Zhang Xin-Hua, Filippi Sandra, Morelli Annamaria, Vignozzi Linda, Luconi Michaela, Donati Silvia, Forti Gianni, Maggi Mario
Andrology Unit, Department of Clinical Physiopathology, Center of Research, Transfer and High Education, University of Florence, Florence, Italy.
J Sex Med. 2006 Mar;3(2):253-64; discussion 264-5, author reply 265-6. doi: 10.1111/j.1743-6109.2006.00207.x.
Hypogonadism is often associated with diabetes and both conditions represent major risk factors for erectile dysfunction (ED).
To investigate the role of hypogonadism on phosphodiesterase type 5 (PDE5) expression and sildenafil responsiveness in diabetes.
Two different models of experimental diabetes were used: (i) alloxan-induced diabetic rabbit; and (ii) streptozotocin (STZ)-induced diabetic rat. In both experimental models, animals were separated into three groups: control, diabetic, diabetic supplemented with testosterone (T) enanthate. Rabbits were used for "in vitro" experiments. Conversely, each rats group was further subdivided: no further treatment or acute sildenafil dosing (25 mg/kg, 1 hour before "in vivo" electrical stimulation [ES]).
Erectile capacity was evaluated either by "in vitro" contractility study (alloxan-induced diabetic rabbit) and "in vivo" evaluation of erectile response elicited by ES of cavernous nerve (STZ-induced diabetic rats). Also endothelial nitric oxide synthase, neural nitric oxide synthase (nNOS), and PDE5 protein (Western blot) and mRNA (quantitative real-time reverse transcriptase polymerase chain reaction [RT-PCR]) expression were measured in rat penile samples of each group.
In both models, hypogonadism was observed, characterized by reduced T and atrophy of androgen-dependent accessory glands. T substitution completely reverted hypogonadism and diabetes-induced penile hyposensitivity to "in vitro" (acetylcholine, rabbit) or "in vivo" (ES, rat) relaxant stimuli, along with nNOS expression, which was reduced (P < 0.05) in STZ rats. In diabetic animals, T substitution reinstated sildenafil-induced enhancement of both "in vitro" nitric oxide donor (NCX 4040) relaxant effect (rabbit) and "in vivo" ES-induced erection (rat). PDE5 was reduced in diabetic STZ rats (P < 0.05) and normalized by T. In STZ rats, sodium nitroprusside (SNP) intracavernous injection induced a more sustained erection than in control rats, which was no further enhanced by sildenafil. T substitution normalized both hyper-responsiveness to SNP and sildenafil efficacy.
In two models of diabetes T deficiency underlies biochemical alterations leading to ED. Normalizing T in diabetes restores nNOS and PDE5, and reinstates sensitivity to relaxant stimuli and responsiveness to sildenafil.
性腺功能减退常与糖尿病相关，这两种情况均是勃起功能障碍（ED）的主要危险因素。
研究性腺功能减退在糖尿病中对5型磷酸二酯酶（PDE5）表达及西地那非反应性的作用。
采用两种不同的实验性糖尿病模型：（i）四氧嘧啶诱导的糖尿病兔；（ii）链脲佐菌素（STZ）诱导的糖尿病大鼠。在这两种实验模型中，动物被分为三组：对照组、糖尿病组、补充庚酸睾酮（T）的糖尿病组。兔子用于“体外”实验。相反，每组大鼠进一步细分：不再接受进一步治疗或急性给予西地那非（25mg/kg，在“体内”电刺激[ES]前1小时）。
通过“体外”收缩性研究（四氧嘧啶诱导的糖尿病兔）和“体内”对海绵体神经电刺激引发的勃起反应评估（STZ诱导的糖尿病大鼠）来评估勃起能力。同时，在每组大鼠阴茎样本中测量内皮型一氧化氮合酶、神经型一氧化氮合酶（nNOS）以及PDE5蛋白（蛋白质免疫印迹法）和mRNA（定量实时逆转录聚合酶链反应[RT-PCR]）表达。
在两种模型中均观察到性腺功能减退，其特征为睾酮降低以及雄激素依赖性附属腺体萎缩。睾酮替代完全逆转了性腺功能减退以及糖尿病诱导的阴茎对“体外”（乙酰胆碱，兔）或“体内”（电刺激，大鼠）松弛刺激的低敏感性，同时恢复了nNOS表达，nNOS表达在STZ大鼠中降低（P<0.05）。在糖尿病动物中，睾酮替代恢复了西地那非诱导的“体外”一氧化氮供体（NCX 4040）松弛效应增强（兔）以及“体内”电刺激诱导的勃起（大鼠）。PDE5在糖尿病STZ大鼠中降低（P<0.05），并通过睾酮恢复正常。在STZ大鼠中，海绵体内注射硝普钠（SNP）诱导的勃起比对照组大鼠更持久，西地那非对此无进一步增强作用。睾酮替代使对SNP的高反应性和西地那非疗效均恢复正常。
在两种糖尿病模型中，睾酮缺乏是导致ED的生化改变的基础。糖尿病患者睾酮水平正常化可恢复nNOS和PDE5，并恢复对松弛刺激的敏感性和对西地那非的反应性。
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