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.

Vessel-sparing Radiotherapy for Localized Prostate Cancer to Preserve Erectile Function: A Single-arm Phase 2 Trial.

BACKGROUND: Erectile dysfunction remains the most common side effect from radical treatment of localized prostate cancer. We hypothesized that the use of vessel-sparing radiotherapy, analogous to the functional anatomy approach of nerve-sparing radical prostatectomy (RP), would improve erectile function preservation while maintaining tumor control for men with localized prostate cancer. OBJECTIVE: To determine erectile function rates after vessel-sparing radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: Men with localized prostate cancer were enrolled in a phase 2 single-arm trial (NCT02958787) at a single academic center. INTERVENTION: Patients received vessel-sparing radiotherapy utilizing a planning MRI and MRI-angiogram to delineate and avoid the erectile vasculature. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Both physician- and patient-reported inventories were used to capture erectile function at baseline and at 2 and 5 yr after treatment. Validated model-based comparisons were performed to compare vessel-sparing results to nerve-sparing RP and conventional radiotherapy. RESULTS AND LIMITATIONS: From 2001 to 2009, 135 men underwent vessel-sparing radiotherapy. After a planned interim analysis, the trial was stopped after meeting the primary endpoint. The median follow-up was 8.7 yr, with a ≥94% response rate to all inventories at each time point. At 5 yr, 88% of patients were sexually active with or without the use of sexual aids. The 2-yr erectile function rates were significantly improved with vessel-sparing radiotherapy (78%, 95% confidence interval [CI] 71-85%) compared to modeled rates for convention radiotherapy (42%, 95% CI 38-45%; p<0.001) or nerve-sparing prostatectomy (24%, 95% CI 22-27%; p<0.001). At 2 yr after treatment, 87% of baseline-potent men retained erections suitable for intercourse. The 5- and 10-yr rates of biochemical relapse-free survival were 99.3% and 89.9%, and at 5 yr the biochemical failures were limited to the National Comprehensive Cancer Network high-risk group. The single-arm design is a limitation. CONCLUSIONS: Vessel-sparing radiotherapy appears to more effectively preserve erectile function when compared to historical series and model-predicted outcomes following nerve-sparing RP or conventional radiotherapy, with maintenance of tumor control. This approach warrants independent validation. PATIENT SUMMARY: In this interim analysis we looked at using a novel approach to spare critical erectile structures to preserve erectile function after prostate cancer radiotherapy. We found that almost 90% of patients at 5 yr after treatment remained sexually active, significantly higher than previous studies with surgery or radiotherapy.

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.

Dietary antioxidants improve arteriogenic erectile dysfunction.

Most cases of erectile dysfunction (ED) are associated with oxidative stress risk factors such as diabetes mellitus, smoking, hypercholesterolaemia and hypertension. Our goal was to search for markers of oxidative stress in arteriogenic ED and examine the protective role of dietary antioxidants. Atherosclerosis-induced ED was developed in rabbits by balloon de-endothelialization of the iliac arteries. Ballooned and age-matched control animals were assigned into subgroups receiving pomegranate extract antioxidants in drinking water or tap water as placebo. After 8 weeks, penile blood flow and erectile activity were recorded. Erectile tissue relaxation, oxidative products, oxidative stress-responsive genes and structure were examined using organ bath, enzyme immunoassay, quantitative real-time polymerase chain reaction and transmission electron microscopy, respectively. Arterial ballooning caused diffused atherosclerosis, decreased intracavernosal blood flow and led to ED. Impairment of endothelium-dependent relaxation, diffused fibrosis, increased oxidative products, upregulation of superoxide dismutase (SOD) and aldose reductase (AR) gene expression, mitochondrial and endothelial structural damage and increased caveolae were evident in erectile tissues from atherosclerotic animals receiving placebo. Upregulation of antioxidant enzymes SOD and AR failed to protect ischaemic erectile tissue from oxidative injury. Pomegranate extract significantly improved intracavernosal blood flow, erectile activity, smooth muscle relaxation and fibrosis of the atherosclerotic group in comparison with the atherosclerotic group receiving placebo, but did not normalize them to the age-matched control levels. Pomegranate extract appeared more effective in diminishing oxidative products, preventing SOD and AR gene upregulation, and protecting mitochondrial, endothelial and caveolae structural integrity of the atherosclerotic group. Our data suggest the presence of oxidative stress in ED and a more efficient action of antioxidants on molecular and ultrastructural alterations than on distinct functional deficit and structural damage in the ischaemic penis.

The effect of intracavernous injection of adipose tissue-derived stem cells on hyperlipidemia-associated erectile dysfunction in a rat model.

INTRODUCTION: Hyperlipidemia has been associated with erectile dysfunction (ED) via damage to the cavernous endothelium and nerves. Adipose tissue-derived stem cells (ADSC) have been shown to differentiate into endothelial cells and secrete vasculotrophic and neurotrophic factors. AIM: To assess whether ADSC have therapeutic effects on hyperlipidemia-associated ED. METHODS: Twenty-eight male rats were induced to develop hyperlipidemia with a high-fat diet (hyperlipidemic rats, HR). Ten additional male rats were fed a normal diet to serve as controls (normal rats, NR). Five months later, all rats were subjected to ADSC isolation from paragonadal fat. The cells were cultured for 1 week, labeled with 5-ethynyl-2'-deoxyuridine (EdU), and then injected autologously into the corpus cavernosum of 18 HR. The remaining 10 HR rats were injected with phosphate buffered saline (PBS). At 2 and 14 days post-transplantation, four rats in the HR + ADSC group were sacrificed for tracking of the transplanted cells. At 28 days post-transplantation, all remaining rats were analyzed for serum biochemistry, erectile function, and penile histology. MAIN OUTCOME MEASURES: Erectile function was assessed by intracavernous pressure (ICP) measurement during electrostimulation of the cavernous nerve. Cavernous nerves, endothelium, and smooth muscle were assessed by immunohistochemistry. RESULTS: Serum total cholesterol and low-density lipoprotein levels were significantly higher in HR than in NR. High-density lipoprotein level was significantly lower in HR than in NR. Mean ICP/mean arterial pressure ratio was significantly lower in HR + PBS than in NR + PBS or HR + ADSC. Neuronal nitric oxide synthase (nNOS)-positive nerve fibers and endothelial cells were fewer in HR + PBS than in HR + ADSC. Smooth muscle content was significantly higher in both HR groups than in NR. CONCLUSIONS: Hyperlipidemia is associated with abnormalities in both the nerves and endothelium. Treatment with ADSC ameliorates these adverse effects and holds promise as a potential new therapy for ED.

[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.

[Functional electromyostimulation of the penile corpus cavernosum (FEMCC)]. Initial results of a new therapeutic option of erectile dysfunction]. / Funktionelle Elektromyostimulation des Corpus cavernosum penis (FEMCC). Erste Ergebnisse einer neuen therapeutischen Option bei erektiler Dysfunktion.

Transcutaneous application of low-frequency electric current in the treatment of partially or temporarily denervated striated muscles is widely used to prevent or treat muscular atrophy. Due to the high regenerative capacity of smooth muscle cells, this approach should be beneficial in the treatment of diseases with smooth muscle degeneration due to partial denervation. Our study was done to evaluate the possible beneficial effect of transcutaneous application of low-frequency electric current to the corpus cavernosum penis in the treatment of erectile dysfunction. After a comprehensive work-up, 22 patients with chronic erectile dysfunction (21/22 vasoactive nonresponders) received daily (3-5 x 20 min) transcutaneous functional electromyostimulation of the corpus cavernosum smooth muscles (FEMCC; zero line symmetric impulses of trapezoid shape, two-channel device with alternating stimulations, f = 10-20 Hz for channel I and 20-35 Hz for channel II; t(i) = 100-2000 microseconds, approx. 12 mA, rise time 0.5 s, stimulation time 5 s per channel, interval between stimulations 0.5 s). Five of 22 patients (23%) regained full spontaneous erections and another three (14%) responded to vasoactive drugs after FEMCC. Fourteen were FEMCC failures, including two who subjectively 'improved'. In a similar group of patients evaluated during the same period but receiving no therapy, no spontaneous improvement of the erectile function was observed. Our preliminary results suggest that FEMCC is feasible and results in an improvement of the erectile capacity in a significant proportion (37%) of patients. Further studies will be carried out to corroborate our results, to improve stimulation parameters and to evaluate selection criteria for FEMCC.

Chronic penile denervation in the rat: effect on cavernous tissue morphology and function.

We evaluated the effects of chronic penile denervation on cavernous tissue morphology and function in 36 Sprague-Dawley rats. At age seven weeks, 18 animals underwent bilateral cavernous nerve neurectomy: 18 animals underwent sham operation as a control. A functional, biochemical and morphological assessment of the rats' penises was performed at 4 months. In denervated rats, intracavernous pressure failed to rise with electrostimulation of the pelvic plexus. However, a normal rise in pressure was found with direct intracavernous injection of sodium nitroprusside and papaverine. Sodium dodecylsulfate polyacrylamide (SDS) gel electrophoresis of the penile homogenate showed subtle differences between denervated and control animals. Based upon the histological findings there was no difference in staining of the cavernous tissue for acetylcholinesterase- and catecholamine-positive nerve fibers between experimental and control animals, since the innervation density was not quantified and the number of fibers was not counted. We conclude that chronic cavernous nerve neurectomy does not cause significant morphological or functional changes to the penile erectile tissue of rats.