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A Chinese Herbal Formula, Shuganyiyang Capsule, Improves Erectile Function in Male Rats by Modulating Nos-CGMP Mediators
Abstract
To evaluate the effects of the Chinese herbal formula Shuganyiyang (SGYY) capsule on arteriogenic erectile dysfunction (ED) in a rat model and to investigate the underlying molecular mechanism.
Forty male Sprague-Dawley rats were subjected to bilateral ligation of the internal iliac artery and then divided into 4 groups (n=10 per group). They were treated daily with either sildenafil (10.5 mg/kg), or SGYY at 1 of 2 dosages (1 g/kg and 0.5 g/kg) for 30 days. Erectile function was evaluated using cavernous nerve electrical stimulation after treatment, and the cavernous tissue specimens of all animals were harvested for gene and protein examination using real-time reverse transcriptase polymerase chain reaction, Western blot analysis, and cyclic guanosine monophosphate (cGMP) measurement.
The ratio of the maximal intracavernous pressure to the mean arterial pressure was significantly higher in the SGYY (1 g/kg and 0.5 g/kg) rats than that in the models (P<.01). The gene and protein expression of 3 subtypes of nitric oxide synthase (NOS)--neuropathic (nNOS), inducible (iNOS), and endothelial (eNOS)--and cGMP concentrations in cavernous tissue in SGYY-treated rats were significantly higher than in the models. However, phosphodiesterase type 5 (PDE5) expression in the SGYY rats was lower than those in models (P<.01 or P<.05).
SGYY significantly improves the maximal intracavernous pressure in arteriogenic ED in a rat model. The underlying mechanism of action of SGYY involves increasing the expression of some main factors in the NOS-cGMP pathway and reducing the expression of PDE5.
... Recent epidemiological reports showed that depending on the definition used and study design, ED prevalence ranged from 10% to 52%, and the annual incidence is 30 new cases per 1000 inhabitants in western countries [2]. Even though numerous ED animal models have been established, such as those involving hyperlipidemia, internal iliac artery ligation, diabetes mellitus, denervation, hypertension, smoking, pelvic irradiation and prostanoids, the arteriogenic ED model remains the most common type of model [3][4][5][6][7][8][9][10]. One reason for the popularity of the arteriogenic ED model is that performing internal iliac artery ligation is quite simple. ...
... In addition, nNOS and eNOS initiate penile erection and are involved in sustaining the erection [28,29]. Recently, many studies have associated eNOS and nNOS with the level of erectile function [4,30]. Accordingly, BCH-induced ED showed lower ICP without recovery, and the NOS levels were consistently lower than normal. ...
Objective
To investigate a novel method, namely using bilateral internal iliac artery ligation combined with a high-fat diet (BCH), for establishing a rat model of erectile dysfunction (ED) that, compared to classical approaches, more closely mimics the chronic pathophysiology of human ED after acute ischemic insult.
Materials and Methods
Forty 4-month-old male Sprague Dawley rats were randomly placed into five groups (n = 8 per group): normal control (NC), bilateral internal iliac artery ligation (BIIAL), high-fat diet (HFD), BCH, and mock surgery (MS). All rats were induced for 12 weeks. Copulatory behavior, intracavernosal pressure (ICP), ICP/mean arterial pressure, hematoxylin-eosin staining, Masson's trichrome staining, serum lipid levels, and endothelial and neuronal nitric oxide synthase immunohistochemical staining of the cavernous smooth muscle and endothelium were assessed. Data were analyzed by SAS 8.0 for Windows.
Results
Serum total cholesterol and triglyceride levels were significantly higher in the HFD and BCH groups than the NC and MS groups. High density lipoprotein levels were significantly lower in the HFD and BCH groups than the NC and MS groups. The ICP values and mount and intromission numbers were significantly lower in the BIIAL, HFD, and BCH groups than in the NC and MS groups. ICP was significantly lower in the BCH group than in the BIIAL and HFD groups. Cavernous smooth muscle and endothelial damage increased in the HFD and BCH groups. Cavernous smooth muscle to collagen ratio, nNOS and eNOS staining decreased significantly in the BIIAL, HFD, and BCH groups compared to the NC and MS groups.
Conclusions
The novel BCH model mimics the chronic pathophysiology of ED in humans and avoids the drawbacks of traditional ED models.
... 2,12,13 However, the patients with ED caused by cavernous nerve (CN) injury due to the diabetes and radical prostatectomy respond poorly to these drugs, 13,14 and they should be precautious when given with alpha receptor blocking drugs and CYP3A inhibitors such as anti-retroviral protease inhibitors or macrolide antibiotics, etc. 12 due to side effects such as hot flush, digestive disorder and headache. 13 There are many reports that natural formulae [15][16][17][18][19] may improve ED by modulating NO synthase (NOS) activity and cGMP amount in cavernous tissues after bilateral CN injury, and they may also improve the ED related to diabetes. [5][6][7][20][21][22] Lycium barbarum (wolfberry) is known to have various biological activities and has been widely used in the last decades as a popular functional food. ...
... Three NOS isoforms exist in the penis: nNOS, eNOS, and inducible NOS [26]. Only eNOS and nNOS are crucial for initiating and maintaining an erection [27]. Preincubation with ROE or EA increased the eNOS and nNOS levels in PCCSM tissue, whereas PCCSM relaxation induced by ROE or EA was strongly inhibited by L-NAME. ...
The present study was designed to evaluate the relaxation effect of Rubus occidentalis (RO) and ellagic acid (EA) on rabbit penile corpus cavernosum smooth muscle (PCCSM). Rabbit PCCSM was treated with ROE or EA after preincubation with nitric oxide synthase (NOS), guanylate cyclase (GC), adenylyl cyclase (AC) or protein kinase A (PKA) blocker. Cyclic nucleotides in the perfusate were analyzed using radioimmunoassay (RIA). Subsequently, perfused PCCSMs were subjected to analysis to evaluate the expression level of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS). The interaction of ROE or EA with phosphodiesterase (PDE) 5 and PDE4 inhibitors, such as udenafil (UDE) and rolipram (ROL), were also evaluated. Both ROE and EA relaxed the PCCSM in a concentration-dependent manner. Coincubation of ROE or EA with NOS, GC, AC, or PKA blocker significantly decreased the ROE- and EA-induced relaxation. Pretreatment of ROE and EA significantly upregulated the cyclic guanosine monophosphate (cGMP), cyclic adenosine 3′,5′-monophosphate (cAMP), and eNOS levels in the perfused PCCSM. Furthermore, the treatment of ROE and EA markedly increased the UDE- and ROL-induced relaxation of the PCCSM. In conclusion, ROE and EA induced PCCSM relaxation by activating the nitric oxide (NO)-cGMp and cAMp signaling pathways and may have a synergistic action to improve erectile function.
... In addition, COP3 was also shown to increase NOS activity in mouse penile tissues (Fig. 3) and promote NO production in testicular TM3 cells (Fig. 4). This is interesting because NO is known to play important roles during penile erection and enhancing NOS to synthesize NO may facilitate initiation of penile erection (Kandeel et al., 2001;Wang et al., 2012). ...
Ethnopharmacological relevance:
Crassostrea gigas Thunberg and other oysters have been traditionally used in China as folk remedies to invigorate the kidney and as natural aphrodisiacs to combat male impotence.
Aim of the study:
Erectile dysfunction (ED) has become a major health problem for the global ageing population. The aim of this study is therefore to evaluate the effect of peptide-rich preparations from C. gigas oysters on ED and related conditions as increasing evidence suggests that peptides are important bioactive components of marine remedies and seafood.
Materials and methods:
Crassostrea oyster peptide (COP) preparations COP1, COP2 and COP3 were obtained from C. gigas oysters by trypsin, papain or sequential trypsin-papain digestion, respectively. The contents of testosterone, cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) and the activity of nitric oxide synthase (NOS) in mice and/or cells were measured by enzyme-linked immunosorbent assays. Real-time PCR was used to assess the expression of genes associated with sex hormone secretion pathways. The model animal Caenorhabditis elegans was also used to analyze the gene expression of a conserved steroidogenic enzyme. In silico analysis of constituent peptides was performed using bioinformatic tools based on public databases.
Results:
The peptide-rich preparation COP3, in which >95% peptides were <3000 Da, was found to increase the contents of male mouse serum testosterone and cAMP, both of which are known to play important roles in erectile function, and to increase the activity of mouse penile NOS, which is closely associated with ED. Further investigation using mouse Leydig-derived TM3 cells demonstrates that COP3 was able to stimulate the production of testosterone as well as NO, a pivotal mediator of penile erection. Real-time PCR analysis reveals that COP3 up-regulated the expression of Areg and Acvr2b, the genes known to promote sex hormone secretion, but not Fst, a gene involved in suppressing follicle-stimulating hormone release. Furthermore, COP3 was also shown to up-regulate the expression of let-767, a well-conserved C. elegans gene encoding a protein homologous to human 17-β-hydroxysteroid dehydrogenases. Preliminary bioinformatic analysis using the peptide sequences in COP3 cryptome identified 19 prospective motifs, each of which occurred in more than 10 peptides.
Conclusions:
In this paper, Crassostrea oyster peptides were prepared by enzymatic hydrolysis and were found for the first time to increase ED-associated biochemical as well as molecular biology parameters. These results may help to explain the ethnopharmacological use of oysters and provide an important insight into the potentials of oyster peptides in overcoming ED-related health issues.
... [10] Animal experiments showed that SGYY capsule improved ED of rats by regulating mediators of nitric oxide synthase-cyclic guanosine monophosphate pathway. [11] It also significantly upregulated vascular endothelial growth factor, insulin-like growth factor, protein kinase B and improved vascular endothelial function thereby improving erectile function of rats. [12] In recent years, the clinical trials of SGYY capsule have increased, but there are inconsistent results. ...
Background:
Erectile dysfunction (ED) is a common disease. It affects the quality of life of both husband and wife and becomes an independent risk factor for cardiovascular events. In China, Shugan Yiyang (SGYY) capsule has been increasingly reported in clinical trials for the treatment of ED and reported inconsistent findings. Therefore, it is necessary to conduct a systematic review to evaluate the efficacy and safety of this drug for the treatment of ED.
Methods:
Chinese and English literature of SGYY capsule for ED published before August 31, 2019 will be comprehensive searched in PubMed, Cochrane Library, EMBASE, WANFANG, China National Knowledge Infrastructure, VIP Chinese Science and Technology Journal Database, Chinese biomedical document service system, and Clinicaltrials.gov. All randomized controlled trials that meet the eligibility criteria will be included and other studies will be excluded. Two investigators will conduct literature screening, data extraction and assess risk of bias alone, and the third investigator will handle disagreements. Two outcomes involving the international index of erectile function 5 score and adverse events will be evaluated. RevMan 5.3 and Stata 14.0 will be used to conduct this systematic review. The preferred reporting items for systematic reviews and meta-analysis protocols (PRISMA-P) statement is followed in this protocol and the the PRISMA statement will be followed in the completed systematic review.
Conclusion and dissemination:
The efficacy and safety of SGYY capsule for ED will be evaluated. We will publish the results of this systematic review in peer-reviewed journals to provide new evidence to clinicians.Registration information: PROSPERO CRD42019140903.
... Shuganyiyang capsule is a formula composed of 15 Chinese herbs, which could increase blood circulation, activate Yang and replenish vital essence of human bodies. It was reported that Shuganyiyang capsule improved the intracavernous pressure in arteriogenic ED in rats by activating the NOS-cGMP pathway and reducing the expression of PDE5 (44). ...
Traditional Chinese medicine (TCM), including acupuncture and Chinese herbs, is used as an alternative therapy to increase the curative effect for erectile dysfunction (ED). A large number of studies have been conducted to investigate the effect and mechanism of TCM for treating ED. The therapeutic effect of acupuncture on ED is still controversial at present. However, some Chinese herbs exhibited satisfying outcomes and they might improve erectile function by activating nitric oxide synthase (NOS)-cyclic guanosine monophosphate (cGMP) pathway, increasing cyclic adenosine monophosphate (cAMP) expression, elevating testosterone level, reducing intracellular Ca²⁺ concentration, down-regulating transforming growth factor β1 (TGFβ1)/Smad2 signaling pathway, or ameliorating the oxidative stress.
... Losing collagen fiber within the corpus cavernosa has been reported to increase muscle tone for initiation and sustenance of penile erection while increasing sinusoid space related to the increased blood volume required for penile erection initiation [5,73] . The effect on sexual behaviour and structural improvement of the corpus cavernosa might be involved with polyphenols or phytochemicals with antioxidant activity which could be due to eNOS activation as has been previously reported [74] . In the diabetic condition, serum NO levels and the expression of NOS genes, PDE5 and intracellular cGMP levels will deteriorate [75,76] . ...
Objective:
To investigate the biological effects of the Mucuna pruriens (M. pruriens) seed extracts that lacked l-DOPA, which was formerly reported as the active ingredient, on erectile dysfunction (ED) both in vitro and in vivo.
Methods:
Seed of M. pruriens plant that cultivated in Mae Taeng District, Chiang Mai Province, Thailand, was collected. Component of its seeds were extracted and isolated into 2 fractions using methanol, polar and nonpolar. Each fraction was investigated for phytochemicals using gas chromatography and mass spectroscopy and was screened for biological activity in vitro using three different cell lines. The most biological active fraction was used to treat both streptozotocin (STZ)-induced diabetes mellitus-erectile dysfunction (DM-ED) male Wistar rats and normal rats (n = 6 per groups) to compare the effect on sexual behavior parameters, including number of intromission, mounting and ejaculation, with that of rats given Sildenafil by individually pairing with their female counterparts. Penile tissues and serums were collected to determine histological structure, related gene expression and biomolecules.
Results:
The phytochemicals of the polar fraction were possibly catechol and its derivatives plus polyphenols, whereas the nonpolar fraction consisted of lipid derivatives. l-DOPA was not detected in either of the extracts. The polar fraction was able to up-regulate the expression of ED-related genes including eNOS and nNOS in vitro which subsequently promotes nitric oxide production and maintains intracellular cyclic guanosine monophosphate levels. When administrated to DM-ED rats, the polar extract significantly improved all sexual behavior parameters in DM-ED rats compared to untreated group (18.3 ± 1.8 to 10.8 ± 2.9 for intromission, 9.8 ± 2.2 to 5.7 ± 1.3 for mounting, and 1.8 ± 0.6 to 0.2 ± 0.4 for ejaculation). That effect might due to the ability of the extract to stimulate the expression of eNOS and nNOS which results in nitric oxide production and subsequently maintains cyclic guanosine monophosphate levels in penile tissue. Moreover, this extract may also prevent penile tissue deterioration due to diabetes.
Conclusions:
The polar extract of M. pruriens seed can be used for ED therapy, especially in patients with metabolic diseases including diabetes. The action of the extract might be due to catechol and its derivatives and polyphenols.
... Depending on its etiology, ED can be classified as psychogenic, organic, or mixed ED (Cohan and Korenman, 2001;Grant et al., 2013;Barassi et al., 2014;Vodusek, 2014). Neuronal nitric oxide synthase (nNOS) is currently believed to play an important role in penile erection (Burnett et al., 1992;Hurt et al., 2012;Wang et al., 2012;Amany and Heba, 2013;Hu et al., 2014). Pathogenic factors may decrease NOS activity, subsequently reducing nitric oxide production and thereby leading to ED. ...
Our previous studies have demonstrated that some male patients suffering from brachial plexus injury, particularly brachial plexus root avulsion, show erectile dysfunction to varying degrees. However, the underlying mechanism remains poorly understood. In this study, we evaluated the erectile function after establishing brachial plexus root avulsion models with or without spinal cord injury in rats. After these models were established, we administered apomorphine (via a subcutaneous injection in the neck) to observe changes in erectile function. Rats subjected to simple brachial plexus root avulsion or those subjected to brachial plexus root avulsion combined with spinal cord injury had significantly fewer erections than those subjected to the sham operation. Expression of neuronal nitric oxide synthase did not change in brachial plexus root avulsion rats. However, neuronal nitric oxide synthase expression was significantly decreased in brachial plexus root avulsion + spinal cord injury rats. These findings suggest that a decrease in neuronal nitric oxide synthase expression in the penis may play a role in erectile dysfunction caused by the combination of brachial plexus root avulsion and spinal cord injury.
Objective:
The study was aimed to evaluate the influences of erectile dysfunction (ED) in a rat model of stroke combined with hyperlipidemia (HLP).
Methods:
Male Sprague-Dawley rats were divided into control and hyperlipidemia (HLP) groups. HLP model was constructed by feeding with high-fat and cholesterol diets. Serum levels of total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), triglyceride (TG), and non-HDL were identified to check the model was success. Stroke model was established by FeCl3. ICP/MAP value was detected to evaluate the erectile function of rats. Serum level of lipoproteins and the expressions of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) were detected by ELISA. Hematoxylin-eosin (HE) staining of corpus cavernosum and measurement of penis length were utilized to assessment erectile function. Western blot was used.
Results:
TC, TG, LDL, and non-HDL-C in serum were up-regulated, while HDL level was attenuated. After treatment, the serum lipid level recovered. From the ICP/MAP values, the erectile function of both two treatment groups recovered. The expression of PDE5A was up-regulated, while the levels of eNOS and cGMP were suppressed after surgery. The length of penis was decreased, and corpus cavernosum was damaged following HLP and stroke. However, the erectile function was recovered after treatment.
Conclusion:
Stroke combined HLP caused ED through NO-cGMP-PDE5 pathway.
Male infertility normally refers a male's inability to cause pregnancy in a fertile female partner after 1 year of unprotected intercourse. Male infertility in recent years has been attracting increasing interest from public due to the evidence in decline in semen quality. There are many factors contributing to the male infertility including abnormal spermatogenesis; reproductive tract anomalies or obstruction; inadequate sexual and ejaculatory functions; and impaired sperm motility, imbalance in hormone levels, and immune system dysfunction. Although conventional treatments such as medication, surgical operation, and advanced techniques have helped many male with infertility cause pregnancy in their female partners, effectiveness is not satisfactory and associated with adverse effects. Chinese herbal medicine (CHM) has been used to improve male infertility in China for a very long time and has now been increasingly popular in Western countries for treating infertility. In this chapter we summarized recent development in basic research and clinical studies of CHM in treating male infertility. It has showed that CHM improved sperm motility and quality, increased sperm count and rebalanced inadequate hormone levels, and adjusted immune functions leading to the increased number of fertility. Further, CHM in combination with conventional therapies improved efficacy of conventional treatments. More studies are needed to indentify the new drugs from CHM and ensure safety, efficacy, and consistency of CHM.
The aim of the present study was to explore the regulation status of genes in oxidative stress (OS)‑induced endothelial dysfunction and to elucidate the mechanism of action of OS‑associated genes, which induce cavernosal endothelial dysfunction in erectile dysfunction (ED). OS was established in purified cavernosal endothelial cells (CECs) using xanthine/xanthine oxidase and the differentially expressed OS‑associated genes were analyzed using gene microarrays. In addition, an ED rat model was established through bilateral internal iliac artery ligation with hyperlipidemia and was verified by an intracavernosal pressure test. The selected OS‑associated genes were validated in the CECs and ED rat model using reverse transcription‑quantitative polymerase chain reaction. Student's t‑test and one‑way analysis of variance were performed using SBC analysis system. Gene microarray analysis revealed that 13090 (31.92%) genes were expressed in the control group, whereas 12039 (29.35%) genes were expressed in the treated group. The cut‑off value for differential expression was set at 2.0 fold‑change and 2480 genes were found to be differentially expressed compared with the control group. Of these cells, 1454 were upregulated and 1026 were downregulated. Cluster analysis identified relevant cell signaling pathways that were hypothesized to be significant in OS‑associated endothelial dysfunction, including the cytokine‑cytokine receptor interactions, nitrogen metabolism, coagulation cascades and cell adherens. Cxcl12, Tgfbr1, Asns, Bdkrb1 and Cdh3 genes showed a corresponding variation in the CECs and ED rat model compared with the results of the gene microarray analysis. In conclusion, in the present study, the network of differentially expressed genes and OS‑associated signaling pathways identified using gene microarray analysis were validated in the CECs and ED rat model. The results indicated that OS may lead to endothelial dysfunction through certain cell signaling pathways, inducing ED. However, further functional verification is required in order to elucidate the underlying mechanisms of OS‑associated cell signaling pathways in ED.
In recent years research on penile erection has increasingly been centered on the molecular mechanisms involved. Major progress has been made in the field and at present a whole number of neurotransmitters, chemical effectors, growth factors, second-messenger molecules, ions, intercellular proteins, and hormones have been characterized as components of the complex process of erection. This knowledge has led to the discovery of several new therapeutic targets and multiple medical approaches for the treatment of erectile dysfunction (ED). This review focuses on the progress made in this field within the last few years.
To elucidate the effects of summer cover crops on vegetable production, on soil water conservation and on reducing nutrient leaching from the soil, a pot experiment was conducted on Krome soil with legume and non-legume cover crops. Natural weedy fallow served as the control. The cover crops were sunn hemp (Crotalaria juncea L.), cowpea (Vigna unguiculata (L. Walp)), velvetbean (Mucuna deeringiana (Bort.) Merr.), and sorghum sudangrass (Sorghum bicolor x S. bicolor var. sudanense (Piper) Stapf). The leachate from under each pot was collected weekly, measured, and analyzed for concentrations of nitrate (NO 3-N), ammonium (NH4-N) and inorganic phosphorus (P). The results showed that compared to the control, legume cover crops, especially sunn hemp, significantly improved tomato yields, and all the cover crops significantly reduced water and nutrient leaching. The amounts of NO 3-N in the leachates collected during six-week period from pots with cover crops was equivalent to 0.9 to 2.2 kg ha-1(0.8 to 2.0 lb ac-1), which was significantly less than 16.1 kg ha-1 (14.4 lb ac-1) from the weedy fallow (control). In the fallow treatment, 21.3 percent of fertilizer nitrogen (N) was lost through leaching, but only 1.3 to 3.2 percent was lost with cover crops. Taking account of plant uptake and leaching, total amounts of 26.9 and 40.6 kg N ha-1 (24.0 and 36.3 lb ac-1) were lost from the soil pool for the treatments in fallow and sorghum sudangrass but 28 to 252.7 kg N ha-1 (25.0 to 225.7 lb ac-1) were obtained mostly by N fixation via rhizobia and accumulated in leguminous cover crops. Although relative amounts of fertilizer P lost via leaching were meager for all treatments, at least twice as much was lost from fallow (0.4 percent) rather than from treatments with cover crops (0.1 to 0.2 percent). Compared to the control (fallow with weeds), velvetbean and sunn hemp reduced inorganic P losses by 70 percent and 66 percent, while cowpea and sorghum sudangrass reduced losses by only 19 percent and 13 percent. Leguminous cover crops reduced leachate volume by 55 percent to 91 percent, sorghum sudangrass reduced leachate by 61 percent, while fallow soil with natural weeds only reduced leachate by 48 percent of applied water. The results suggest that summer leguminous cover crops can not only prevent the loss through leaching of 88 to 94 percent of soil N and of 50-83 percent of inorganic P but also accumulated 2.0 to 8.7 fold more N in the plants, which contribute to improving the subsequent vegetable yield after returned to the soil.
In 1993 the NIH (National Institute of Health) Consensus Conference on Impotence defined erectile dysfunction as the permanent incompetence to start or maintain an erection enough to enable satisfactory sexual intercourse. Erectile dysfunction (ED) is a frequent disorder that affects negatively quality of life of males suffering it. Its prevalence varies between different countries, cultures and races. The first population studies published date from early 90's and still keep their validity. All of them show the influence of age on prevalence of ED, as well as its close relationship with cardiovascular diseases. Depending on the definition used and study design prevalence varies from 10 to 52%, mainly in men between 40-70 years, with an incidence in western countries between 25-30 new cases per 1000 inhabitants year.
To assess the mean age of sexual activity termination, the prevalence of erectile dysfunction (ED), and their related factors in the old male population in Beijing.
We included in this study 764 males aged over 60 years old received in the health examination clinic and investigated the prevalence of ED and the related factors using the sexual health assessment resource (SHARE) and IIEF-5 questionnaires.
The average age of sexual activity termination (no sexual intercourse in over 2 years) was 68.4 +/- 5.2 years among the subjects. The prevalence of ED was 89.4% , of which the rates of mild, moderate and severe ED and non-sexuality were 6.7, 18.6, 28.4 and 35.7% , respectively. Those who had no sexual intercourse for over 2 years because of severe ED accounted for 26.8% among the 60-64 years old males and more than 50% in the >70 yr group. The main risk factors for ED-induced sexual activity termination included age, diabetes, cardiovascular and cerebrovascular diseases, obesity, and low urinary tract symptoms (LUTS).
ED is a common problem as well as the main risk factor for sexual activity termination, and age and general health status are significantly associated with the prevalence of ED among aging males.
Nitric oxide (NO) synthesized by nitric oxide synthase (NOS) is recognized as the central mediator of penile erection. This process appears to be mediated mainly by neuronal NOS (nNOS), which is localized to the nonadrenergic, noncholinergic innervation of the penis. However, the role of non-neuronal penile constituents (specifically the cavernosal smooth muscle), as well as other NOS isoforms in NO production in the human penis is not well understood. The present study evaluates the expression of non-neuronal (inducible and endothelial) isoforms of NOS in human penile cavernosal smooth muscle cells in culture.
Primary culture was initiated with explants of human corpora cavernosa. For gene expression studies, total RNA was extracted from cavernosal cells and subjected to reverse transcriptase polymerase chain reaction (RT-PCR). For NADPH-diaphorase histochemistry, the cells were incubated with 1 mM beta-NADPH and 0.5 mM nitrobluetetrazolium at 37C for 3 hours. For indirect immunofluorescence and electron microscopy, cells were incubated overnight at 4C with specific primary (eNOS; calmodulin) and secondary antibodies. A conventional avidin biotin complex technique was used for electron microscopy.
The mRNA expression studies revealed that these cells express both endothelial (eNOS) and inducible (iNOS) forms. Localization studies showed positive signals for NADPH-diaphorase, eNOS, and calmodulin. The electron microscopic evaluation confirmed the localization of eNOS to the cytoplasm and small vesicles in the cells.
These findings support the hypothesis that human cavernosal smooth muscle cells express both endothelial and inducible forms of NOS, which may significantly contribute to NO production in the penile architecture during the erectile process.
With the development of transgenic mice to evaluate mechanisms of erectile function, it appears particularly advantageous to develop a standardized mouse model of penile erection. The purpose of the study reported here was to evaluate the novel application of intracavernosal pressure (ICP) monitoring in the mouse during electrophysiologic and pharmacologic induction of penile erection. In anesthetized adult male mice, the cavernous nerves (CN) were isolated unilaterally, and the corpora cavernosa were exposed. A 24-gauge angiocath (intravenous catheter) was inserted into the right corpus cavernosum to monitor the ICP, and a 30.5-gauge needle was inserted into the left corpus cavernosum for intracavernosal drug administration. ICP was recorded during CN-stimulated or pharmacostimulated erections. Electrical stimulation of the CN significantly increased the ICP (from 10.09 +/- 2.01 to 34.62 +/- 2.71 mm Hg, P < .05), which then returned to baseline pressure after termination of the electrical stimulation. Pretreatment with intracavernosal administration of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (0.1 mg), inhibited the electrical stimulation-induced changes in ICP (7.17 +/- 1.46 vs 10.38 +/- 2.17 mm Hg, not significant [NS]). Also, intracavernosal administration of papaverine (0.4 mg) produced a significant increase in ICP (from 8.51 +/- 0.69 to 26.37 +/- 5.7 mm Hg, P < .05). We concluded that this technique might be applied to perform quantitative erection physiologic experiments with the mouse as an economical and experimentally advantageous animal model, particularly with the development of transgenic mice to evaluate mechanisms of erectile function.
Constitutively produced nitric oxide released by endothelial cells has been shown to act as an endogenous agent which inhibits the rolling and adhesion of leucocytes in the microcirculation. However, during various types of inflammation, expression of the inducible form of nitric oxide synthase (iNOS) can dramatically increase the amount of nitric oxide present in tissues. Furthermore, as iNOS can be expressed by a wide variety of cell types, the distribution of nitric oxide is likely to be altered relative to that in unstimulated tissue. Under these conditions, it is less well understood whether iNOS-derived nitric oxide retains the anti-adhesive capabilities of constitutively produced nitric oxide. This review summarizes work done to examine this issue. Three main approaches have been used. In vitro studies have examined the role of iNOS in adhesive interactions between stimulated endothelial cells and leucocytes, providing evidence of an anti-adhesive effect of iNOS. In addition, the role of iNOS has been examined in vivo in animal models of inflammation using pharmacological iNOS inhibitors. These experiments were extended by the advent of the iNOS-deficient (iNOS(-/-)) mouse. Intravital microscopy studies of these mice have indicated that, under conditions of low-dose endotoxaemia, iNOS-derived nitric oxide can inhibit leucocyte rolling and adhesion. The potential mechanisms for these effects are discussed. In contrast, several other studies have observed either no effect or an enhancing effect of iNOS on inflammatory leucocyte recruitment. Taken together, these studies suggest that the importance of iNOS in modulating leucocyte recruitment can vary according to the type of inflammatory response.
We developed a rat model of traumatic arteriogenic erectile dysfunction (ED) for the study of vasculogenic ED. Bilateral ligation of the internal iliac artery was performed on 30 three-month old male Sprague-Dawley rats as an experimental group. The control group consisted of 12 rats which underwent dissection of the internal iliac artery without ligation. Before their euthanization at 3 days, 7 days, and 1 month (10 rats in the experimental group and four rats in the control group at each time point), erectile function was assessed by electrostimulation of the cavernous nerves. Penile tissues were collected for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining, trichrome staining, electron microscopy and RT-PCR for transforming growth factor beta (TGF-beta1), insulin like growth factor-I (IGF-I) and fibroblast growth factors (FGF) mRNA expression. Electrostimulation of the cavernous nerves revealed a highly significant declining of the intracavernous pressure after 3 and 7 days. No significant recovery of erectile function was noted at 1 month. Histology showed degeneration of the dorsal nerve fibers in all experimental rats. There was little decrease in the bulk of intracavernous smooth muscle in the experimental rats euthanazed 7 and 30 days. NADPH diaphorase staining revealed a significant decrease in nitric oxide synthase (NOS) containing nerve fibers in the dorsal and intracavernosal nerves in all rats in the experimental group. Electron microscopy showed a variety of changes such as collapse of sinusoids, increased cell debris, fibroblast and myofibroblast loss, intracellular deposition of fat and collagen and fatty degeneration. RT-PCR revealed up-regulation of TGF-beta1 after 3 days but not after 7 days or 1 month. There is no significant difference in IGF-I or FGF expression between the experimental and control group. Bilateral ligation of internal iliac arteries produces a reliable animal model for traumatic arteriogenic ED. Further studies are needed to investigate the molecular mechanism of ED in this model.
The advent of sildenafil (Viagra) for the treatment of erectile dysfunction has attracted widespread interests in phosphodiesterase type 5 (PDE5), the target of sildenafil, 1 and other members of the PDE superfamily. PDEs are intracellular enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). By counterbalancing adenyl and guanyl cyclases, which catalyze the formation of cAMP and cGMP, respectively, PDEs serve to adjust the cellular concentrations of cAMP and cGMP, thereby influencing cellular functions. 2 In addition to sildenafil, hundreds of PDE inhibitors broadly or specifically target various PDE isoforms. Those with specificity and currently seeking approval from the United States Food and Drug Administration (FDA) or under clinical trials are the focus of this review. Emphasis is given to those with urologic applications (eg, erectile dysfunction and benign prostatic hyperplasia [BPH]-associated urinary dysfunction).
To study the pharmacological effect of Shugan Yiyang(SGYY) capsule.
kongming mice and Wistar rats were used to observe the effects of SGYY capsule on sexual desire, erection, ejaculation and fatigue. The weight of prostate, seminal vesicle, testes, levators and thymus and serum testosterone level were also measured. Furthermore, Rhesus monkey were used to construct animal model of erectile dysfunction. Effects of SGYY capsule on sexual behavior, penile blood flow and electromyogram were observed.
SGYY capsule can remarkably reduce the incubation period of erection, ejaculation and innovate the sexual desire,erection, ejaculation both on rats and rhesus monkeys. The weight of prostate, seminal vesicle, testes, levators in mice and serum testosterone level of rats increased while the weight of thymus decreased. It can also diminish the luminar of vein and reduce the venous outflow while the transmission of peripheral nervous system remained stable.
SGYY capsule can remarkably improve the erectile activity, sexual desire and ejaculatory activity. The mechanism of SGYY capsule may be related to the increase of androgen and adrenocorticohormone levels. as well as the reduction of penile venous outflow. [Key words] shuganyiyang capsule; er
Penile tumescence (erection) and detumescence (return to the flaccid state) are regulated by a complex neurophysiological process involving the relaxation and contraction, respectively, of smooth muscle (SM) within the two corpus cavernosum (CC) of the penis. Failure of the above SM-mediated process to function properly results in the inability to obtain an erection sufficient for sexual satisfaction and has been termed erectile dysfunction (ED). It is predicted that an estimated 322 million men worldwide will have ED by the year 2025 and, relevant to this review article, is that roughly 50% of men with diabetes also have ED. Furthermore, one of the largest classes of nonresponders to oral phosphodiesterase V (PDE5) inhibitors (the predominant pharmacological treatment for organic ED) are diabetics. This review article examines the current knowledge about the contractile pathways that fine-tune SM tone with particular emphasis on vascular SM including corpus cavernosum smooth muscle (CCSM). The role of the contractile apparatus, SM myosin phosphorylation/dephosphorylation pathways, calcium "sensitization" and "desensitization" pathways and the main neurotransmitters/modulators responsible for regulating CCSM contraction are outlined along with how they are modified or potentially may be modified in response to diabetes. The overall hypothesis generated from this review is that an increased CCSM tone, resulting from an enhancement of contractile mechanisms, may contribute to the higher than average nonresponse rate of diabetic men to PDE5 inhibitors. Knowledge gained from this review will hopefully lead to the generation of drugs that specifically target CCSM contractile pathways which may prove to have therapeutic usefulness in treating ED in diabetics either alone or in combination with existing PDE5 inhibitors.
Huang di Nei Jing-Su Wen (Chinese).
- Huang D.