Comparable efficacy of once-daily versus on-demand vardenafil in men with mild-to-moderate erectile dysfunction: findings of the RESTORE study

BACKGROUND: Phosphodiesterase (type) 5 (PDE5) inhibitors are currently administered on demand for treatment of erectile dysfunction (ED). Once-daily dosing has been suggested to benefit patients. OBJECTIVE: To determine whether daily vardenafil use provides added clinical benefits to patients compared with on-demand dosing. DESIGN, SETTING, AND PARTICIPANTS: In this placebo-controlled, double-blind, multicentre parallel-group study, men with mild-to-moderate ED were randomised to 24 wk of treatment, followed by a 4-wk washout. INTERVENTION: Patients were randomised to receive once-daily vardenafil 10mg plus on-demand placebo for 12 or 24 wk, or once-daily placebo plus on-demand vardenafil 10mg for 24 wk. MEASUREMENTS: Primary efficacy variable was the between-group difference in change in International Index of Erectile Function-Erectile Function domain (IIEF-EF) score from baseline to end of washout. Secondary variables included change from baseline in proportion of positive respondents to Sexual Encounter Profile questions and in satisfaction with treatment as assessed with the Treatment Satisfaction Scale (TSS). RESULTS AND LIMITATIONS: LS mean changes from baseline in IIEF-EF scores were 2.02, 2.29, and 2.63 for vardenafil 12 wk once daily, 24 wk once daily, and 24 wk on demand, respectively. After washout, the trend was towards improved IIEF-EF scores in the on-demand group (20.58 [+/-0.96]) versus both once-daily groups (12 wk, 19.88 [+/-0.93]; 24 wk, 20.11 [+/-0.94]). Furthermore, there were no significant between-group differences in the percentage of patients with "normal" erectile function. TSS analyses demonstrated no significant differences between treatment groups. This study recruited patients with mild-to-moderate ED; therefore, the results may not be the same as in patients with severe ED. CONCLUSIONS: Once-daily vardenafil did not produce greater sustained effects on EF than on-demand vardenafil in men with mild-to-moderate ED, suggesting that daily dosing of PDE5 inhibitors does not produce sustained clinical benefits beyond cessation of treatment above those observed with on-demand administration.     

Effect of basic fibroblast growth factor incorporating gelatin microspheres on erectile function in the diabetic rat

PURPOSE: We report the potential of basic fibroblast growth factor (bFGF) incorporating gelatin microspheres to preserve erectile function in a diabetic rat model. MATERIALS AND METHODS: A total of 48 adult male rats were divided into 3 groups, namely control (nondiabetic rats), diabetes mellitus (DM) (diabetic rats that received gelatin microspheres with saline) and bFGF (diabetic rats that received gelatin microspheres with bFGF). After 4 and 8 weeks we examined intracavernous pressure responses with electrical stimulation to the cavernous nerve. For histological examination of the penis we performed Azan-Mallory staining for smooth muscle and collagen, and immunohistochemistry for endothelial nitric oxide synthase (NOS) in endothelium and neuronal NOS in cavernous nerve fiber. RESULTS: Although the intracavernous pressure response was significantly lower in the DM group than in the control group, pressure in the bFGF group was maintained at the normal level found in controls. Azan-Mallory staining showed a mass decrease in smooth muscle in cavernous tissue in the DM group. However, that in the bFGF group was maintained. There was no significant difference in endothelial NOS positive areas and the distribution of the diameter of neuronal NOS positive nerve fibers in cavernous tissue among the 3 groups. CONCLUSIONS: We report the maintenance of erectile function with bFGF incorporating gelatin microspheres in diabetic rats. The rationale of this maneuver is smooth muscle preservation by the long-term release of bFGF. This is a novel therapeutic option that is clinically applicable for diabetes induced erectile dysfunction.     

Vascular endothelial growth factor (VEGF) gene therapy using a nonviral gene delivery system improves erectile function in a diabetic rat model

Erectile dysfunction (ED) is a cause of decreased quality of life in more than 70% of diabetic men. Vascular endothelial growth factor (VEGF) has shown to improve overall endothelial and smooth muscle cell dysfunction in models of ED. We describe a novel technique for nonviral, in vivo gene transfection of VEGF in the rat corpus cavernosum. Diabetic rats were transfected with DNA encoding a fusion VEGF/green fluorescent protein (GFP) complex and fluorescence microscopy was used to monitor the expression of VEGF-GFP fusion protein. Western blot and PCR analyses confirmed the expression of the GFP-VEGF fusion protein and mRNA. Functional studies using cavernous nerve stimulation revealed maximal intracavernous pressures (ICPs) of 63.1 mm Hg, and 30.7 mm Hg in the normal and diabetic control groups, respectively, and 47.4 mm Hg in VEGF-GFP-transfected diabetic group. Immunohistochemical analysis of the cavernosal tissue from transfected rats showed increased smooth muscle content compared with the diabetic control group. We show for the first time in our animal model that expression of the transfected VEGF in cavernosal tissue leads to an overall improvement of maximal ICP and smooth muscle content. On the basis of these results, it is tempting to speculate that our nonviral vector system offers an excellent system for gene delivery into cavernosal tissue, and that VEGF gene therapy using this system could be useful in improving erectile function in diabetic men.     

Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors

A large body of evidence has accumulated demonstrating that a common pathway in conditions such as hypertension, atherosclerosis, hypercholesterolemia, diabetes mellitus, and erectile dysfunction (ED) is endothelial dysfunction. Although a complete pharmacological cure for ED is currently unavailable, the phosphodiesterase 5 (PDE5) inhibitors sildenafil, vardenafil, and tadalafil are efficacious oral therapy for ED. Results from recent studies suggest that regular treatment with a PDE5 inhibitor may lead to enhanced erectile function (EF) beyond that observed with on-demand usage, possibly through improvement of endothelial function. Such an effect may be viewed as rehabilitation of damaged erectile tissue. The present review focuses on several recent studies which provide evidence for the beneficial effect of regular PDE5 inhibitor administration on the improvement of EF by rehabilitation of vascular endothelium.     

Effects of Icariside II on Improving Erectile Function in Rats With Streptozotocin-Induced Diabetes

Icariin and icariside II (ICA II), 2 active components isolated from herba epimedii, have a closely structural relationship. There is evidence that icariin may be useful in the treatment of erectile dysfunction (ED); however, the study on the therapeutic efficacy of ICA II on ED is currently scant. We investigated the effects of ICA II on improving erectile function of rats with streptozocin-induced diabetes. Fifty 8-week-old Sprague-Dawley rats were randomly distributed into normal control and diabetic groups. Diabetes was induced by a one-time intraperitoneal injection of streptozocin (60 mg/kg). Three days later, the diabetic rats were randomly divided into 4 groups including a saline-treated placebo arm and 3 ICA II-treated models (1, 5, and 10 mg/kg/d). After 3 months, penile hemodynamics was measured by cavernous nerve electrostimulation (CNE) with real time intracorporal pressure assessment. Penises were harvested with subsequent histological examination (picrosirius red stain, Hart elastin stain, and immunohistochemical stain) and Western blots to explore the expression of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) and transforming growth factor β1 (TGFβ1)/Smad2 signaling pathways. Diabetes significantly attenuated erectile responses to CNE. Diabetic rats had decreased corpus cavernosum smooth muscle/collagen ratio and endothelial cell content relative to the control group. The ratio of collagen I to III was significantly lower in the corpora of diabetic rats; furthermore, cavernous elastic fibers were fragmented in the diabetic animals. Neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase, and vascular endothelial growth factor were expressed at lower levels in the diabetic group; ICA II-treated diabetic rats had higher expression in the penis relative to placebo-treated diabetic animals. Both the TGFβ1/Smad2/connective tissue growth factor (CTGF) signaling pathway and apoptosis were down-regulated in the penis from ICA II-treated rats. ICA II treatment attenuates diabetes-related impairment of penile hemodynamics, likely by increasing smooth muscle, endothelial function, and nNOS expression. ICA II could alter corpus cavernosum fibrous-muscular pathological structure in diabetic rats, which could be regulated by the TGFβ1/Smad2/CTGF and NO-cGMP signaling pathways.     

伐地那非治疗老年糖尿病性勃起功能障碍疗效分析

目的:观察伐地那非治疗老年糖尿病(DM)性勃起功能障碍(ED)患者的临床疗效和安全性。方法:选择男性科门诊100例老年ED患者,其中DMED40例,非DMED60例。2组均使用伐地那非,首次剂量20mg,以后维持剂量10mg,1次/周,连续8周。采用国际勃起功能问卷勃起功能评分(IIEF-5)和勃起质量量表问卷(EQS)对患者勃起功能状况进行评估。结果:治疗前后,DMED组患者IIEF-5和EQS评分值分别为(8.1±0.5)分,(18.9±0.2)分(P<0.01);(9.1±1.3)分,(25.1±1.4)分(P<0.01);非DMED组患者评分值分别为(10.1±0.3)分,(21.1±0.2)分(P<0.01),(10.1±1.7)分,(34.2±1.2)分(P<0.01),2组间统计学处理差异有显著性(P<0.05)。DMED组显效17例(42.5%),有效9例(22.5%),总有效率65%。非DMED组显效28例(46.7%),有效16例(26.7%),总有效率73.3%。DMED和非DMED2组间统计学处理差异有显著性(P<0.05)。结论:伐地那非治疗能显著改善老年DMED患者的勃起能力,提高生活质量。     

The effect of vardenafil on endothelial function of brachial and cavernous arteries

The aim of the present study was to examine the effect of new phosphodiesterase type 5 inhibitor vardenafil on endothelial function of cavernous and brachial arteries in healthy men and in patients with different forms of erectile dysfunction (ED). This prospective, double-blind, placebo-controlled study was performed on 135 men with ED and 30 healthy controls. Complex evaluation was performed in all patients with ED. All participants also underwent our modification of ultrasound (US) assessment of postocclusive changes in the diameter of cavernosal arteries and endothelium-dependent flow-mediated dilation (FMD) of the brachial artery before and 1 h after administration of 20 mg of vardenafil or placebo. After study drug administration, PICAD and FMD significantly increased in patients receiving vardenafil (P < 0.001) but not in patients receiving placebo. Increase in PICAD values was significantly greater in patients with arteriogenic ED compared with patients with organic nonarterial ED (P = 0.007), psychogenic ED (P < 0.001) and controls (P = 0.001). The most prominent increase in brachial artery FMD values were found in patients with arteriogenic ED, although statistically significant differences were present only between patients with arteriogenic ED and control group (P = 0.035). We have found a moderate negative correlation between initial PICAD and its increase after vardenafil and between pretreatment flow-mediated vasodilation of brachial arteries and its increase after vardenafil administration (r = -0.57 and -0.55, respectively). These findings suggest that the use of vardenafil restores impaired endothelial function of cavernous and brachial arteries.     

Effect of PDE5 inhibition combined with free oxygen radical scavenger therapy on erectile function in a diabetic animal model

Phosphodiesterase (PDE) inhibitors represent an important advance in the treatment of erectile dysfunction (ED). In spite of widespread use and generally good efficacy, as a class they remain ineffective in 15-57% of men. Specific cohorts of patients with severe vascular or neurogenic basis to their ED, such as diabetic men or those who have undergone radical pelvic surgery, demonstrate lower response rates with PDE inhibition treatment. We believe that circulating levels of nitric oxide (NO) may be enhanced through delivery of adequate concentrations of free oxygen radical scavenger molecules such as vitamin E. Higher levels of NO, theoretically, should produce increased penile blood flow with the potential for a synergistic effect when combined with a PDE5 inhibitor. With this hypothesis in mind, 20 adult male Sprague-Dawley streptozotocin-induced (60 mg/kg i.p.) diabetic rats were divided into four therapeutic groups (n=5). Group I--control animals received peanut oil, group II--vitamin E 20 IU/day, group III--sildenafil 5 mg/kg/day and group IV--vitamin E 20 IU/day plus sildenafil 5 mg/kg/day, by oral gavage daily for 3 weeks. Erectile function was assessed as a rise in intracavernous pressure following cavernous nerve electrostimulation. Penile tissue was harvested to determine the changes in tissue morphology including neuronal nitric oxide synthase, smooth muscle alpha-actin and endothelial cell integrity. PDE5 protein content and activity were measured. Significant increases in intracavernous pressure were measured in the animals receiving combined vitamin E plus sildenafil treatment. Immunohistochemical staining showed increases of neuronal nitric oxide synthase, endothelial cell and smooth muscle cell staining. Western blot analysis did not show significant differences of PDE5 protein between the groups. However, higher PDE5 activity was measured in the sildenafil group and lower activity of PDE5 was recorded in the cohort receiving vitamin E with sildenafil. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in a meaningful way in this animal model of diabetes. This study indicates a potential means of salvaging erectile function among patients who are refractory to sildenafil.     

Altered expression of mitofusin 2 in penile tissues of diabetic rats

Diabetic erectile dysfunction (ED) is a common complication in diabetes mellitus, and the efficacy of first‐line therapies is not satisfactory. Recent studies revealed that corporal apoptosis was responsible for the nonresponsiveness of severe ED to phosphodiesterase type 5 inhibitors. Mitofusin 2 (Mfn2) is a versatile protein, regulating mitochondrial morphology and playing an important role in apoptosis. Several studies showed that expression of Mfn2 was decreased in STZ‐induced diabetic rats' kidney, myocardium and retina, which was associated with diabetic nephropathy, cardiomyopathy and retinopathy respectively. In this study, our aim was to explore the expression of Mfn2 and apoptosis in diabetic rats' penes. We found that erectile function (ICP/MAP) elicited by electrical stimulation of cavernous nerve was markedly impaired in diabetic rats compared with the normal rats. The mRNA and protein levels of Mfn2 were found to be significantly reduced in diabetic rats' penile tissues. Compared with normal rats, the content of smooth muscle and B‐cell lymphoma 2 (Bcl‐2)/Bcl‐2‐associated X protein (Bax) ratio were dramatically decreased, and penile apoptotic index and expression of activated‐caspase‐3 were dramatically increased in diabetic rats. This data indicated that repression of Mfn2 in diabetic rats' penes might be associated with excessive apoptosis in diabetes‐induced severe ED.     

Efficacy of vardenafil in men with erectile dysfunction: a flexible-dose community practice study

OBJECTIVE: To determine the efficacy and tolerability of flexible dosing with vardenafil in a broad population of men with erectile dysfunction (ED). METHODS: 10-week, open-label, flexible-dose study starting with vardenafil 10 mg, titrating to 5 mg or 20 mg at weeks 2 and 6 based on efficacy and tolerability, set in 78 community practice centers in Germany and France. Participants comprised 398 men aged > or =18 years with ED. Main outcome measures were self-reported improvement in erections according to a Global Assessment Question (GAQ), diary questions from the Sexual Encounter Profile (SEP2 and SEP3), and the erectile function domain score from the International Index of Erectile Function (IIEF) questionnaire. RESULTS: In a last observation carried forward (LOCF) analysis, a total of 92% (336/366) of men with ED reported an improvement of erections according to the GAQ. Per-patient success rates for penetration (SEP2) and maintenance (SEP3) of erection for intercourse were 89% (348/390) and 78% (303/390), respectively. Mean erectile function domain scores increased from 13.9 at baseline to 25.9 at LOCF. Vardenafil was generally well tolerated; headache (6%, 25/398) and flushing (6%, 24/398) were the most frequent adverse events. CONCLUSIONS: In this community practice setting, vardenafil was shown to be a highly effective and generally well-tolerated treatment for men with ED when dosing was titrated by the physician to individual patient requirements.     

Nitric oxide-cyclic GMP pathway with some emphasis on cavernosal contractility

Nitric oxide (NO) is formed from the conversion of L-arginine by nitric oxide synthase (NOS), which exists in three isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). nNOS is expressed in penile neurons innervating the corpus cavernosum, and eNOS protein expression has been identified primarily in both cavernosal smooth muscle and endothelium. NO is released from nerve endings and endothelial cells and stimulates the activity of soluble guanylate cyclase (sGC), leading to an increase in cyclic guanosine-3',5'-monophosphate (cGMP) and, finally, to calcium depletion from the cytosolic space and cavernous smooth muscle relaxation. The effects of cGMP are mediated by cGMP dependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesterases (PDE). Thus, cGMP effect depends on the expression of a cell-specific cGMP-receptor protein in a given cell type. Numerous systemic vasculature diseases that cause erectile dysfunction (ED) are highly associated with endothelial dysfunction, which has been shown to contribute to decreased erectile function in men and a number of animal models of penile erection. Based on the increasing knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation, selective PDE inhibitors have recently been introduced in the treatment of ED. Phosphodiesterase 5 (PDE5) inactivates cGMP, which terminates NO-cGMP-mediated smooth muscle relaxation. Inhibition of PDE5 is expected to enhance penile erection by preventing cGMP degradation. Development of pharmacologic agents with this effect has closely paralleled the emerging science.     

Reduction of endothelial and smooth muscle density in the corpora cavernosa of the streptozotocin induced diabetic rat

PURPOSE: Erectile dysfunction is one of the most prevalent complications of diabetes in males. Because adequate vascular perfusion is needed for appropriate erectile tissue function a likely reason for the high incidence of this complication in diabetics is a pathological change associated with the disease in vascularization of erectile tissues. We investigate whether chronic diabetes may induce changes in vascularization of the corpora cavernosa using a computerized image analysis system to quantify changes in the smooth muscle and endothelial cell content of the corpora cavernosa of diabetic rats induced by streptozotocin 6 months previously, and compare these changes to those associated with aging. MATERIALS AND METHODS: We studied 3 groups of rats, including 10-week-old untreated controls, diabetic rats treated with streptozotocin for 6 months starting at age 10 weeks and 18-month-old rats (aged). Penile shafts from these groups were excised, fixed, sectioned and immunostained with anti-smooth muscle actin to identify smooth muscle cells and anti-CD31 to identify endothelial cells. Computerized image analysis was used to quantify the percent area within the corpora cavernosa occupied by smooth muscle cells or endothelial cells, and the data were compared among the groups. RESULTS: We identified a highly significant decrease in the percentage of smooth muscle and endothelial cells within the cavernosa areas of diabetic rats compared to control or aged rats. Mean cavernous smooth muscle cell content was 15.28 +/- 2.54% in control rats and 9.83 +/- 1.21% in diabetic rats (p = 0.0001). Likewise, cavernous endothelial cell content was 6.93 +/- 0.86% in the control group and 4.01 +/- 1.08% in the diabetic group (p = 0. 0001). However, no statistical difference of smooth muscle or endothelial cell content was found between control and aged rats. CONCLUSIONS: Using the streptozotocin treated rat as a model for diabetes, we showed that smooth muscle and endothelial cell density is significantly decreased in diabetic corpora cavernosa but not in normal aged rats. This observation is a further step toward the understanding of the pathomechanisms for diabetic related erectile dysfunction.     

Oxidative stress in arteriogenic erectile dysfunction: prophylactic role of antioxidants

PURPOSE: We searched for markers of oxidative stress in cavernous ischemia and examined the effect of long-term antioxidant intake on arteriogenic erectile dysfunction (ED) in the rabbit. MATERIALS AND METHODS: Antioxidant activity of known antioxidant beverages, such as pomegranate juice (PJ), red wine, blueberry juice, cranberry juice, orange juice and green tea, was examined spectrophotometrically. PJ demonstrated the highest free radical scavenging capacity. The effect of long-term PJ intake on intracavernous blood flow and penile erection was then examined in the rabbit model. Erectile tissues were processed to assess oxidative stress and smooth muscle relaxation, immunohistochemical staining of nitric oxide synthase (NOS) and histomorphometry. RESULTS: On spectrophotometric analysis PJ showed the highest capacity to decrease low density lipoprotein oxidation and inhibit cellular oxidative stress in macrophages. The rabbit model of arteriogenic ED demonstrated decreased intracavernous blood flow, erectile dysfunction, loss of smooth muscle relaxation, decreased endothelial NOS and neuronal NOS, increased inducible NOS expression, diffused cavernous fibrosis and increased cavernous levels of the oxidative product isoprostane 8-epi-prostaglandin F2alpha. Long-term PJ intake increased intracavernous blood flow, improved erectile response and smooth muscle relaxation in ED and control groups while having no significant effect on NOS expression. PJ intake prevented erectile tissue fibrosis in the ED group. CONCLUSIONS: Arteriogenic ED accumulates oxidative products in erectile tissue, possibly via an intrinsic mechanism. Oxidative stress may be of great importance in the pathophysiology of arteriogenic ED. Antioxidant therapy may be a useful prophylactic tool for preventing smooth muscle dysfunction and fibrosis in ED.     

伐地那非治疗糖尿病患者的勃起功能障碍

勃起功能障碍 (erectiledysfunction ,ED)在糖尿病患者中发生率要高于非糖尿病人群 ,而且更难治疗。伐地那非是一种高选择性的新型磷酸二酯酶 5抑制剂 ,是广泛ED人群的一线治疗药物。最近发表的大型临床试验表明 ,无论糖尿病合并ED的患者基线时的病情严重程度如何 ,也无论他们的血糖控制情况如何 ,伐地那非都能有效地改善其勃起功能 ,而且使用安全 ,耐受性良好     

Effect of caffeine on erectile function via up-regulating cavernous cyclic guanosine monophosphate in diabetic rats

Erectile dysfunction (ED) is a common complication of diabetes mellitus. Phosphodiesterase-5 (PDE5) inhibitors, which inhibit the breakdown of intracellular cyclic guanosine monophosphate (cGMP), are used to treat diabetic ED. Caffeine, a nonselective PDE inhibitor used in our daily diet, is controversial regarding its effect on erectile function. To investigate the effect of caffeine on erectile function in diabetic rat models and explore the mechanism, male Sprague-Dawley rats were injected with streptozotocin to induce diabetes mellitus. The rats with blood glucose levels above 300 mg/dL were selected for the study. The rats were divided into 4 groups: group A (normal control rats), group B (diabetic rats treated with normal saline), group C (diabetic rats treated with caffeine, 10 mg/kg per day), and group D (diabetic rats treated with caffeine, 20 mg/kg per day). After 8 weeks of treatment, intracavernous pressure (ICP) was measured to assess erectile function. The radioimmunoassay was used to evaluate the level of cGMP in the cavernosum. The ICP and the cavernous cGMP decreased significantly in the diabetic rats compared with normal controls. An 8-week administration of caffeine at the given dosages increased the ICP and cavernous cGMP in diabetic rats. Caffeine consumption improved the erectile function of diabetic rats by up-regulating cavernous cGMP.     

Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy

BACKGROUND: To date, no data have been available from large, well-designed trials comparing on demand and nightly dosing of phosphodiesterase type 5 (PDE5) inhibitors on recovery of erectile function in postprostatectomy patients with erectile dysfunction (ED). OBJECTIVE: To investigate the effect of early postoperative dosing with vardenafil, administered either nightly or on demand, compared with placebo on recovery of erectile function in men with ED following bilateral nerve-sparing radical prostatectomy (NSRP) surgery. DESIGN, SETTING, AND PARTICIPANTS: A randomised, double-blind, double-dummy, multicentre, parallel group study conducted at 87 centres across Europe, Canada, South Africa, and the United States. For inclusion, patients had to be scheduled to undergo bilateral NSRP within 1 mo of screening and have a normal International Index of Erectile Function erectile function domain (IIEF-EF) score of >/=26 at screening. A total of 628 men, aged 18-64 yr, were randomised to treatment. Study design consisted of a 9-mo double-blind treatment period, a 2-mo single-blind washout period, and an optional 2-mo open-label period. INTERVENTION: Patients received placebo, nightly vardenafil, or on demand vardenafil. MEASUREMENTS: Primary outcome measure was the percentage of subjects with an IIEF-EF score of >/=22 after the 2-mo washout period. Secondary variables included mean per-patient success rates for Sexual Encounter Profile (SEP) questions 2 and 3. RESULTS AND LIMITATIONS: No statistically significant differences were observed among treatment groups in the proportion of patients with an IIEF-EF score of >/=22 or in SEP3 success rates after the washout period. On-demand vardenafil treatment resulted in significantly greater IIEF-EF scores and better SEP3 response rates than placebo over the entire treatment period. CONCLUSIONS: In this study of men with ED following bilateral NSRP, vardenafil was efficacious when used on demand, supporting a paradigm shift towards on demand dosing with PDE5 inhibitors in this patient group. TRIAL REGISTRATION: European clinical trials database (EudraCT; available at http://eudract.emea.europa.eu/). Trial registration number: 11336.     

Gene transfer of endothelial nitric oxide synthase partially restores nitric oxide synthesis and erectile function in streptozotocin diabetic rats

PURPOSE: We determined whether adenoviral gene transfer of endothelial nitric oxide synthase (eNOS) to the penis of streptozotocin induced diabetic rats could improve the impaired erectile response. MATERIALS AND METHODS: Two experimental groups of animals were transfected with adenoviruses, including streptozotocin (Sigma Chemical Company, St. Louis, Missouri) diabetic rats with AdCMVbetagal and streptozotocin diabetic rats with AdCMVeNOS. At 1 to 2 days after transfection these study animals underwent cavernous nerve stimulation to assess erectile function and their responses were compared with those of age matched control rats. In control and transfected streptozotocin diabetic rats eNOS and neuronal NOS (nNOS) were examined by Western blot analysis. Constitutive and inducible NOS activities were evaluated in the presence and absence of calcium by L-arginine to L-citrulline conversion and nitrate plus nitrite levels were measured. In control and streptozotocin diabetic penes beta-galactosidase activity and localization were determined. RESULTS: After transfection with AdCMVbetagal beta-galactosidase was localized to the endothelium and smooth muscle cells of the streptozotocin diabetic rat penis. Streptozotocin diabetic rats had a significant decrease in erectile function, as determined by peak and total intracavernous pressure (area under the curve) after cavernous nerve stimulation compared with control rats. Streptozotocin diabetic rats transfected with AdCMVeNOS had peak intracavernous pressure and area under the curve similar to those in control animals. This change in erectile function was a result of eNOS over expression with an increase in eNOS protein expression and constitutive NOS activity as well as an increase in nitric oxide biosynthesis, as reflected by an increase in cavernous nitrate plus nitrite formation. There was no change in nNOS protein expression or calcium independent conversion of NOS (inducible NOS activity). CONCLUSIONS: Adenoviral gene transfer of eNOS significantly increased peak and total intracavernous pressure to cavernous nerve stimulation in streptozotocin diabetic rats to a value similar to the response observed in control rats. Our results suggest that eNOS contributes significantly to the physiology of penile erection. These data demonstrate that in vivo adenoviral gene transfer of eNOS can physiologically improve erectile function in the streptozotocin diabetic rat.     

Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome

There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle‐to‐collagen ratio and alpha‐smooth muscle actin expression and an increase in transforming growth factor‐beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats.     

The effect of PDE5 inhibition on the erectile function in streptozotocin-induced diabetic rats

The aim of this study was to assess the effect of phosphodiesterase 5 inhibitor, DA-8159, on erectile function throughout the quantitative analysis of vascular endothelial cell, smooth muscle (SM), TGF-beta1 expression in rat corpus cavernosum and measurement of intracavernous pressure (ICP) in diabetic rats. DA-8159 (0, 5, 10, 20 mg/kg) was administered orally once a day to diabetic rats. After 8 weeks, immunohistochemistry and computerized image analysis were performed to quantify the percent area within the Corpora Cavernosa occupied by the endothelial cells, SM cells and fibrotic tissues. ICP/mean arterial pressure (MAP) was also measured by electrostimulation of the cavernous nerve. Diabetic rats showed a significant decrease in the SM and endothelial cell content, and an increase in the TGF-beta1 expression level within the cavernosa areas compared to the normal rats. The mean cavernous SM, endothelial cell content and TGF-beta1 expression level were 9.7+/-0.7, 4.5+/-0.7 and 17.9+/-2.1%, respectively. DA-8159 prevented reduction of SM (12.3+/-0.4% (5 mg/kg), 13.8+/-0.4% (20 mg/kg)) and endothelial cell content (5.6+/-0.5% (5 mg/kg), 6.3+/-0.6% (20 mg/kg)). Immunoreactivity of TGF-beta1 and intracorporal fibrosis were also significantly lower in DA-8159-treated groups (11.8+/-1.2% (5 mg/kg), 9.5+/-1.1% (20 mg/kg)). Electrostimulation of the cavernous nerve induced significant increase in maximum ICP (62.2+/-13.6 mmHg in 10 mg/kg vs 37.5+/-17.5 mmHg in diabetic group) and area under the curve of the ratio of ICP/MAP (8891.09+/-1957 in 10 mg/kg vs 6315.87+/-2272 in diabetic group). These results suggest that subchronic treatment of DA-8159 can prevent the development of erectile dysfunction (ED), and provides a rationale for the use of DA-8159 as treatment of diabetic ED.     

糖尿病与勃起功能障碍病因研究进展

糖尿病 (DM)是勃起功能障碍 (ED)的危险因子之一。DM性ED病人阴茎组织出现以下病理变化 :平滑肌、内皮细胞退变 ,白膜增厚 ,血管及周围神经递质发生改变