Couplet medicines of leech and centipede granules improve erectile dysfunction via inactivation of the CaSR/PLC/PKC signaling in streptozotocin-induced diabetic rats.

Erectile dysfunction (ED) is one of the significant complications of diabetes mellitus (DM), and CASR plays an important role in cellular antiapoptosis and NO production in the vascular endothelium by activating PKC. The present study was aimed to investigate the efficacy of Leech and Centipede Granules (LCG) through the CaSR/PLC/PKC signaling. Fifty male Sprague-Dawley rats were treated with streptozotocin to induce the DM model. After 10 weeks, an apomorphine test was used to confirm DMED. Rats with DMED were administrated with LCG and U73122 for 4 weeks. Fasting blood glucose, body weight, insulin and glucagon levels were measured. Erectile function in rats was assessed by apomorphine. Serums were measured using enzyme-linked immunosorbent assay and flow cytometry, and penile tissues were harvested for histologic and the expression of related targets analyses. After treatment, fasting blood glucose, body weight, insulin, glucagon levels, and erectile function were significantly ameliorated in the LCG groups. The LOX-1, NOX, and EMPs concentrations were significantly decreased with LCG treatment. LCG also continuously increased NO and decreased ET-1 content in penile tissues. LCG and U73122 administration also improved penile fibrosis by significantly decreasing VCAM-1, ICAM-1, and CD62P. The data also showed that LCG reduced the apoptosis level in the penis. Furthermore, the inhibited activation of the CaSR/PLC/PKC pathway was observed in DMED rats with LCG treatment. Collectively, LCG significantly ameliorated erectile function of DMED rats via increased NO generation, inhibiting endothelial cells apoptosis and penile fibrosis, which might benefit from the suppression of CaSR/PLC/PKC pathway in DMED rats.

Folic acid supplementation improves erectile function in patients with idiopathic vasculogenic erectile dysfunction by lowering peripheral and penile homocysteine plasma levels: a case-control study.

BACKGROUND: Erectile dysfunction (ED) has common risk factors with many cardiovascular (CV) impairments. In view of these facts, hyperhomocysteinemia (HHcys) has been postulated for involvement in endothelial dysfunction. OBJECTIVES: We evaluated peripheral and penile homocysteine (Hcys) plasma levels before and after folic acid supplementation in idiopathic vasculogenic erectile dysfunction (ED) patients. MATERIALS AND METHODS: This study included 50 consecutive patients and 50 consecutive healthy controls that were recruited from December 2017 to December 2018. The patients received folic acid (FA) daily for 3 months and were evaluated by the abridged 5-item International Index of Erectile Function (IIEF-5) and penile duplex before and after therapy, in addition to plasma Hcys levels. RESULTS: Our study showed improvement in the severity of ED in our patients as all of them became mild to moderate ED after folic acid administration. Additionally, the median scores of IIEF-5 significantly increased from 6 to 14, respectively (p < 0.001). Furthermore, the median peripheral and penile Hcys plasma levels (µmol/l) significantly decreased after folic acid administration as 39 patients with moderate ED and 11 patients with severe ED were 0.62, 0.34, 5.37, 0.37, respectively, became mild to moderate ED with their median peripheral and penile Hcys plasma levels became 0.19, 0.15, p < 0.001, <0.001, respectively. Peripheral Hcys level correlates significantly with penile Hcys before and after folic acid administration (r: -0.06 p: 0.8, r: 0.9, p < 0.001, respectively). DISCUSSION AND CONCLUSION: Recently, an emerging body of evidence suggests a role for Hcys and folate in erectile function. Interestingly, our interventional study is one of the first that evaluated the effect of folic acid supplementation on HHcys where it demonstrated a significant decrease in peripheral and penile Hcys plasma levels after folic acid administration. Thus, FA should be prescribed concomitantly with phosphodiesterase type 5 inhibitors in ED patients.

Herb formula enhances treatment of impotent patients after penile venous stripping: a randomised clinical trials.

Herbs have been regarded as aphrodisiacs in treating impotence for many centuries despite little true scientific evidence. Our latest refined penile venous stripping (PVS) technique is effective in treating impotence, although this procedure remains controversial. A synergic effect of PVS and oral herbs was confirmed in our practice but lacked rigorous scientific proof. The objective of this report was to review our experience with this combination. From August 2010 to May 2014, 263 males underwent PVS. Among these, 67 unsatisfied men chose additional salvage therapy and were randomly assigned to oral herbs (n = 35) or placebo treatment (n = 32) which replaced herb eventually. All were evaluated with the international index of erectile function (IIEF-5) scoring and our dual pharmaco-cavernosography. The pre-op IIEF-5 score for the herb group was 9.7 ± 3.7, post-operative 13.9 ± 3.3 and post-herb 19.6 ± 3.4, while the control group scores were as follows: pre-op 9.3 ± 4.1, post-op 14.5 ± 3.6, post-placebo 15.1 ± 3.5 and post-herb 19.9 ± 3.2. Although there was no significant difference between the two groups pre-operatively, post-operatively and post-herb, a statistically significant difference was found post-salvage therapy (19.6 ± 3.4 versus 15.1 ± 3.6, P < 0.001). It appears that the combination of oral herbs and PVS treatment provides an enhanced outcome to impotent patients refractory to medicine and unsatisfied with PVS monotherapy alone.

Oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction.

INTRODUCTION: Oral L-citrulline supplementation increases serum L-arginine levels more efficiently than L-arginine itself and increases nitric oxide (NO) production. AIM: To investigate whether oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction (ED). METHODS: We divided 8-week-old male Wistar-ST rats into 3 groups: sham-operated rats (control group), arteriogenic ED rats who underwent ligation of both internal iliac arteries (ligation group), and arteriogenic ED rats receiving oral 2% L-citrulline water supplementation (citrulline group). Citrulline water was given to arteriogenic ED rats for 3 weeks from 1 week after surgery. Erectile function was evaluated by maximum intracavernous pressure/mean arterial pressure (ICP/MAP) ratios via cavernous nerve stimulation at 4 weeks after surgery. Then, the penises were resected, stained with Masson's trichrome, and observed microscopically. Serum nitrogen oxides (NOx) levels were measured by high-performance liquid chromatography. Bonferroni's multiple t-test was used for statistical analysis. MAIN OUTCOME MEASURES: The main outcome measures were changes in ICP/MAP, smooth muscle (SM)/collagen ratios, and NOx levels following L-citrulline supplementation. RESULTS: The ICP/MAP ratio in the ligation group was significantly lower than that in the control group (P<0.05), denoting ED. The ICP/MAP ratio of the citrulline group was significantly higher than that of the ligation group (P<0.05), indicating ED amelioration. Levels of NOx in the ligation group were significantly lower than in the control group (P<0.05), while those in the citrulline group were significantly higher than in the ligation group (P<0.05). SM/collagen ratios in the ligation group were significantly lower than in the control group (P<0.05), while ratios in the citrulline group were significantly higher than those in the ligation group (P<0.05). CONCLUSIONS: Oral L-citrulline supplementation improved ICP/MAP and SM/collagen ratios and increased NOx. Therefore, oral L-citrulline supplementation might be a useful novel therapy for acute arteriogenic ED.

Extracellular signal-regulated kinase (ERK) inhibition decreases arginase activity and improves corpora cavernosal relaxation in streptozotocin (STZ)-induced diabetic mice.

INTRODUCTION: Increased arginase activity (AA) has been implicated in hypertension and diabetes-induced endothelial dysfunction by reducing L-arginine availability and nitric oxide production. Higher levels of active extracellular signal-regulated kinase (ERK) have been found in patients with erectile dysfunction (ED) compared to patients without it. Both ERK and arginase have been reported to affect the expression and activity of nitric oxide synthase (NOS) and consequently penile erection. Nevertheless, signaling pathways activated by ERK in the penis are not well known. AIM: We hypothesized that inhibition of ERK by ERK inhibitor PD98059 decreases AA and thus improves cavernosal relaxation in streptozotocin (STZ)-diabetic mice. METHODS: The AA, ERK, eNOS, and arginase I and II expressions were examined through Western blot, and functional response of cavernosal tissue were determined. Control and diabetic cavernosal tissues were pretreated with PD98059 (10(-5) M) and arginase inhibitor ((S)-(2-boronoethyl)-L-cysteine hydrochloride, [BEC]10(-4) M]). MAIN OUTCOME MEASURES: Diabetes increased AA significantly (twofold) over control mice and this effect was blocked by acute treatment with PD98059. Cavernosal strips from diabetic mice exhibited decreased relaxation (STZ-diabetic vs. control, respectively) to both the endothelium-dependent agonist acetylcholine (38.0 ± 5% vs. 82.5 ± 7%) and nitrergic stimulation (27 ± 2% vs. 76 ± 6%) by electrical field stimulation (EFS, 1-32 Hz). However, this impairment in cavernosal relaxation from diabetic mice was attenuated by treatment with PD98059 in nitrergic (27 ± 2% vs. 60 ± 4%) and endothelium-dependent relaxation responses (38.0 ± 5% vs. 67.5 ± 6%). Acute treatment with the arginase inhibitor BEC (10(-4) M) also improves EFS-induced relaxation in diabetic mice (31 ± 3% vs. 49 ± 2%). Moreover, vascular expression of activated ERK was increased in diabetic over control mice. CONCLUSION: These data suggest that ERK inhibition prevents elevation of penile AA and protects against ED caused by diabetes.

Chronic vardenafil treatment improves erectile function via structural maintenance of penile corpora cavernosa in rats with acute arteriogenic erectile dysfunction.

INTRODUCTION: Chronic phosphodiesterase type 5 inhibitor treatment may be useful in reversing erectile dysfunction (ED). However, the mechanisms of this improvement remain unknown. AIM: The aim of this article was to determine the mechanisms of the improvement by chronic vardenafil treatment for acute arteriogenic ED in rats. METHODS: Eight-week-old male Wistar-ST rats were divided into four groups: sham-operated rats (Control group) and rats with acute arteriogenic ED induced by ligating bilateral internal iliac arteries (Ligation group), subsequently treated with low-dose (0.4 mg/kg/day; VL group) or high-dose (4.0 mg/kg/day; VH group) vardenafil for 20 days from 1 week after ligature. MAIN OUTCOME MEASURES: Erectile function was assessed based on changes of intracavernous pressure (ICP) followed by electrostimulation of the cavernous nerves and was evaluated by the area under the curve of ICP/area under the curve of mean arterial pressure (area of ICP/MAP). Transforming growth factor (TGF)-ß(1), vascular endothelial growth factor-A, endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS mRNA expression levels in penile corpus cavernosum were determined by real-time PCR. Western blotting for TGF-ß(1) protein levels and Masson trichrome staining of penile tissues were performed in each at group 4 weeks after surgery. RESULTS: In the VH group, area of ICP/MAP was significantly improved when compared with the Ligation group (P < 0.01). The smooth muscle (SM)/collagen ratio in the VH group was significantly higher than in the Ligation group (P < 0.05), and was comparable with that in the Control group. TGF-ß(1) mRNA and protein levels in the VH group were significantly lower when compared with the Ligation group (P < 0.05). CONCLUSIONS: Chronic vardenafil administration ameliorates impairment of penile hemodynamics and maintains normal SM to collagen ratio in cavernous tissues after acute arterial injury in rats.

Investigation of a complex plant extract for mild to moderate erectile dysfunction in a randomized, double-blind, placebo-controlled, parallel-arm study.

OBJECTIVE: To assess the effects of a complex plant extract (Prelox®, a formulation of pine bark extract and l-arginine aspartate; Horphag Research UK Ltd, London, UK) on erectile dysfunction (ED) in men, as sexual desire typically persists in ageing men, while their erectile and endothelial function gradually declines. PATIENTS AND METHODS: In this double-blind, placebo-controlled study we assessed the effects of Prelox in 124 patients (aged 30-50 years) with moderate ED over an investigational period of 6 months. The International Index Of Erectile Function (IIEF) was used to quantify changes in sexual function. RESULTS: The erectile domain of the IIEF (questions 1-5 plus 15) improved with Prelox from a baseline mean (sd) score of 15.2 (6.6) to 25.2 (2.1) after 3 months and 27.1 (2.1) after 6 months of treatment. In the placebo group there was an increase from a baseline score of 15.1 (7.0) to 19.1 (3.0) and 19.0 (3.1) after 3 and 6 months, respectively. The effects with Prelox were statistically significant compared with placebo (P < 0.05). Mean (SD) total plasma testosterone levels increased significantly from 15.9 (2.3) to 18.9 (2.6) nmol/L (P < 0.05) after 6 months with Prelox, compared to an increase from 16.9 (2.4) to 17.3 (2.3) nmol/L in the placebo group. CONCLUSION: This study shows that Prelox is effective for improving erectile function, and that this effect persists on continuous therapy for up to 6 months. Moreover, there is some evidence that erectile function continues to improve the longer the therapy is used.

The use of Butea superba (Roxb.) compared to sildenafil for treating erectile dysfunction.

OBJECTIVE: To evaluate the effect of an extract of Butea superba (Roxb.) (BS) compared to sildenafil for treating erectile dysfunction (ED). PATIENTS AND METHODS: An open label study was carried out among 32 men with organic ED to evaluate the response on the International Index of Erectile Function 5 (IIEF-5) to BS, a 'natural health' product (100 mg), compared to 50 mg of sildenafil (a phosphodiesterase-5 inhibitor). After a 1-week wash-out, responders to BS received either 100 mg starch or 100 mg of another batch of BS (double-blind). RESULTS: Of the patients in the BS group, 27 (84%) responded positively, compared with 26 (81%) in the sildenafil group. When assessing the score alone, 12 (38%) had a better score after taking BS, compared to seven (22%) after sildenafil, and eight (25%) had the same score. The results were surprising and could not be repeated in the double-blind part of the study, where no effect of BS was recorded. CONCLUSIONS: A 'natural' health product containing BS was more effective than sildenafil in the first part of the study, but in the second, using another batch of BS, the positive result could not be repeated and no effect was recorded. The conclusion is that the first preparation of BS was most likely blended with a phosphodiesterase-5 inhibitor, later confirmed by the supplier of BS (a natural health products company) after their own analysis.

Combination of vacuum erection device and PDE5 inhibitors as salvage therapy in PDE5 inhibitor nonresponders with erectile dysfunction.

INTRODUCTION: Oral phosphodiesterase type 5 inhibitors (PDE5i) have improved treatment options for erectile dysfunction (ED). In case of unresponsiveness to PDE5i, alternative therapies are considered. AIM: To evaluate whether combination of vacuum erection device (VED) and PDE5i is effective as salvage therapy in subjects with ED in whom PDE5i alone failed. METHODS: From September 2007 to May 2008, we evaluated 69 men (aged 36-82 years) in whom PDE5i treatment at the highest recommended dose, with at least 4-6 attempts at intercourse during a 3 months period, had failed. The clinical efficacy of combination therapy was evaluated using the International Index of Erectile Function-5 (IIEF-5) questionnaire, Sexual Encounter Profile (SEP)-2, SEP-3, and Global Patient Assessment Scale (GPAS). MAIN OUTCOME MEASURES: Scores on IIEF-5, SEP-2, SEP-3, and GPAS before and after combination therapy were measured. RESULTS: After 4 weeks of combination therapy, the mean IIEF-5 score increased significantly over baseline from 9.0 to 17.6 (P < 0.001). Of the 34 subjects with a SEP-2 response of "no" at baseline, 27 (79%) responded "yes" after combination therapy (P < 0.001). Of the 50 subjects with a SEP-3 response of "no" at baseline, 35 (70%) responded "yes" after combination therapy (P < 0.001). Furthermore, of the 42 subjects with a GPAS response of "not at all" or "slightly" improved at baseline, 31 (74%) responded "moderately" or "greatly" improved after combination therapy (P < 0.001). One subject (1.5%) experienced device-related intermittent penile pain, which resolved after 4 days without any action. CONCLUSIONS: Statistically significant improvements over baseline were seen in IIEF-5, SEP-2, SEP-3, and GPAS measures following 4 weeks of combination therapy of PDE5i and VED. This study supports the use of PDE5i with VED in men in whom PDE5i alone failed. This combination therapy may be offered to patients not satisfied with PDE5i alone before being switched to more invasive alternatives.

[Metabolism of nitric oxide (NO) and arginine: significance for male health]. / Stickstoffmonooxid(NO)- und Arginin-Stoffwechsel und deren Bedeutung in der Männergesundheit.

Since the first description of the "endothelium-derived relaxing factor" (EDRF) in 1980 the function of the endothelium has developed into a field of research of its own. The most important endothelial factor is nitric oxide (NO), which is formed from l-arginine with the help of NO synthase (NOS). Disturbances of the endothelial function play an important role in men's health such as atherogenesis and erectile dysfunction and are also followed by morphological vessel changes. Furthermore, NO seems to play an important role in LUTS (lower urinary tract symptoms) and male fertility.

Guide to drug therapy for lower urinary tract symptoms in patients with benign prostatic obstruction : implications for sexual dysfunction.

The relationship between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) caused by benign prostatic obstruction (BPO) has recently gained increasing attention. Both BPO and ED are highly prevalent in older men and both conditions frequently contribute to a reduction in overall quality of life. Current medical treatment of LUTS/BPO consists of monotherapy with alpha(1)-adrenoceptor antagonists or 5alpha-reductase inhibitors, a combination of these two agents or, in some cases, various phytotherapeutic approaches. When choosing a drug therapy, it is important to recognize that while 5alpha-reductase inhibitors increase the risk of ED and ejaculatory disorders, and combined therapy carries the cumulative risk of causing sexual dysfunction, some alpha(1)-adrenergic receptor antagonists have been reported to improve overall sexual function. Therefore, the successful evaluation and management of older men with LUTS associated with BPO should include an assessment of baseline sexual function and subsequent monitoring of medication-induced sexual adverse effects. In this review, we detail the pathophysiological mechanisms involved in LUTS/BPO-associated ED, including reduced nitric oxide/cyclic guanosine monophosphate system activity, enhanced endothelin-1/rhoA/rho kinase pathway activity, sympathetic overactivity, pelvic organ atherosclerosis and potential preventive approaches.

[Effect of Zhenyangjian on the penile hemodynamics of the patients with arterial erectile dysfunction].

OBJECTIVE: To explore an efficacious therapy for arterial erectile dysfunction (ED) by observing the effect of the Chinese traditional medicine Zhenyangjian on the penile hemodynamics of the patient. METHODS: Forty-seven patients with arterial ED, aged from 40 to 49 years, were treated with Zhenyangjian for 1 month. Intracavernous injection of papaverine and phentolamine (30 mg/l mg) was given and multifunctional color Doppler ultrasound was used to measure the peak systolic velocity(PSV) of the corpus cavernous arteries before and after Zhenyangjian administration. RESULTS: The PSV of the penis corpus cavernous arteries was obviously ameliorated in all the patients (P < 0.05). CONCLUSION: The Chinese traditional medicine Zhenyangjian can promote penile erection effectively.

Accumulated endogenous NOS inhibitors, decreased NOS activity, and impaired cavernosal relaxation with ischemia.

We examined whether endogenous inhibitors of nitric oxide (NO) synthesis are involved in the impaired cavernosal relaxation with ischemia in rabbits. Two weeks after cavernosal ischemia caused by partial vessel occlusion, endothelium-dependent and electrical field stimulation (EFS)-induced neurogenic NO-mediated relaxations, but not sodium nitroprusside (SNP)-induced relaxation, were significantly impaired in the isolated corpus cavernosum. The Ca(2+)-dependent NO synthase (NOS) activity and the basal and stimulated cGMP productions with carbachol or EFS were significantly decreased after ischemia. Supplementation of excess L-arginine partially recovered both of the impaired relaxations. The contents of N(G)-monomethyl-L-arginine (L-NMMA) and asymmetric N(G), N(G)-dimethyl-L-arginine (ADMA) but not L-arginine and symmetric N(G),N'(G)-dimethyl-L-arginine (SDMA) were increased in the cavernosal tissues after ischemia. Authentic L-NMMA and ADMA but not SDMA concentration dependently inhibited both relaxations without affecting the relaxation produced by SNP in the control. Excess L-arginine abolished the inhibition with L-NMMA and ADMA. These results suggest that the impaired NO-mediated cavernosal relaxations after ischemia are closely related to the decreased NOS activity and the increased accumulation of L-NMMA and ADMA.

Topical vasoactive cream in the treatment of erectile failure: a prospective, randomized placebo-controlled trial.

OBJECTIVE: To repeat a previous study on the use of a topical treatment for erectile failure using a vasoactive cream. PATIENTS AND METHODS: Fourteen patients with erectile failure who had previously responded to intracorporeal injection therapy were enrolled in a randomized placebo-controlled trial. They were given two topical applications, comprising either a cream containing aminophylline, isosorbide dinitrate and co-dergocrine mesylate, or a placebo cream of similar appearance containing no pharmacologically active ingredients. Each patient received 16 applications, eight of the active cream and eight placebo. The creams were applied alternatively on successive occasions and the results recorded. RESULTS: The active cream, applied on 77 occasions, resulted in three good and 13 partial erections. The placebo cream, applied on 76 occasions, yielded four good and 13 partial erections. CONCLUSIONS: We were unable to reproduce the successful results reported by others; in the present study the active cream performed no better than placebo.

Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study.

OBJECTIVES: To determine, in a prospective randomized, double-blind placebo-controlled study, the effect of 6 weeks of high-dose (5 g/day) orally administered nitric oxide (NO) donor L-arginine on men with organic erectile dysfunction (ED). PATIENTS AND METHODS: The study included 50 men with confirmed organic ED who were randomized after a 2-week placebo run-in period to receive L-arginine or placebo. A detailed medical and sexual history, O'Leary's questionnaire, a specially designed sexual function questionnaire and a sexual activity diary were obtained for each patient. All participants underwent a complete physical examination including an assessment of bulbocavernosus reflex and penile haemodynamics. Plasma and urine nitrite and nitrate (designated NOx), both stable metabolites of nitric oxide, were determined at the end of the placebo run-in period, and after 3 and 6 weeks. RESULTS: Nine of 29 (31%) patients taking L-arginine and two of 17 controls reported a significant subjective improvement in sexual function. All objective variables assessed remained unchanged. All nine patients treated with L-arginine and who had subjectively improved sexual performance had had an initially low urinary NOx, and this level had doubled at the end of the study. CONCLUSIONS: Oral administration of L-arginine in high doses seems to cause significant subjective improvement in sexual function in men with organic ED only if they have decreased NOx excretion or production. The haemodynamics of the corpus cavernosum were not affected by oral L-arginine at the dosage used.