Effect of hydrogen sulphide‐donating sildenafil (ACS6) on erectile function and oxidative stress in rabbit isolated corpus cavernosum and in hypertensive rats

OBJECTIVE

To study the effect of the H₂S‐donating derivative of sildenafil (ACS6) compared to sildenafil citrate and sodium hydrosulphide (NaHS) on relaxation, superoxide formation and NADPH oxidase and type 5 phosphodiesterase (PDE5) expression in isolated rabbit cavernosal tissue and smooth muscle cells (CSMCs), and in vivo on indices of oxidative stress induced with buthionine sulphoximine (BSO).

MATERIALS AND METHODS

Relaxation was studied in an organ bath in response to carbachol and after incubation with interleukin‐1β for 12 h. CSMCs were incubated with tumour‐necrosis factor‐α or the thromboxane A₂ (TXA₂) analogue, U46619, with or with no sildenafil citrate, ACS6 or NaHS for 16 h. Superoxide formation and the expression of p47^phox (an active subunit of the NADPH oxidase complex) and PDE5 protein was then assessed using Western blotting. Rats were also treated with BSO (with or with no sildenafil citrate or ACS6) for 7 days; cavernosal cGMP, cAMP, glutathionine and plasma TXA₂ and 8‐isoprostane F_2α was measured by enzyme‐linked immunosorbent assay.

RESULTS

ACS6 and sildenafil citrate relaxed cavernosal smooth muscle equipotently; NaHS alone had little effect at up to 100 µm . The formation of superoxide and expression of p47^phox and PDE5 was reduced by ACS6, sildenafil citrate and NaHS (order of potency: ACS6 > sildenafil citrate > NaHS). The effects of ACS6 were blocked by inhibitors of protein kinase A (PKA) and PKG. In rats treated with BSO, both ASC6 and sildenafil citrate reduced the increased plasma levels of TXA₂ and 8‐isoprostane F_2α but increased cGMP, cAMP and glutathionine levels in corpus cavernosum.

CONCLUSIONS

By virtue of a dual action on PKA and PKG activation, ACS6 not only promotes erection, acutely, but might also have a long‐term beneficial effect through inhibition of oxidative stress and downregulation of PDE5.     

抗高血压药物对中老年男性高血压患者勃起功能的影响

目的 探讨不同抗高血压药物对于男性勃起功能的影响.方法 问卷调查2008年10月至2008年12月来我院就诊的已婚男性、原发性高血压患者244例,年龄40～70岁.记录服用的抗高血压药物并应用国际勃起功能指数-5(IIEF-5)评估其勃起功能.结果 244例高血压患者勃起功能正常者69例(28.28%),勃起功能障碍(ED)者175例(71.72%).其中轻度障碍者120例(49.1 8%),中度障碍者16例(6.56%),重度障碍者39例(15.98%).β受体滞剂组IIEF分值低于非β受体阻滞剂组,ED发生率高于非β受体阻滞剂组,其他药物组如血管紧张素转换酶抑制剂组、血管紧张素Ⅱ受体拮抗剂组、钙离子拮抗剂组、利尿剂组间差异均无统计学意义.结论 高血压患者中ED的发生率较高(175/244,71.72%), 服用β受体阻滞剂对患者勃起功能有不利影响,而其他药物对于勃起功能影响相似.     

Hypertension might be a risk factor for erectile dysfunction: a meta‐analysis

The study aimed to evaluate whether hypertension was a risk factor for erectile dysfunction (ED). Databases including PubMed and Embase were retrieved to identify studies related to hypertension in ED patients. Odds ratio (OR) and 95% confidence interval (CI) were used as the effect size. Subgroup analyses stratified by total number of enrolled subjects and research regions were performed. Sensitivity analysis was performed by removing a single study at one time. Egger's test was used to evaluate the publication bias. Totally, 40 studies including 121,641 subjects were included in the meta‐analysis. As a result, hypertension was closely related to ED (OR = 1.74, 95% CI, 0.63–0.80, p < .01). Subgroup analysis indicated hypertension was the risk factor for ED whatever the participants numbers. When stratified by different regions, hypertension was a risk factor for ED in Africa (OR = 3.35, 95% CI, 1.45–7.77, p < .01), Americas (OR = 1.97, 95% CI, 1.68–2.31, p < 0.01), Asia (OR = 1.46, 95% CI, 1.16–1.84, p < .01) and Europe (OR = 1.83, 95% CI, 1.34–2.49, p < .01), but not in Australia. Hypertension may be a potential risk factor for ED.     

Increased expression of insulin-like growth factor-binding protein-3 is implicated in erectile dysfunction in two-kidney one-clip hypertensive rats after propranolol treatment

This study aimed to investigate the role of insulin-like growth factor-binding protein-3 (IGFBP-3) in erectile dysfunction (ED) in two-kidney one-clip (2K-1C) hypertensive rats treated with the β-blocking agent propranolol. Adult male Wistar rats were randomly divided into three groups: a normal control group, a hypertensive control group and a propranolol treatment group (n=9). After 4 weeks of propranolol treatment, intracavernous pressure (ICP) responses to electrical stimulation of the cavernous nerves were evaluated. The expression of IGFBP-3 and insulin-like growth factor-1 (IGF-1) mRNA and protein in the rat cavernous tissue were detected by quantitative real-time PCR and Western blot, respectively. The concentration of cyclic guanosine monophosphate (cGMP) in the cavernous tissue was determined by enzyme-linked immunosorbent assay (ELISA). Cavernosal pressure in response to cavernous nerve stimulation was decreased 4 weeks after propranolol treatment (P<0.01, compared to the hypertensive control group). IGFBP-3 mRNA and protein expression was increased in the propranolol treatment group compared to the hypertensive control group (P<0.01), whereas IGF-1 expression was decreased in the propranolol treatment group compared to the hypertensive control group (P<0.01). In addition, cavernous cGMP concentration was decreased in the propranolol treatment group compared to the hypertensive control group (P<0.01). Taken together, these results suggest that the upregulation of IGFBP-3 may play a role in the development of ED in hypertensive rats.     

己酮可可碱治疗勃起功能障碍的临床研究

目的　为探讨己酮可可碱治疗勃起功能障碍 (ED)的有效性。方法　以勃起功能国际问卷 (IIEF 5 )的量表作为指标 ,对 30例ED患者进行了临床观察。结果　服用己酮可可碱后阴茎勃起功能明显改善 ,有效率为6 3.33%。结论　己酮可可碱可以用于ED的临床治疗     

Decrease of the insulin‐like growth factor‐1 bioavailability in spontaneously hypertensive rats with erectile dysfunction

We investigated the role of insulin‐like growth factor‐1 (IGF‐1) in spontaneously hypertensive rats with erectile dysfunction. Firstly, we evaluated intracavernous pressure. The bioavailability of IGF‐1 at both mRNA and protein levels were measured by quantitative real‐time PCR and Western blot respectively. Then, cavernous cyclic guanosine monophosphate concentrations were detected by enzyme‐linked immunosorbent assay. The cavernosal pressure was significantly decreased in the hypertensive and the propranolol treatment groups compared to the normal control group (P < 0.01). Cavernous IGF‐1 bioavailability and the concentrations of cavernous cyclic guanosine monophosphate were both significantly decreased in the hypertensive and the propranolol treatment groups compared to the normal control group (P < 0.01). This study suggests that an obvious decrease in cavernous IGF‐1 levels might play an important role in spontaneously hypertensive rats with erectile dysfunction.     

滋阴壮阳胶囊对糖尿病性勃起功能障碍大鼠血清NO、ET-1的影响*

目的通过研究滋阴壮阳胶囊对糖尿病性勃起功能障碍(DED)大鼠血清中NO和ET-1的影响,探讨该药治疗DED的作用机制.方法雄性SD大鼠70只,60只以STZ诱导建立糖尿病(DM)模型后,通过阿朴吗啡(APO)进行阴茎勃起实验筛选DED模型,余10只为空白对照组.造模后的DED大鼠随机分成滋阴壮阳胶囊治疗组、六味地黄软胶囊对照组和模型组,在灌胃2周后,腹主动脉取血检测各组大鼠NO和ET-1.结果各组间ET-1和NO差异均有统计学意义(P<0.01);与空白对照组比较,模型组ET-1水平显著升高、NO显著下降(P<0.01);与模型组比较,治疗组和对照组均可降低ET-1水平,升高NO水平(P<0.01、P<0.05),且在降低ET-1方面治疗组优于对照组(P<0.05).结论滋阴壮阳胶囊可通过升高NO的浓度,降低ET-1的水平,重新调整ET-1与NO之间的平衡,这可能是该药治DED的机理之一.     

重视轻症勃起功能障碍的诊治

轻症勃起功能障碍(MSED)在临床实践中常见,但临床医生和患者均对其认识不足,导致就诊率较低。越来越多的研究表明,MSED不仅与不良生活方式和精神心理因素有关,更与血管内皮、代谢、内分泌等器质性病变的早期进展具有相关性。MSED的诊治应参考ED的相关指南,但要注意其自身的特点,充分考虑共病的情况;MSED的治疗原则是整体治疗、防治并行与针对病因的个性化方案相结合;心理治疗无效时需要及时进行药物干预。延误MSED的诊治不仅影响生活质量,而且可能延误对潜在重大疾病的诊治。重视MSED的早期诊治,有利于提高对ED发病机制的认识水平,以及预防心血管、代谢等重大相关疾病,对改善男性整体健康具有重要意义。     

多剂量伐地那非治疗男性勃起功能障碍的临床研究

目的评估不同剂量新型磷酸二酯酶5（PED5）抑制剂伐地那非治疗男性勃起功能障碍（ED）的有效性和安全性。方法采用随机、双盲、安慰剂平行对照、3个药物剂量（5、10和20mg）的方法，对88例ED患者进行为期12周的临床研究。结果伐地那非5mg、10mg和20mg组均能改善患者国际勃起功能指数（IIEF）中勃起功能部分的得分、患者日记中插入和保持勃起的成功率，改善程度优于安慰剂组。伐地那非20mg组对IIEF问卷中勃起功能部分得分的改善优于伐地那非5mg组。伐地那非组不良事件的发生率高于安慰剂组，但多为轻中度，且可自行缓解。结论伐地那非是治疗男性勃起功能障碍的安全、有效药物。     

Effect of systemic arterial pressure on erectile dysfunction in the initial stages of chronic arterial insufficiency

Study Type – Prognosis (case series)
Level of Evidence 4

OBJECTIVE

To report the effect of systemic arterial pressure on erectile dysfunction (ED) in patients in the initial stages of peripheral arterial disease.

PATIENTS AND METHODS

All patients with a diagnosis of ED in the urology outpatient clinic of the Medicine School in São José do Rio Preto, Brazil were evaluated in a cross‐sectional, quantitative study. The patients were assessed using the International Index of Erectile Function, the ankle‐brachial index, and measurement of arterial blood pressure. Binary logistic regression, log‐likelihood, Pearson chi‐square and likelihood ratio chi‐square and Kruskal–Wallis Test were used for statistical analysis with P < 0.05 being considered acceptable. Fifty‐two patients (mean age 56.63 years) were enrolled in the study.

RESULTS

Differences were detected between the median grades of ED of patients with differing degrees of chronic arterial insufficiency. Hypertensive patients in the initial stages of peripheral arterial disease had less severe grades of ED than normotensive patients.

CONCLUSIONS

The progression of ED parallels the development of chronic arterial insufficiency. Systemic arterial hypertension in the initial stages of peripheral arterial disease might protect against ED, but peripheral arterial disease constitutes an aggravating factor for ED, and thus hypertension might exert a paradoxical effect in this stage of the disease.     

Psychosomatic aspects in the diagnosis and treatment of erectile dysfunction

After a critical review of prevalence data, psychosocial determinants and psychosomatic aspects in the diagnosis and treatment of erectile dysfunction are discussed (with reference to age-related changes). Widely used laboratory assessments are responsive to psychological factors (e.g. anxiety). Inclusion of the partner in the diagnostic process may change the clinical picture and the treatment recommendations considerably. As illustrated by penile prosthetis treatment and self-injection of vasoactive substances, acceptance and success of widely used surgical and medical treatments depend largely upon the patient's expectations, and the adaptation of the couple to the procedure. Even in cases with a clear organic pathology, fluctuations in erectile functioning may be attributable to psychological influences. As recent psychotherapeutic and psychoeducational approaches underscore, erectile failure is best conceived as a final common pathway of somatic, lifestyle, psychological and partnership determinants. These should be taken into account in comprehensive diagnostic and treatment formulations if the goal of therapy is not only to produce rigid erections, but to increase sexual satisfaction.     

Chronic inhibition of nitric‐oxide synthase induces hypertension and erectile dysfunction in the rat that is not reversed by sildenafil

Study Type – Aetiology (case control)
Level of Evidence 3b

OBJECTIVE

To evaluate the effect of N(G)‐nitro‐l ‐arginine methyl ester (L‐NAME)‐induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)‐5 inhibitor, sildenafil, can reverse the effects of nitric oxide (NO) deficiency, as HT is a risk factor for erectile dysfunction (ED) and the NO synthase (NOS) inhibitor L‐NAME induces NO‐deficient HT.

MATERIALS AND METHODS

Thirty‐six adult Sprague‐Dawley male rats were divided into three groups, i.e. a control, L‐NAME‐HT (40 mg/rat/day in the drinking water for 4 weeks), and sildenafil‐treated L‐NAME‐HT (1.5 mg/rat/day sildenafil, by oral gavage concomitantly with L‐NAME). The erectile response expressed as a ratio of intracavernosal pressure (ICP)/mean arterial pressure (MAP), evaluated after electrical stimulation of the right cavernous nerve. The isometric tension of corpus cavernosum smooth muscle (CCSM) was measured in organ‐bath experiments. NOS expression was determined immunohistochemically for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein. cGMP levels were evaluated by enzyme‐linked immunosorbent assay.

RESULTS

The erectile response was diminished in the HT group. Nitrergic and endothelium‐dependent relaxation was reduced, while the relaxation response to sodium nitroprusside and contractile response to phenylephrine were not altered in CCSM from L‐NAME‐treated rats. HT rats showed decreased expression of nNOS, whereas eNOS and iNOS protein expression was increased. Sildenafil partly restored endothelial and molecular changes in CCSM from HT rats, but did not reverse the decreased erectile response, even as cGMP levels returned to normal levels.

CONCLUSIONS

Sildenafil treatment did not correct the ED in L‐NAME‐treated HT rats. Under sustained high blood pressure, up‐regulation of PDE5 expression failed to reverse the depletion of neuronal NO and/or impaired nNOS activity. However, endothelium‐dependent relaxation was restored. Drug targeting of neuronal dysfunction might delay the onset of ED in HT.     

还原型谷胱甘肽在预防糖尿病大鼠勃起功能障碍中的研究

目的探讨还原型谷胱甘肽(GSH)在预防糖尿病大鼠勃起功能障碍中的作用。方法通过腹腔注射链脲佐菌素65mg/kg建立糖尿病大鼠模型,然后随机分成DM组和DM+GSH组,DM+GSH组每天肌肉注射GSH200mg/kg。10周后观察大鼠勃起功能,并获取海绵体组织检测其谷胱甘肽、一氧化氮合酶(NOS)与丙二醛(MDA)水平,用TUNEL法检测细胞凋亡。结果成功建立糖尿病大鼠模型。与未注射GSH的DM组相比,DM+GSH组和正常对照组(C组)勃起功能更好,勃起率分别是20%,62.5%和100%。GSH水平DM+GSH组和C组明显比DM组高,其3组含量每克蛋白分别是(75.83±15.62)、(61.47±8.65)和(35.03±12.29)mg(P<0.05);NOS水平在DM+GSH组每毫克蛋白为(133.9±31.9)U,与正常对照组每毫克蛋白为(142.2±31.2)U相当,但较DM组每毫克蛋白为(58.4±18.9)U高(P<0.05);MDA含量在DM组每毫克蛋白为(3.71±0.62)nmol,明显高于正常对照组和DM+GSH组(P<0.05),这两组每毫克蛋白为(2.08±0.34)nmol和(2.44±0.28)nmol;细胞凋亡率在DM组、DM+GSH组和C组的分别是(22.6±3.6)%、(10.8±1.7)%和(7.2±2.1)%(P<0.05)。结论还原型谷胱甘肽对糖尿病大鼠阴茎组织有较好的抗氧化作用,能减少细胞凋亡,对延缓糖尿病性ED的发生有一定的作用。     

Essential role of brain‐derived neurotrophic factor (bdnf) in diabetic erectile dysfunction

Erectile dysfunction (ED) is a worldwide problem threatens men's health. The incidence of ED in diabetic patients is higher than that in the healthy population. The incidence of peripheral and autonomic neuropathy is significantly higher in diabetic patients than in normal men. Vasomotor nerves play an important role in the regulation of erectile function. Degeneration of autonomic and sensory nerves is a common type of diabetic neuropathy (DNP) and is closely related to erectile function. Brain‐derived neurotrophic factor (BDNF) has been demonstrated to improve diabetic erectile dysfunction in rat models and in humans. However, this process has not yet been fully elucidated yet. In this article, we summarise the mechanisms by which BDNF improves diabetic erectile dysfunction.     

胱硫醚-γ-裂解酶和胱硫醚-β-合成酶在高血压大鼠阴茎海绵体中的表达

目的:探讨高血压对大鼠阴茎海绵体组织胱硫醚-γ-裂解酶(CSE)和胱硫醚-β-合成酶(CBS)表达的影响及与大鼠勃起功能的关系。方法:健康雄性SPF级自发性高血压大鼠(SHR)与对照组WKY(Wistar-Kyoto)大鼠各10只,于12周龄时测定大鼠血清睾酮、阴茎海绵体内压/平均动脉压(ICP/MAP)、血浆和阴茎海绵体内源性H2S的含量,采用免疫组化和Western印迹分析CSE和CBS在阴茎海绵体内的表达。结果:SHR与WKY大鼠的血清睾酮值没有显著差别,SHR的ICP/MAP在0、3和5 V电刺激盆腔神经节(MPG)时均显著低于WKY组(n=10,P0.05)。SHR血浆H2S含量显著低于WKY大鼠[(10.49±1.35)μmol/Lvs(21.92±2.75)μmol/L,P0.05],SHR阴茎海绵体组织内源性H2S含量显著低于WKY大鼠[(52.60±3.44)nmol/mg prot vs(87.67±2.12)nmol/mg prot,P0.05],SHR阴茎海绵体组织内源性H2S生成率也较WKY大鼠显著降低[(1.14±0.07)nmol/(mg·min)vs(4.35±0.32)nmol/(mg·min),P0.05]。CSE及CBS主要表达在SHR和WKY大鼠阴茎海绵体平滑肌细胞和血管内皮细胞的胞质,SHR的CSE及CBS蛋白表达量均显著低于WKY大鼠(P0.05)。ICP/MAP与CSE和CBS表达呈高度正相关(r=0.955、0.977,P均0.05)。结论:高血压大鼠阴茎海绵体组织中CBS和CSE的表达下降,导致阴茎海绵体内H2S合成减少,可能是高血压引起勃起功能下降的机制之一。     

盐酸伐地那非治疗男性勃起功能障碍临床研究

目的 观察盐酸伐地那非治疗男性勃起功能障碍的安全性和有效性。方法 随机、双盲、安慰剂对照，对88例勃起功能障碍口服伐地那非治疗的患者进行了为期7个月的观察随访。结果 主要疗效指标的统计学分析结果，显示出5mg、10mg和20mg三个剂量组的伐地那非疗效均优于安慰剂组。次要疗效指标的分析结果与主要疗效指标一致。与药物相关的不良事件依次为潮红、头痛、眼胀、鼻塞、头晕和背痛，多为轻度，且可以自行缓解。结论 盐酸伐地那非治疗勃起功能障碍安全、有效、耐受性好。     

胰岛素对糖尿病大鼠阴茎内nNOS神经纤维的影响

目的探讨糖尿病性阴茎勃起功能障碍（ED）的发病机制及胰岛素的治疗作用。方法注射链脲佐菌素建立糖尿病（DM）大鼠模型，胰岛素治疗组于成模后注射胰岛素。7周和12周后注射阿扑吗啡（APO）进行大鼠阴茎勃起功能实验，取大鼠阴茎和血浆，用ABC免疫组织化学法观察nNOS神经纤维的变化。测定血浆NOS活性。结果（1）与对照组相比，DM组大鼠阴茎勃起次数明显减少;胰岛素治疗后症状缓解;（2）与对照组相比，DM组血浆NOS活性明显增高;DM组血浆NOS活性与病程延长呈负相关;与DM组比较，胰岛素治疗组血浆NOS活性明显降低;（3）与对照组相比，DM组阴茎内nNOS阳性神经纤维明显减少;与DM组比较，胰岛素治疗组nNOS阳性神经纤维表达增加。结论糖尿病性ED阴茎内nNOS阳性纤维的数量及光密度随DM病程的延长而下降;早期给予胰岛素治疗可预防糖尿病大鼠ED的出现及阴茎内nNOS含量的下降。