafil. We suggest that the impairment of NO-mediated relaxation of the corpus cavernosum reflect, at least in part, a defect in guanylyl cyclase activity. These findings support the use of sildenafil as an effective, orally administered, treatment for diabetic erectile dysfunction.
西地那非是一种Ⅴ型磷酸二酯酶抑制剂，可增强正常人及兔海绵体平滑肌的舒张。鉴于糖尿病性勃起功能障碍患者存在该通路的改变，我们研究了西地那非对糖尿病兔非肾上腺素能、非胆碱能及一氧化氮（NO）介导的海绵体平滑肌舒张的体外作用。用四氧嘧啶诱导雄性新西兰白兔患糖尿病。将年龄匹配的对照动物、糖尿病3个月及6个月的动物的海绵体条安装在器官浴槽中。在有无西地那非（10⁻⁸和10⁻⁷M）的情况下，评估电场刺激（1 - 20Hz）或硝普钠（10⁻⁸ - 10⁻⁴M）引起的舒张反应。在用硝普钠、A23187和乙酰胆碱刺激后，还评估了西地那非对海绵体cGMP生成的影响。来自两个糖尿病组的海绵体中，硝普钠刺激的舒张均显著受损（P<0.03）（糖尿病3个月后IC₅₀ = 4.6×10⁻⁶M，糖尿病6个月后IC₅₀ = 4.0×10⁻⁶M；而年龄匹配的对照组合计为7.5×10⁻⁷M）。西地那非（10⁻⁷M）显著增强了对照（P<0.05）和糖尿病组（P<0.03）中硝普钠刺激的舒张。糖尿病6个月后，电场刺激介导的海绵体舒张显著受损，而西地那非（10⁻⁸M）可增强其舒张。糖尿病海绵体的cGMP生成显著受损，但西地那非可使其恢复至正常水平。我们认为，NO介导的海绵体舒张受损至少部分反映了鸟苷酸环化酶活性的缺陷。这些发现支持将西地那非作为治疗糖尿病性勃起功能障碍有效的口服药物。
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