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Glutathione levels in patients with erectile dysfunction, with or without diabetes mellitus
Abstract
The reduced form of glutathione (GSH) is the most important cell antioxidant and is also an essential cofactor for nitric oxide (NO) synthase that synthesizes NO from l-arginine. Reduced levels of GSH, due both to a hyperglycaemia-induced increase of free radical production and to a decrease of NADPH levels [like in diabetes mellitus (DM)], can hamper the endothelial cell functions. This condition may play an important role in the aetiology of some clinical signs, like erectile dysfunction (ED). The aim of this study was to test the hypothesis that GSH concentration is reduced in patients with ED and type 2 diabetes mellitus. We studied 111 male patients with ED: 64 with diabetes (ED/DM) and 47 without diabetes (ED/wDM); 20 patients with diabetes but without ED (DM) and 26 male normal subjects as a control group (C). The GSH red blood cell concentration was significantly lower in ED than in C (X +/- SD; 1782.12 +/- 518.02 vs. 2269.20 +/- 231.56 mumol/L, p < 0.001). In particular, GSH was significantly reduced in ED/DM vs. ED/wDM (1670.74 +/- 437.68 vs. 1930.63 +/- 581.01 micromol/L, p < 0.01). In DM, GSH was significantly lower than in C and significantly higher than in ED/DM (2084.20 +/- 118.14 vs. 2269.20 +/- 231.56 and vs. 1670.74 +/- 437.68 micromol/L, p < 0.002 and p < 0.001 respectively). GSH showed a negative correlation with fasting glucose concentrations (r = -0.34, p < 0.01) and with the duration of DM (r = -0.25, p < 0.05). A GSH depletion can lead to a reduction of NO synthesis, thus impairing vasodilation in the corpora cavernosa.
... The reduced form of glutathione (GSH) is the most important cellular antioxidant and is also an essential cofactor for nitric oxide (NO) synthase that synthesizes NO from l-arginine [19]. Therefore, GSH depletion could lead to reduction of NO synthesis, and consequently impairs vasodilation in the corpora cavernosa [51]. In the present study, the activity of GR and GSH levels were markedly decreased in liver tissues after treatment of rats with sildenafil, vardenafil and tadalafil. ...
... In the present study, the activity of GR and GSH levels were markedly decreased in liver tissues after treatment of rats with sildenafil, vardenafil and tadalafil. In accordance with the present study, it has been found that sildenafil reduced GSH levels in both prostate and brain tissues of rat [54,20] and in red blood cell of human [51]. It has been proposed that the total GSH level is partially dependent on the reduction of the oxidized form of glutathione (GSSG) to the reduced form (GSH) by glutathione reductase [45]. ...
... The reduced form of glutathione (GSH) is the most important cellular antioxidant and is also an essential cofactor for nitric oxide (NO) synthase that synthesizes NO from L-arginine (Ghigo et al., 1993). Therefore, GSH depletion could lead to reduction of NO synthesis, and consequently impairs vasodilation in the corpora cavernosa (Tagliabue et al., 2005). In the present study, the activity of GR and GSH levels were markedly decreased in liver tissues after treatment of rats with sildenafil, vardenafil and tadalafil. ...
... In the present study, the activity of GR and GSH levels were markedly decreased in liver tissues after treatment of rats with sildenafil, vardenafil and tadalafil. In accordance with the present study, it has been found that sildenafil reduced GSH levels in both prostate and brain tissues of rat (Thakur et al., 2013;Guzmán et al., 2011) and in red blood cell of human (Tagliabue et al., 2005). It has been proposed that the total GSH level is partially dependent on the reduction of the oxidized form of glutathione (GSSG) to the reduced form (GSH) by glutathione reductase (Sheweita & Mostafa, 1996). ...
Erectile dysfunction (ED) affected the lives of more than 300 million men worldwide. Erectile dysfunction drugs (EDD), known as phosphodiesterase inhibitors (PDEIs), have been used for treatment of ED. It has been shown that oxidative stress plays an important role in the progression of erectile dysfunction. Oxidative stress can be alleviated or decreased by antioxidant enzymes. Therefore, the present study aims at investigating the changes in the activity of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione reductase as well as protein expression of glutathione peroxidase and glutathione S-transferase after treatment of male rats with a daily dose of sildenafil (1.48 mg/kg), tadalafil (0.285 mg/kg) and vardenafil (0.285 mg/kg) for three weeks. In addition, levels of reduced glutathione and malondialdyhyde (MDA) were assayed. The present study showed that sildenafil, vardenafil, and tadalafil treatments significantly decreased the levels of glutathione, MDA and the activity of glutathione reductase. In addition, vardenafil and sildenafil increased the activity of superoxide dismutase and catalase. Interestingly, western immunoblotting data showed that vardenafil induced the activity of glutathione peroxidase (GPX) and its protein expression, whereas tadalafil and sildenafil inhibited such enzyme activity and its protein expression. In addition, the protein expression of GST π isozyme was markedly reduced after treatment of rats with sildenafil. It is concluded that ED drugs induced the activities of both SOD and catalase which consequently decreased MDA level. Therefore, decrement in MDA levels could increase nitric oxide-cGMP level which in turn promotes the erection mechanism.
... In support of this assumption, it has been reported that rats fed chitosan also showed lower liver activity of GST [46]. As reported previously, SF therapy reduced GSH levels and inhibited GST activity in the liver tissues of rats [11] and human red blood cells [47]. Possible conversion of reduced glutathione (GSH) into its oxidized form as a result of SF, SF-CS NPs, and T-SF-CS NPs treatments may account for the decline in GSH levels. ...
Sildenafil (SF) is widely used for erectile dysfunction and other conditions, though with limitations regarding oral absorption and adverse effects. Despite nanotechnological improvements, the effect of nanocarriers on SF hepatotoxicity has not been documented to date. This study aimed at assessing the impact of chitosan nanoparticles either uncoated (CS NPs) or Tween 80-coated (T-CS NPs) on the effects of SF on oxidative stress markers and antioxidant enzyme activities in rats. Test SF-CS NPs prepared by ionic gelation were uniform positively charged nanospheres (diameter 178-215 nm). SF was administered intraperitoneally to male rats (1.5 mg/kg body weight) in free or nanoencapsulated forms as SF-CS NPs and T-SF-CS NPs for 3 weeks. Free SF significantly suppressed the activity of the antioxidant enzymes glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and superoxide dismutase (SOD), as well as the levels of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) as in an indirect measure of free radicals. Interestingly, SF-CS NPs and T-SF-CS-NPs treatments significantly attenuated the inhibitory effects of SF on the activity of these enzymes whereas, GST activity was inhibited. Moreover, the protein expression of GST was downregulated upon treatment of rats with free SF, SF-CS-NPs, and T-SF CS-NPs. In contrast, the activity and protein expression of GPx was induced by SF-CS NPs and T-SF-CS-NPs treatments. The histopathological study showed that SF induced multiple adverse effects on the rat liver architecture which were markedly suppressed particularly by T-SF-CS NPs. In conclusion, chitosan nanoencapsulation of SF counteracted the adverse effects of SF on the activity of antioxidant enzymes and liver architecture. Findings might have significant implications in improving the safety and efficacy of SF treatment of the widely expanding disease conditions.
... Data shows that chronic hyperglycemia can increase oxidative stress due to inflammation, elevated production of reactive oxygen species (ROS), hyperhomocysteinemia, and reduced cellular antioxidants. [20][21][22][23] Morano et al. demonstrated higher levels of oxidative activity in circulating monocytes of patients with DM and ED than in diabetic patients without ED (mean± standard error of mean oxidation index, 9.3±1.6 vs 4.8±0.5, p <0.03, respectively) 21 . ...
Introduction:
Erectile dysfunction (ED) is associated with diabetes mellitus with an estimated prevalence of 52.5% in the diabetic population. The first-line therapy for ED are phosphodiesterase type 5 inhibitors (PDE5i), but data suggests that diabetic men may be less responsive than non-diabetic men. Thus, other treatments, including intracavernosal injections, intraurethral prostaglandin, vacuum erection devices, and penile prosthetic surgery, should be considered in management of diabetic men with ED refractory to PDE5i. Furthermore, combination therapy of PDE5i and other oral treatments such as arginine or L-carnitine may have synergistic effects resulting in better outcomes. In addition, there are novel therapies such as low-intensity shockwave therapy and stem cell therapy which may also be effective targeted treatment modalities. Furthermore, studies suggest that ED can be improved by targeting concurrent comorbidities or metabolic diseases such as depression, hypertension, hypogonadism, and dyslipidaemia. We present an evidence-based narrative review focussing on the management of ED in diabetic men who have not responded to PDE5i.
Conclusions:
Both clinicians and patients should be aware of the different management options in Diabetic patients who have responded to PDE5i. This article is protected by copyright. All rights reserved.
... The result was in agreement with the previous study that CR-WPI supplementation increased the intracellular GSH levels and augmented antioxidant defenses [34]. Tagliabue et al. compared diabetic and nondiabetic erectile dysfunction patients and found lower GSH levels in DMED patients; moreover, GSH depletion could bring about a reduction of NO synthesis, followed by a vasodilation dysfunction in the corpora cavernosa [35]. It is well known that NO is synthesized by NOS in the presence of Larginine, which is regulated by the DDAH/ADMA/NOS pathway. ...
Nitric oxide synthase- (NOS-) dependent endothelial dysfunction induced by oxidative stress (OS) is assumed to play a pivotal role in the pathogenesis and progression of diabetes mellitus-related erectile dysfunction (DMED). Cysteine-rich whey protein isolate (CR-WPI) is a widely used protein supplement and has been confirmed to reduce reactive oxygen species (ROS) by increasing cellular antioxidant glutathione (GSH). However, it is currently unknown whether CR-WPI elicits therapeutic effects in DMED. Here, we provide diabetic rats with CR-WPI to determine its effect on DMED and the underlying mechanisms. The results suggest that CR-WPI supplementation increased GSH biosynthesis and reduced ROS content and simultaneously upregulated the dimethylarginine dimethylaminohydrolase (DDAH)/asymmetrical dimethylarginine (ADMA)/nitric oxide synthase (NOS) metabolic pathway. Evaluation of intracavernous pressure (ICP) also showed an improvement of penile erectile function in CR-WPI-treated rats. The results of the vitro cell culture showed that glutathione pretreatment protected corpus cavernosum smooth muscle cells (CCSMC) from H2O2-induced apoptosis by decreasing Caspase 9 and Caspase 3 expressions. These results augur well for the potential therapeutic application of dietary CR-WPI supplementation for treating diabetic erectile dysfunction.
... Therefore, the decrease in ROS observed when the rats were treated with citrus juices individually or in combination with sildenafil could be due to the increase in the levels of the antioxidant enzymes (SOD and catalase) or the restoration of glutathione-mediated protection (Fernandes et al., 2008;Hotston et al., 2008;Sheweita & Tilmisany, 2003). Tagliabue et al., (2005) had previously established that glutathione depletion could lead to decreased NO synthesis and impaired vasodilation in the corpora cavernosa. The results of this study also showed a similarity between the GSH and GST levels and the NO production among the groups and the consequent effect on sexual behavior was also revealed. ...
The use of lemon (Citrus limon) and lime (Citrus aurantifolia) juices for the treatment of erectile dysfunction (ED) is fast becoming common practice, even though there is dearth of information on the effect of such functional food and drug combination in the management of ED. This study evaluated the effect of lemon and lime juices on the erectogenic properties of sildenafil. ED was induced with L‐NAME (40 mg/kg body weight). The rats were divided into 11 groups (n = 6) and given various doses of the test samples. Immediately after the sexual behavior studies, the animals were sacrificed and the penile and brain tissues were isolated. The results revealed that lime and lemon juices improved sexual behavior in rats by improving NO production and inhibiting the activities of PDE‐5, arginase, ACE, MAO, ATPdase, AMPdase, and activated antioxidant enzymes. Furthermore, lime at 1.0 ml/kg significantly improved the therapeutic properties of sildenafil. While, lemon (0.5 and 1.0 ml/kg) and lime (0.5 ml/kg) did not show any synergistic effect. This study revealed that lime and lemon juices could improve erectile function and combining lime juice with sildenafil could be very effective in the management of ED.
Practical applications
The therapeutic management of erectile dysfunction has involved maximizing NO production through the modulation of macromolecules such as phosphodiesterase‐5 and arginase with the use of drugs such as sildenafil. Combining such drugs with functional foods such as lime and lemon juices is becoming common practice. However, there is dearth of report on the effect of lime and lemon juices on the erectogenic potentials of sildenafil. The present study shows that combining 1 ml/kg lime juice (got from 2 lime fruits) with sildenafil will boost the erectogenic properties of the drug. While combining lime (0.5 ml/kg) and lemon (0.5 and 1.0 ml/kg) juices with the drug did not have any synergistic effect.
... [81,82] On depletion of endogenous antioxidants such as glutathione, in endothelial cells, they develop exceptional sensitivity to nitrosative as well as oxidative injury. [83] AGEs are produced on the augmented oxidative stress influence & joining of such end products to their receptors causes activation of pro-inflammatory reactions together with the generation of a prooxidative atmosphere. [84,85] The PKC pathway & oxidative stress also results in reactive oxidants formation. ...
Diabetic nephropathy is one of the major complications associated with diabetes mellitus. Morbidity and mortality due to this disease are constantly progressing in industrialized nations. If left untreated, 40% of diabetic patients with microalbuminuria will progress to overt nephropathy and 20% of them will develop end-stage renal failure within 20 years. Diabetic nephropathy is intervened by a host of processes, but none is as important as the gradual, renal glomerulus inexorable scarring well-known as glomerulosclerosis. DN is characterized by initial oxidative stress, inflammatory response, thickening of basement membranes, expansion of mesangial matrix and interstitial fibrosis, podocyte and renal cell death, increased albuminuria, and renal dysfunction. Diabetic nephropathy has numerous distinct phases of multiple mechanisms contributing to the disease development and its outcomes. This chapter deals with variations in various cytokines & their related interaction with advanced glycation end-(AGE) and oxidant stress products and also the role of the polyol pathway in the development of diabetic nephropathy. Additionally, the role of growth factors like VEGF and the interactions between hemodynamic and fibrotic cytokines, including Angiotensin-II (AG-II) as well as the transformation of growth factor-β1 (TGF-β1) in the development of diabetic nephropathy are discussed in this chapter.
... [81,82] On depletion of endogenous antioxidants such as glutathione, in endothelial cells, they develop exceptional sensitivity to nitrosative as well as oxidative injury. [83] AGEs are produced on the augmented oxidative stress influence & joining of such end products to their receptors causes activation of pro-inflammatory reactions together with the generation of a prooxidative atmosphere. [84,85] The PKC pathway & oxidative stress also results in reactive oxidants formation. ...
Diabetic nephropathy is one of the major complications associated with the diabetes
mellitus. Morbidity and mortality due to this disease are constantly progressing in
industrialized nations. If left untreated, 40% of diabetic patients with microalbuminuria
will progress to overt nephropathy and 20% of them will develop end-stage renal failure
within 20 years. Diabetic nephropathy is intervened by a host of processes, but none is as
important as the gradual, renal glomerulus inexorable scarring well-known as
glomerulosclerosis. DN is characterized by initial oxidative stress, inflammatory
response, thickening of basement membranes, expansion of mesangial matrix and
interstitial fibrosis, podocyte and renal cell death, increased albuminuria, and renal
dysfunction. Diabetic nephropathy has numerous distinct phases of multiple mechanisms
contributing to the disease development and its outcomes. This chapter deals with
variations in various cytokines & their related interaction with advanced glycation end-
(AGE) and oxidant stress products and also the role of polyol pathway in the
development of diabetic nephropathy. Additionally, the role of growth factors like VEGF
and the interactions between hemodynamic and fibrotic cytokines, including
Angiotensin-II (AG-II) as well as transformation of growth factor-β1 (TGF-β1) in the
development of diabetic nephropathy are discussed in this chapter.
... OS can be counteracted by endogenous mechanisms or by exogenous ingestion of antioxidants. The principal intracellular antioxidant, glutathione, is reduced in men with ED [17], and its synthesis decreases with age [18]. A key circulating antioxidant, paraoxinas-1 (PON-1), is reduced with ED [19]. ...
The authors review and discuss numerous factors that influence erectile function and their interactions, based on the published literature. Of critical importance are vascular nitric oxide; nutrition; exercise; weight control and maintaining insulin sensitivity; early treatment of hypertension with attention to effects on erectile function; avoiding sources of oxidative stress such as obesity and smoking; reducing inflammation (e.g. from gingivitis); improving pelvic floor muscle strength; and inhibiting cyclic GMP break-down. The described interventions act on different aspects of erectile biochemistry and physiology. Therefore, combining multiple therapeutic approaches will yield maximum benefits for erectile and vascular and general health.
... AGEs are also known to be generated on the background of increased oxidative stress, and binding of these end products to their cellular receptors triggers pro-inflammatory responses and creates a pro-oxidative environment (Goldin et al., 2006;Ramasamy et al., 2005;Rosca et al., 2005). When endogenous antioxidants such as glutathione are depleted in endothelial cells, the cells become extremely sensitive to oxidative and nitrosative injury (Cuzzocrea et al., 1998;Tagliabue et al., 2005). These results can be related to the oxidant-antioxidant status of the cells suggesting that high blood glucose and NO level induce oxidative and nitrosative stress. ...
Chronic hyperglycemia (glucotoxicity) is reported to have detrimental effects on various brain functions leading to neurodegenerative changes. However, the effect of hyperglycemia in combination with high nitric oxide (NO) level (reported to be increased during glucotoxicity), on brain functions is not clear yet. The present study was designed to investigate the effects of hyperglycemic drug Streptozotocin (STZ) and NO donor Sodium nitroprusside (SNP) on the brain of laboratory mouse, Mus musculus. Effects of these conditions were studied on the markers of oxidative stress, NF-κB signalling and the markers of neuronal and glial cell activation/inflammation. Results indicate increased level of MDA and altered antioxidant enzymes activity in both the treated groups compared to control but high levels of AGEs, AOPP and AR activity (markers of diabetic complications) were observed in STZ group only. On the other hand, while STZ group showed decreased IL-6 level, it was increased in SNP group but IFN-ϒ level increased in both the treated groups compared to control. Further, in addition to alterations in the expressions of iNOS, IKKβ, IKBα and NF-κB subunits (RelA-p65/RelB-p50) observed in the neurons and glial cells of different brain regions (hypothalamus, basolateral amygdala and cerebral cortex), enhanced expression of microglial CD11b and astrocytic GFAP was also found in both the treated groups compared to control.
... Polyphenols may also act as antioxidants: resveratrol, a polyphenol commonly found in red wine, is known to improve endothelial function by activation of NOS [ 17 ] and by suppression of apoptosis [ 59 ]; similar effects have been discovered following administration of a different polyphenol, quercetin, in animal models [ 60 ]. As previously discussed, NO reacts with free radicals, ultimately resulting in production of cytotoxic compounds; antioxidants and free radical scavengersincluding vitamin E, selenium, and glutathione [ 54 ] -reduce the quantity of ROS and, therefore, improve the availability of NO while at the same time reducing ROSmediated endothelial damage [ 1 , 10 ]. It has recently been hypothesized that testosterone is somehow involved in ROS production [ 35 ]: oxidative stress might be the missing link between testosterone defi ciency and cardiovascular risk [ 56 ]. ...
Besides their widely discussed role in empirical therapy of male infertility, antioxidants have been used in experimental studies also for treating male sexual dysfunctions. Oxidative stress is clearly involved in the pathogenesis of infertility: less consisting evidence has been found in regard to its involvement in erectile and ejaculatory dysfunctions. Nitric oxide (NO) is an endothelium-derived relaxing factor, acting as a vasodilator and as an antioxidant: it is also the key molecule involved in obtaining and maintaining an erection. Administration of NO has been investigated as a substitute for phosphodiesterase type 5 (PDE-5) inhibitors or an additional treatment for nonresponders to standard treatments. Furthermore, a possible role for testosterone as a free radical scavenger has been postulated: testosterone replacement therapy might help prevent oxidative stress-related dysfunctions in several organs. Oxidative stress is also involved in some forms of priapism: antioxidants might therefore be helpful in preventing recurrences or in treating vascular damage resulting from ischemia-reperfusion injury.
... 8,9 Tagliabue, M. et al in their study presented that levels of GSH are significantly decreased in type 2 diabetics. 10 In conjugation to this, Soliman, GZ. and Ozdemir, G. carried out experiments to evaluate the role of GSH levels in the pathophysiology of type 2 diabetes . They emphasized on the link between exaggerated oxidative stress and hyperglycemia leading to clinical complications of type 2 diabetics. ...
... The aldose reductase pathways is known to exert its pathological actions by enhancing the oxidative stress responses by depleting endogenous glutathione levels (Lee and Chung, 1999;Song et al., 2003;Obrosova et al., 2005). When endogenous antioxidants such as glutathione are depleted in endothelial cells, the cells become extremely sensitive to oxidative and nitrosative injury Tagliabue et al., 2005). AGEs are also known to be generated on the background of increased oxidative stress, and binding of these end products to their cellular receptors triggers pro-inflammatory responses and creates a pro-oxidative environment (Yan et al., 1994;Scivittaro et al., 2000;Ramasamy et al., 2005;Rosca et al., 2005;Goldin et al., 2006). ...
Here we overview the role of reactive nitrogen species (nitrosative stress) and associated pathways in the pathogenesis of diabetic vascular complications. Increased extracellular glucose concentration, a principal feature of diabetes mellitus, induces a dysregulation of reactive oxygen and nitrogen generating pathways. These processes lead to a loss of the vascular endothelium to produce biologically active nitric oxide (NO), which impairs vascular relaxations. Mitochondria play a crucial role in this process: endothelial cells placed in increase extracellular glucose respond with a marked increase in mitochondrial superoxide formation. Superoxide, when combining with NO generated by the endothelial cells (produced by the endothelial isoform of NO synthase), leads to the formation of peroxynitrite, a cytotoxic oxidant. Reactive oxygen and nitrogen species trigger endothelial cell dysfunction through a multitude of mechanisms including substrate depletion and uncoupling of endothelial isoform of NO synthase. Another pathomechanism involves DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). PARP-mediated poly(ADP-ribosyl)ation and inhibition of glyceraldehyde-3-phosphate dehydrogenase importantly contributes to the development of diabetic vascular complications: it induces activation of multiple pathways of injury including activation of nuclear factor kappa B, activation of protein kinase C and generation of intracellular advanced glycation end products. Reactive species generation and PARP play key roles in the pathogenesis of 'glucose memory' and in the development of injury in endothelial cells exposed to alternating high/low glucose concentrations.
... The decrease in NOx tissue levels in diabetics can be explained with the increase in catabolism or decrease in formation. In this study, decrease in NO formation can be expected depending on reducing in GSH.[33]. Ascorbic acid is a water-soluble antioxidant and its plasma and tissue concentrations decreased in both diabetic animals and humans[34]. ...
Unlabelled:
Streptozotocin (STZ) is an agent used in creating experimental diabetes. Varying findings have been reported about the striated muscle glycogen levels in diabetes. In this study, it was planned to observe interaction of vitamin C (AA), of which deficiency has been shown in diabetics, with soleus muscle glycogen levels and oxidative events on STZ-diabetic subjects.
Material and method:
In the study, 38 male adult Wistar Albino rats with weights 200 +/- 20 g were used by separating them into four groups: Control, Vitamin C, Diabetes, Diabetes + Vitamin C. Body weights and fasting blood glucose were measured at the beginning and end of the experiment. AA, TBARS, GSH, NOx and glycogen levels of soleus muscles, and AA level of blood were measured. The results were compared using Anova variance and Mann-Whitney U tests. Results showed that AA levels in blood increased with vitamin C administration; AA, GSH and NOx levels in the muscle were low and MDA and glycogen levels were high in diabetics; and that vitamin C in the given dosage partially corrected these values. These results indicate that higher dosage than daily 20 mg/kg Vitamin C is required for being effective on metabolic and oxidizing events in diabetic rats.
Introduction. Most military personnel survive serious injuries, but many are left to live with long-term sexual and reproductive disorders. The injuries often result in psychological trauma and post-traumatic stress disorder, which negatively affect behavioral health and sexual function. There is emerging evidence linking erectile dysfunction (ED) to oxidative stress. Overall, combat trauma is characterized by a broad response of the body to harmful effects involving all body systems, leading to significant changes in the pro-oxidant-antioxidant balance. Materials and Methods. The study was conducted on peripheral blood lymphocytes and serum of men with ED due to combat trauma (shrapnel and bullet wounds) and healthy men (control group). Both the study and control groups were divided into two age groups (young and middle age groups). Antioxidant activity was studied by measuring glutathione peroxidase (GP), glutathione reductase (GR) and glutathione-S-transferase (GsT). Results. A comparison of the groups using the Kruskal–Wallis method revealed a significant decrease in the GPx and GR activity in blood lymphocytes and serum in men with ED due to combat trauma compared with healthy men of corresponding age groups. It was shown that GPx activity in peripheral blood lymphocytes of patients of the young age group was 1.64-fold lower, and in patients of the middle age group 1.70-fold lower than in the control group (P <0.001). Similar changes were observed in blood serum. GR activity in blood lymphocytes in patients of the young and middle age groups was 1.42-fold lower than in healthy men (P <0.001). In blood serum, GR activity in patients of the young age group was 1.70-fold (P <0.001) and in patients of the middle age group 1.56-fold lower than in healthy men (P <0.001). GsT activity in blood lymphocytes in both age groups increases by 1.2-fold, however these changes were not significant (P >0.05). Conclusion. Erectile dysfunction caused by combat trauma is accompanied by a significant decrease in the activities of antioxidant defense enzymes – glutathione peroxidase and glutathione reductase. There is no difference between age groups of patients with erectile dysfunction due to combat trauma. However, the activity of glutathione S-transferase practically does not change, although there is a tendency for its increase.
Glutathione is a thiol-containing tripeptide which is considered as a master antioxidant. Found naturally in fresh leafy vegetables, fruits, and nuts, commercially available preparations of glutathione have been found to be useful in number of medical conditions such as central nervous system disorders, autism, cardiovascular system disorders, peripheral vascular disorders, diabetes and its complications, liver disease, acquired immunodeficiency syndrome/human immunodeficiency virus, and chronic obstructive pulmonary diseases. With regards to the dermatologic disorders, some studies have highlighted the role of glutathione as a skin-lightening agent. The studies on use in other diseases such as psoriasis, pemphigus vulgaris, acne vulgaris, rosacea, etc., are limited and need to be explored more. Glutathione is available as oral preparations (pills, sublingual tablets, solutions, syrups, and sprays), parenteral forms (intravenous [IV] preparations), topical formulations (creams, soaps, and facewashes). The major drawback of oral form of glutathione is its low bioavailability in humans. To overcome this drawback, sublingual tablets and oral liposomal glutathione have been made available. However, the number of studies evaluating its efficacy and safety are less in number. This review article has been written to highlight the role of glutathione in various dermatologic disorders apart from skin-lightening agent.
This book focuses on the use of various molecules with antioxidant properties in the treatment of major male genital tract disorders, especially male infertility, erectile dysfunction, and accessory gland infection. The coverage also includes discussion of pathophysiology, the molecular basis of male infertility, and the rationale for use of antioxidants, with particular attention to coenzyme Q10 and carnitine. Oxidative stress occurs when the production of reactive oxygen species, including free radicals, exceeds the body’s natural antioxidant defences, leading to cellular damage. Oxidative stress is present in about half of all infertile men, and reactive oxygen species can produce infertility both by damaging the sperm membrane, with consequences for sperm motility, and by altering the sperm DNA. There is consequently a clear rationale for the use of antioxidant treatments within andrology, and various in vitro and in vivo studies have indicated that many antioxidants indeed have beneficial impacts. In providing a detailed and up-to-date overview of the subject, this book will be of interest to both practitioners and researchers in andrology, endocrinology, and urology.
Many advances in the understanding of erection physiology and pathophysiology have been made in recent years. These advances have revealed the importance of oxidative stress and a complex interaction between oxidative stress and regulatory pathways in the penis in the development and progression of erectile dysfunction (ED) associated with various disease states. In this chapter, we present current knowledge of the pathophysiology of ED pertaining to the mechanisms of reactive oxygen species (ROS) production, the interaction between ROS-generating sources and the main regulatory pathways in the penis, the status of the antioxidant systems that reduce ROS bioavailability, and cellular targets for ROS action in vasculogenic and neurogenic ED. We further discuss a therapeutic strategy to improve erectile function in disease states by targeting specific ROS mechanisms in the penis.
Mesotherapy is an intradermal medical technique which aims to deliver to the site of the ailment the appropriate hydrosoluble nutrients and medicines. Specific pharmacokinetics of the intradermal pathway and the combination of different drugs and nutrients are reviewed. The use of glutathione, the master oxidant, and its specific applications in mesotherapy is explained. Mesotherapy indications and techniques in anti-aging medicine to slow aging processes and to preserve and enhance physiological functions will be discussed, including: neurosensory, fatigue syndrome, brain protection, cardiovascular prevention, metabolic syndrome, sexual dysfunction, protection of bone, joints, and muscles, and aesthetic medicine.
Purpose: Increased oxidant stress plays an important role in the etiopathogenesis of the chronic complications of diabetes. The aim of this study was to examine the effects of vitamin C treatment on the oxidant and antioxidant processes in the liver of diabetic rats. Materials and Methods: Wistar Albino rats were divided into 4 groups: 1-Control, 2-Ascorbic Acid (AA, vitamin C), 3-Diabetes, 4-Diabetes+AA. For induction of diabetes, the rats were treated with a single dose of Streptozotocin (45 mg/kg, i.p.). After 48 hours, rats whose fasting blood glucose levels were over 200 mg/100 ml were included in the diabetes groups. Rats in the AA and Diabetes+AA groups were treated with AA (20 mg/kg/day), which was administered intragastrically for 21 days. At the end of the experiment, malondialdehyde, glutathione and NOx levels in the liver tissues were determined. ANOVA and Mann-Whitney U tests were used for statistical analyses. Results: In the diabetes groups, malondialdehyde levels were increased, while glutathione and NOx levels were decreased. Malondialdehyde levels were decreased while glutathione levels were increased in the AA and Diabetes+AA groups in comparison with the controls. There were no significant differences amongst the groups in terms of NOx levels. Conclusion: The malondialdehyde and glutathione levels in vitamin C supplemented rat livers indicate that diets rich in vitamin C or vitamin C preparations might be beneficial in the treatment of diabetic patients.
Objective: To investigate the effect of reduced-glutathione on preventing erectile dysfunction in diabetic rats. Methods: Male adult Sprague-Dawley rats were induced for diabetes by an intraperitoneal injection of streptozotocin, then randomly divided into DM group and DM+GSH group. The rats in DM+GSH group were treated with GSH at a dosage of 200mg/kg through a intramuscular injection every day. Ten weeks later the erectile function of all these rats were evaluated,and their penises harvested. The GSH, NOS and MDA level in corpus cavernosum were measured;and TUNEL assay was used to analyse the penile cells for apoptosis. Results: The diabetic rat model was successfully established. The erectile function was much better in normal control group(group C, 100%)and DM+GSH group(62.5%) than DM group (20%), P<0.05. The glutathione level in DM group was significantly decreased (35.03±12.29)mg/g prot, compared to group C (61.47±8.65)mg/g prot and DM+GSH group (75.83±15.62)mg/g prot, P<0.05. The NOS level was approximately equal in DM+GSH group(133.9±31.9)U/mg prot and group C (142.2±31.2)U/mg prot, both much higher than in DM group (58.4±18.9)U/mg prot, P<0.05. The malondialdehyde content in corpus cavernosum was markedly increased in DM group (3.71±0.62)nmol/mg prot, compared to group C (2.08±0.34)nmol/mg prot and DM+GSH group (2.44±0.28)nmol/mg prot, P<0.05. TUNEL showed significantly differences in apoptosis in these groups, and the apoptosis rate in DM group, DM+GSH group and group C were (22.6±3.6)%, (10.8±1.7)% and (7.2±2.1)%, respectively. Conclusion: The reduced-glutathione has the effect of antioxidation on diabetic rats' penis tissues,which can decrease the apoptosis of corpus cavernosum cells, and may play some role in delaying the onset of diabetic erectile dysfunction.
Ageing is a natural process that results in a progressive decline in the function of multiple organs, increasing the incidence of age-associated diseases and ultimately leading to death. In particular, the ageing process has profound effects on the heart and arterial system, causing structural and functional modifications that directly lead to cardiovascular disease, including atherosclerosis, hypertension, heart failure, myocardial infarction and stroke. Currently, it is believed that endothelial dysfunction antedates overt cardiovascular diseases and that erectile dysfunction is an early symptom of this condition. Functional decline of the cardiovascular system depends not only on chronological ageing but also on lifestyle, taking into account that sedentary habits and overnutrition constitute marked risks for cardiovascular disease. In line with this, recent evidence demonstrates that, among the possible interventions for cardiovascular disease mitigation, nutritional pattern and specific nutrient consumption play a relevant role. The present chapter in divided into two parts: the main age-related changes in the heart and vascular system are presented in the first part, and nutritional intervention that favorably affects the cardiovascular system is discussed in the last part.
Penile rigidity depends on maximizing inflow while minimizing outflow.
The aim of this review is to describe the principal factors and mechanisms involved.
Erectile quality is the main outcome measure.
Data from the pertinent literature were examined to inform our conclusions.
Nitric oxide (NO) is the principal factor increasing blood flow into the penis. Penile engorgement and the pelvic floor muscles maintain an adequate erection by impeding outflow of blood by exerting pressure on the penile veins from within and from outside of the penile tunica. Extrinsic pressure by the pelvic floor muscles further raises intracavernosal pressure above maximum inflow pressure to achieve full penile rigidity. Aging and poor lifestyle choices are associated with metabolic impediments to NO production. Aging is also associated with fewer smooth muscle cells and increased fibrosis within the corpora cavernosa, preventing adequate penile engorgement and pressure on the penile veins. Those same penile structural changes occur rapidly following the penile nerve injury that accompanies even "nerve-sparing" radical prostatectomy and are largely prevented in animal models by early chronic use of a phosphodiesterase type 5 (PDE5) inhibitor. Pelvic floor muscles may also decrease in tone and bulk with age, and pelvic floor muscle exercises have been shown to improve erectile function to a similar degree compared with a PDE5 inhibitor in men with erectile dysfunction (ED).
Because NO is critical for vascular health and ED is strongly associated with cardiovascular disease, maximal attention should be focused on measures known to increase vascular NO production, including the use of PDE5 inhibitors. Attention should also be paid to early, regular use of PDE5 inhibition to reduce the incidence of ED following penile nerve injury and to assuring normal function of the pelvic floor muscles. These approaches to maximizing erectile function are complementary rather than competitive, as they operate on entirely different aspects of erectile hydraulics. Meldrum DR, Burnett AL, Dorey G, Esposito K, and Ignarro LJ. Erectile hydraulics: Maximizing inflow while minimizing outflow. J Sex Med **;**:**-**.
Oxidative stress and inflammation, which disrupt nitric oxide (NO) production directly or by causing resistance to insulin, are central determinants of vascular diseases including ED. Decreased vascular NO has been linked to abdominal obesity, smoking and high intakes of fat and sugar, which all cause oxidative stress. Men with ED have decreased vascular NO and circulating and cellular antioxidants. Oxidative stress and inflammatory markers are increased in men with ED, and all increase with age. Exercise increases vascular NO, and more frequent erections are correlated with decreased ED, both in part due to stimulation of endothelial NO production by shear stress. Exercise and weight loss increase insulin sensitivity and endothelial NO production. Potent antioxidants or high doses of weaker antioxidants increase vascular NO and improve vascular and erectile function. Antioxidants may be particularly important in men with ED who smoke, are obese or have diabetes. Omega-3 fatty acids reduce inflammatory markers, decrease cardiac death and increase endothelial NO production, and are therefore critical for men with ED who are under age 60 years, and/or have diabetes, hypertension or coronary artery disease, who are at increased risk of serious or even fatal cardiac events. Phosphodiesterase inhibitors have recently been shown to improve antioxidant status and NO production and allow more frequent and sustained penile exercise. Some angiotensin II receptor blockers decrease oxidative stress and improve vascular and erectile function and are therefore preferred choices for lowering blood pressure in men with ED. Lifestyle modifications, including physical and penile-specific exercise, weight loss, omega-3 and folic acid supplements, reduced intakes of fat and sugar, and improved antioxidant status through diet and/or supplements should be integrated into any comprehensive approach to maximizing erectile function, resulting in greater overall success and patient satisfaction, as well as improved vascular health and longevity.
Lifestyle and nutrition have been increasingly recognized as central factors influencing vascular nitric oxide (NO) production and erectile function. This review underscores the importance of NO as the principal mediator influencing cardiovascular health and erectile function. Erectile dysfunction (ED) is associated with smoking, excessive alcohol intake, physical inactivity, abdominal obesity, diabetes, hypertension, and decreased antioxidant defenses, all of which reduce NO production. Better lifestyle choices; physical exercise; improved nutrition and weight control; adequate intake of or supplementation with omega-3 fatty acids, antioxidants, calcium, and folic acid; and replacement of any testosterone deficiency will all improve vascular and erectile function and the response to phosphodiesterase-5 inhibitors, which also increase vascular NO production. More frequent penile-specific exercise improves local endothelial NO production. Excessive intake of vitamin E, calcium, l-arginine, or l-citrulline may impart significant cardiovascular risks. Interventions discussed also lower blood pressure or prevent hypertension. Certain angiotensin II receptor blockers improve erectile function and reduce oxidative stress. In men aged <60 years and in men with diabetes or hypertension, erectile dysfunction can be a critical warning sign for existing or impending cardiovascular disease and risk for death. The antiarrhythmic effect of omega-3 fatty acids may be particularly crucial for these men at greatest risk for sudden death. In conclusion, by better understanding the complex factors influencing erectile and overall vascular health, physicians can help their patients prevent vascular disease and improve erectile function, which provides more immediate motivation for men to improve their lifestyle habits and cardiovascular health.
Redox homeostasis governs a number of critical cellular processes. In turn, imbalances in pathways that control oxidative and reductive conditions have been linked to a number of human disease pathologies, particularly those associated with aging. Reduced glutathione is the most prevalent biological thiol and plays a crucial role in maintaining a reduced intracellular environment. Exposure to reactive oxygen or nitrogen species is causatively linked to the disease pathologies associated with redox imbalance. In particular, reactive oxygen species can differentially oxidize certain cysteine residues in target proteins and the reversible process of S-glutathionylation may mitigate or mediate the damage. This post-translational modification adds a tripeptide and a net negative charge that can lead to distinct structural and functional changes in the target protein. Because it is reversible, S-glutathionylation has the potential to act as a biological switch and to be integral in a number of critical oxidative signaling events. The present review provides a comprehensive account of how the S-glutathionylation cycle influences protein structure/function and cellular regulatory events, and how these may impact on human diseases. By understanding the components of this cycle, there should be opportunities to intervene in stress- and aging-related pathologies, perhaps through prevention and diagnostic and therapeutic platforms.
To review the role of various factors influencing vascular nitric oxide (NO) and cyclic GMP, and consequently, erectile function and vascular health.
Pertinent publications are reviewed.
Daily moderate exercise stimulates vascular NO production. Maintenance of normal body weight and waist/hip ratio allows NO stimulation by insulin. Decreased intake of fat, sugar, and simple carbohydrates rapidly converted to sugar reduces the adverse effects of fatty acids and sugar on endothelial NO production. Omega-3 fatty acids stimulate endothelial NO release. Antioxidants boost NO production and prevent NO breakdown. Folic acid, calcium, vitamin C, and vitamin E support the biochemical pathways leading to NO release. Cessation of smoking and avoidance of excessive alcohol preserve normal endothelial function. Moderate use of alcohol and certain proprietary supplements may favorably influence erectile and vascular function. Treatment of any remaining testosterone deficit will both increase erectile function and reduce any associated metabolic syndrome. After production of NO and cyclic GMP are improved, use of phosphodiesterase-5 inhibitors should result in greater success in treating remaining erectile dysfunction. Recent studies have also suggested positive effects of phosphodiesterase-5 inhibitors on vascular function.
A multifaceted approach will maximize both erectile function and vascular health.
Diabetes mellitus (DM) is a major risk factor for the development of erectile dysfunction (ED). Although most diabetic ED cases are in patients with type 2 diabetes (T2DM), the majority of basic science studies examining mechanisms of diabetic ED have been conducted in animal models of type 1 diabetes.
Recently, however, clinical and laboratory-based studies have uncovered some key underlying factors of T2DM-associated ED, which we have compiled in this review of T2DM ED.
The outcomes discussed in this review include major mechanisms underlying T2DM, discussing both clinical and basic science studies.
We conducted an extensive search of pertinent clinical and basic science literature using PUBMED.
Mechanisms causing ED in T2DM are multifactorial and often lead to resistance to current therapy. Systemic effects of hyperglycemia and hypogonadism contribute to the development of impaired vasodilatory signaling, smooth muscle cell hypercontractility, and veno-occlusive disorder in T2DM ED.
Understanding the different causes for ED in T2DM patients may allow targeted therapy for improved erectile function.
The effects of short- and long-term experimental diabetes on corporal nerve, endothelium and smooth-muscle responses were investigated, and the reasons for possible alterations in corporal smooth muscle responses such as hyperglycaemia, duration of experimental diabetes and/or altered tissue weight were evaluated. Rabbits were injected with alloxan (125 mg/kg) to induce diabetes. Age-matched non-diabetic and diabetic (3 and 9 weeks) and weight-matched non-diabetic groups (9 weeks) were used as control. In all groups, relaxation (carbachol, electrical field stimulation and sodiumnitroprusside) responses were examined. The relaxation responses were expressed as percentage of the precontraction to phenylephrine and as g response/g tissue weight. The effects of elevated glucose were also examined by incubating cavernosal strips in Krebs-Henseleit solution containing 44.4 mM glucose for 6 h. Cavernosal tissues of non-diabetic and 9-week diabetic rabbits were evaluated histologically. Sodiumnitroprusside (10(-7)-10(-4) M) responses were similar in all groups. Relaxation responses to electrical field stimulation (10 s train; amplitude 50 V; frequency 0.5-32 Hz; width 0.8 ms) were only attenuated in the 9-week diabetic group compared to the non-diabetic group. Carbachol (10(-8)-3 x 10(-5) M) responses were attenuated in both diabetic groups. When the relaxation responses expressed as g response/g tissue weight were evaluated, results were similar compared to those expressed as percentage of phenylephrine (10(-5) M). Neither carbachol nor electrical field stimulation mediated responses were impaired with glucose incubation. No morphological degenerations were observed in the endothelium. Diabetes may interfere with the synthesis and/or release of nitric oxide from both nerves and endothelium in corpus cavernosum, and alterations in endothelium-derived responses occur earlier than neurological disturbances. The sensitivity of cavernosal smooth muscle to nitric oxide did not alter in diabetes. Attenuation of responses was not due to decreased tissue weight caused by diabetes.
To develop a model to direct the prescription of nutritional and botanical medicines in the treatment of type 2 diabetes for both clinical and research purposes.
Available literature on nutritional and botanical medicines was reviewed and categorized as follows: antioxidant/anti-inflammatory; insulin sensitizer; and beta-cell protectant/insulin secretagogue. Literature describing laboratory assessment for glycemic control, insulin resistance, and beta-cell reserve was also reviewed and a clinical decision tree was developed.
Clinical algorithms were created to guide the use of nutritional and botanic medicines using validated laboratory measures of glycemic control, insulin sensitivity, and beta-cell reserve. Nutrient and botanic medicines with clinical trial research support include coenzyme Q10, carnitine, alpha-lipoic acid, N-acetylcysteine, vitamin D, vitamin C, vitamin E, chromium, vanadium, omega-3 fatty acids, cinnamon (Cinnamomum cassia), fenugreek (Trigonella foenum-graecum), and gymnema (Gymnema sylvestre).
Clinical algorithms can direct supplementation in clinical practice and provide research models for clinical investigation. Algorithms also provide a framework for integration of future evidence as it becomes available. Research funding to investigate potentially beneficial practices in complementary medicine is critically important for optimal patient care and safety.
THE PURPOSE of the "Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" (JNC VI) is to provide guidance for primary care clinicians. The committee recognizes that the responsible clinician's judgment of the individual patient's needs remains paramount. Therefore, this national guideline should serve as a tool to be adapted and implemented in local and individual situations. Using evidence-based medicine and consensus, the report updates contemporary approaches to hypertension control. Among the issues covered are the important need for prevention of high blood pressure by improving lifestyles, the cost of health care, the use of self-measurement of blood pressure, the role of managed care in the treatment of high blood pressure, the introduction of new combination antihypertensive medications and angiotensin II receptor blockers, and strategies for improving adherence to treatment. The JNC VI report places more emphasis than earlier reports on absolute
The tripeptide thiol glutathione (GSH) has facile electron-donating capacity, linked to its sulfhydryl (-SH) group. Glutathione is an important water-phase antioxidant and essential cofactor for antioxidant enzymes; it provides protection also for the mitochondria against endogenous oxygen radicals. Its high electron-donating capacity combined with its high intracellular concentration endows GSH with great reducing power, which is used to regulate a complex thiol-exchange system (-SH ⇋ -S-S-). This functions at all levels of cell activity, from the relatively simple (circulating cysteine/SH thiols, ascorbate, other small molecules) to the most complex (cellular-SH proteins). Glutathione is homeostatically controlled, both inside the cell and outside. Enzyme systems synthesize it, utilize it, and regenerate it as per the gamma-glutamyl cycle. Glutathione is most concentrated in the liver (10 mM), where the ©P450 Phase II" enzymes require it to convert fat-soluble substances into water-soluble GSH conjugates, in order to facilitate their excretion. While providing GSH for their specific needs, the liver parenchymal cells export GSH to the outside, where it serves as systemic source of -SH/reducing power. GSH depletion leads to cell death, and has been documented in many degenerative conditions. Mitochondrial GSH depletion may be the ultimate factor determining vulnerability to oxidant attack. Oral ascorbate helps conserve GSH; cysteine is not a safe oral supplement, and of all the oral GSH precursors probably the least flawed and most cost-effective is MAC (N-acetylcysteine).
Our objective was to analyze the prevalence and risk factors for erectile dysfunction (ED) in men with diabetes in Italy in a cross-sectional study.
Eligible for the study were men aged 20-69 years with a diagnosis of IDDM or NIDDM who were observed on randomly selected days in 178 diabetes centers in Italy. ED was defined as a failure to achieve and maintain an erection sufficient for satisfactory sexual performance.
Of the 9,868 diabetic men interviewed, 3,534 (35.8%) reported ED. The prevalence increased with age, from 4.6% in men aged 20-29 to 45.5% in those aged > or =60 years (test for trend, P = 0.0001). After taking into account the confounding role of age, men with NIDDM reported ED less frequently than did men with IDDM (odds ratio [OR], 0.7; 95% CI 0.6-0.8). In comparison with men reporting diabetes lasting < or =5 years, the ORs for ED were 1.3 and 2.0 for subjects with diabetes lasting 6-10 and 11-30 years, respectively. In comparison with men with good metabolic control, the ORs for ED were 1.7 and 2.3 in men with fair and poor control, respectively. A history of diabetes-related arterial, retinal, or renal diseases and neuropathy was associated with an increased risk of ED. Finally, in comparison with never-smokers, the ORs for ED were 1.5 (95% CI 1.3-1.6) for current smokers and 1.4 (95% CI 1.3-1.6) for ex-smokers. The OR increased with number of cigarettes smoked per day: in comparison with men smoking <12 cigarettes per day, the OR was 1.5 (95% CI 1.3-1.7) for those smoking > or =30 cigarettes day.
The study offers a quantitative estimate of the prevalence of ED and of its main risk factors in Italian men with diabetes.
The effects of thimerosal, a sulfhydryl oxidizing agent on nitrergic, endothelium-dependent and -independent relaxations were investigated to examine the possibility that the nitrergic neurotransmitter and endothelium-derived relaxing factor (EDRF) could be S-nitrosothiol or free nitric oxide (NO) in the isolated mouse corpus cavernosum. Thimerosal (5 x 10(-6)-2 x 10(-5) M) inhibited or almost abolished electrical field stimulation--(EFS, 30V, 0.5 ms, 15 sec, 1, 2, 4, 8, 16 Hz), acetylcholine--(ACh, 5 x 10(-8)-1.25 x 10(-6) M), glyceryl trinitrate--(GTN, 3 x 10(-7)-3 x 10(-6) M), and S-nitrosoglutathione--(GSNO, 5 x 10(-6)-1.25 x 10(-4) M) induced relaxations. Thiomerosal inhibition seems to be specific to L-arginine NO pathways since it had no effect on acidified sodium nitrite--(10(-4)-5 x 10(-4) M), photoactivated sodium nitrite--(2 x 10(-4) M), isoprenaline--(10(-6) M), or papaverine--(10(-4) M) elicited relaxations. Moreover, the inhibitory effect of thimerosal on the nitrergic, ACh- or GTN-induced relaxations were partly reversed by sulfhydryl-containing compounds, L-cysteine (10(-3) M), dithiothreitol (10(-3) M), or glutathione (10(-3) M). However L-methionine (10(-3) M), which contains a methyl group on the sulphur atom, failed to restore the thimerosal inhibition. Thimerosal did not change the contraction produced by 10(-4) M NG-nitro-L-arginine methyl ester. These findings indicate that the nitrergic neurotransmitter as well as EDRF may not be free NO but NO-transferring molecules, probably S-nitrosothiols, in the mouse corpus cavernosum.
An abridged five-item version of the 15-item International Index of Erectile Function (IIEF) was developed (IIEF-5) to diagnose the presence and severity of erectile dysfunction (ED). The five items selected were based on ability to identify the presence or absence of ED and on adherence to the National Institute of Health's definition of ED. These items focused on erectile function and intercourse satisfaction. For 1152 men (1036 with ED, 116 controls) analyzed, a receiver operating characteristic curve indicated that the IIEF-5 is an excellent diagnostic test. Based on equal misclassification rates of ED and no ED, a cutoff score of 21 (range of scores, 5-25) discriminated best (sensitivity=0.98, specificity=0. 88). ED was classified into five severity levels, ranging from none (22-25) through severe (5-7). Substantial agreement existed between the predicted and 'true' ED classes (weighted kappa=0.82). These data suggest that the IIEF-5 possesses favorable properties for detecting the presence and severity of ED.
The incidence of erectile dysfunction increases with diabetes, hypertension, hypercholesterolaemia, cardiovascular disease and renal failure. All these conditions are associated with endothelial dysfunction. This review addresses the pathophysiology of erectile dysfunction with a special focus on new insights into nitric oxide (NO)-mediated pathways, oxidative stress and parallels to endothelial dysfunction. NO appears to be the key mediator promoting endothelium-derived vasodilation and penile erection. The possibility is discussed that elevated plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthase inhibitor, may provide an additional pathomechanism for various forms of erectile dysfunction associated with cardiovascular risk factors and disease. Likewise, the role of endothelium-derived factors mediating NO-independent pathways is evaluated.
Erectile dysfunction (ED) has been defined by the National Institute of Health (NIH) as the inability to achieve and/or to maintain an erection for a sufficiently long period of time so as to permit satisfactory sexual intercourse. ED affects millions of men throughout the world and could have a negative influence on the individual's well-being as well as on the quality of life of affected subjects. Discordant data have been reported on ED epidemiology with prevalence ranging from 12% to 52%, probably depending on the different criteria utilized in the different studies for patient selection. ED is a symptom, sometimes the first, of different pathological conditions. In 15.7% of 45-yr-old patients with vascular ED a dynamic ergometric test has shown electrocardiographic alterations in the absence of any cardiac symptom. In 15% of the patients with ED, high fasting glucose plasma levels are discovered for the first time and in patients with ED and normal fasting glucose plasma levels the prevalence of undiagnosed diabetes mellitus is 12.1% after an oral glucose tolerance test (OGTT). The different risk factors are often additive in the possible development of systemic vasculopathy, neuropathy and ED. ED, underestimated in clinical practice due to archaic prejudice which hinders the patient in spontaneously revealing the problem and the physicians in investigating it, can mark the point where evaluation and prevention of important diseases (such as diabetes, arterial hypertension, atherosclerosis) hitherto unknown by the patients, can begin. The physicians' cultural baggage must include the ability to identify the pathology that can determine ED and the ability to program a specific diagnostic workup. In this paper the different specialists involved in ED diagnosis agreed that a clinical approach which allows the identification of systemic pathologies contributing to the development of ED constitutes an improvement in disease prognosis and may either induce a spontaneous reduction of ED or facilitate its specific treatment.
Objective: To determine the prevalence of hypertension in newly diagnosed type 2 diabetic patients and its association with risk factors for cardiovascular and diabetic complications. Design: Cross-sectional study. Patients: Newly diagnosed type 2 diabetic patients (n=3648, mean age 52 years, 59% male) recruited for the UK Prospective Diabetes Study (UKPDS). Measurements: Blood pressure, body mass index, waist: hip ratio, ECG signs of ischaemia and of left ventricular hypertrophy (Minnesota code), fasting plasma glucose, urate, creatinine, insulin, triglycerides, high-density lipoprotein-, low-density lipoprotein- and total cholesterol, urinary albumin: creatinine ratio, retinopathy grading. Results: Thirty-nine per cent of the patients (35% of the males, 46% of the females) were hypertensive (mean blood pressure >=160 systolic and/or >=90mmHg diastolic 2 and 9 months after diagnosis of diabetes, or taking antihypertensive therapy). The hypertensive patients had a greater mean body mass index (30.1 versus 28.0 kg/m2, P< 0.0001) than the normotensive patients. They also had higher fasting plasma triglyceride (1.94 versus 1.69mmol/l, P< 0.0001) and insulin (15.0 versus 12.8 mU/l, P< 0.0001) levels but these associations disappeared or weakened when obesity was taken into account. Hypertensive compared with normotensive subjects suffered a higher prevalence of cardiovascular events before the diagnosis of diabetes (4.8 versus 2.5%, P< 0.0001), of microalbuminuria (albumin: creatinine ratio <5.0g/mol; 24 versus 14%, P< 0.0001), of ECG signs of probable and possible ischaemia (24 versus 14%, P< 0.0001) and of left ventricular hypertrophy (8.5 versus 3.8%; P< 0.0001). The prevalence of retinopathy was similar in the two groups. Conclusions: Hypertension is common in newly diagnosed type 2 diabetes and is associated with obesity. The association between hypertension and higher triglyceride and insulin levels may be secondary to obesity in this population. An association between hypertension and cardiovascular complications is already apparent at diagnosis of diabetes.
The human Interleukin-1 receptor-associated protein kinase IRAK-1 is a highly specific signaling molecule activated by the Toll/IL-1 receptor family. It is a multidomain protein consisting of an N-terminal death domain, a regulatory ProST (proline-, serine-, threonine-rich) region, a conventional serine/threonine protein kinase domain and a large C-terminal rest. IRAK-1 mediates between the active receptor complex and downstream signaling events such as activation of NFκB. This adapter function is guaranteed by protein interactions of the N-terminal death domain to MyD88 and of the C-terminus to TRAF6. The signaling function of IRAK-1 is independent of its enzymatic activity. The kinase domain and the ProST region serve as a self-activating kinetic switch module in IRAK-1. Two different phosphorylation events take place in a sequential fashion in IRAK-1. The first is an autophosphorylation of the kinase domain resulting in full enzymatic activity. This is followed by multiple phosphorylations in the ProST region. The introduction of negative charges adjacent to the death domain has two consequences: First hyperphosphorylated IRAK-1 dissociates from the upstream adapter MyD88 and thus leaves the active receptor complex allowing optimal interaction with the downstream adapter TRAF6. Second, hyperphosphorylated IRAK-1 is targeted to the proteasome where it is proteolytically degraded and thus removed out of the signaling chain. This self-limitation guarantees a transient IL-1 signal. This regulatory function is completely dispensable for IRAK-1's adapter function as a signaling molecule. In summary, IRAK-1 is a highly-sophisticated adapter molecule in the signaling pathway of the Toll/IL-1 receptor family which regulates its own availability as a signaling component by autophosphorylation and autoinduced proteolytical degradation (summarized in Fig. 1).
Background
The effects of streptozotocin-induced diabetes on nitric oxide (NO)-mediated relaxation of rat corpus cavernosum smooth muscle to neurogenic and endothelial stimulation was examined. The aim was to assess the effects of treatment with low doses of the antioxidant, α-lipoic acid, and the ω-6 essential fatty acid, γ-linolenic acid, either separately or in combination.Methods
Treatment was preventive from diabetes induction or corrective over 4 weeks after 4 weeks of untreated diabetes. Corpus cavernosum responses were examined in vitro.ResultsNeither diabetes nor treatment affected contractile responses to transmural electrical field stimulation of noradrenergic nerves. Stimulation of phenylephrine precontracted cavernosa in the presence of guanethidine and atropine caused relaxation via the nitrergic innervation. Maximum relaxation responses were 40% and 46% decreased after 4 and 8 weeks of diabetes, respectively. α-Lipoic acid, γ-linolenic acid combination treatment fully prevented this deficit, and partially (52%) corrected the effect of 4 weeks of untreated diabetes. Neither α-lipoic acid nor γ-linolenic components alone had significant effects, which suggests that there were synergistic interactions between the drugs. Both 4 and 8 weeks of untreated diabetes reduced maximum endothelium-dependent relaxation of phenylephrine precontracted cavernosa to acetylcholine by approximately 40%. While α-lipoic acid or γ-linolenic acid were ineffective, joint treatment fully prevented and corrected this diabetic endothelial deficit. Neither diabetes nor treatment affected endothelium-independent relaxation to the NO donor, sodium nitroprusside.Conclusion
The data show that α-lipoic acid and γ-linolenic acid interact synergistically to improve NO-mediated neurogenic and endothelium-dependent relaxation of corpus cavernosum in experimental diabetes. Copyright © 2001 John Wiley & Sons, Ltd.
Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. With the insulin/glucose-clamp technique, in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells. Physiological maneuvers, such as calorie restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; evidence indicates that these maneuvers can also lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic. Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.
Insulin-mediated glucose metabolism (euglycemic insulin clamp at plasma insulin concentration of 100 microU/mL) and glucose-stimulated insulin secretion (hyperglycemic clamp) were examined in 42 obese subjects (ideal body weight [IBW], 158 +/- 4%) with normal glucose tolerance and in 36 normal weight (IBW, 102% +/- 1%) age-matched controls. In 10 obese and eight control subjects, insulin was infused at six rates to increase plasma insulin concentration by approximately 10, 20, 40, 80, 2,000, and 20,000 microU/mL. Throughout the physiologic range of plasma insulin concentrations, both the increase in total body glucose uptake and the suppression of hepatic glucose production (HGP) were significantly impaired in the obese group (P less than .001 to .01). At the two highest plasma insulin concentrations, inhibition of HGP and the stimulation of glucose disposal were similar in both the obese and control groups. Insulin secretion during the hyperglycemic (+/- 125 mg/dL) clamp was twofold greater in obese subjects than in controls (P less than .01) and was inversely related to the rate of glucose uptake during the insulin clamp (r = -.438, P less than .05), but was still unable to normalize glucose disposal (P less than .05). In conclusion, our results indicate that insulin resistance is a common accompaniment of obesity and can be overcome at supraphysiological insulin concentrations. Both in the basal state and following a hyperglycemic stimulus obese people display hyperinsulinemia, which correlates with the degree of insulin resistance. However, endogenous hyperinsulinemia fails to fully compensate for the insulin resistance.
The metabolism of glutathione and activities of its related enzymes were studied in erythrocytes from patients with non-insulin-dependent diabetes mellitus (NIDDM). A decrease in the levels of the reduced form of glutathione and an increase in the levels of glutathione disulfide were found in erythrocytes of diabetics. To elucidate these changes in the levels of glutathione, synthetic and degradative processes were studied. The activity of gamma-glutamylcysteine synthetase was significantly lower in diabetics than in normal controls. The activity of glutathione synthetase of each group was the same. The rate of outward transport of glutathione disulfide in diabetics decreased to approximately 70% of that of normal controls. The activity of glutathione reductase decreased in diabetics. These data suggest that the decrease in the levels of reduced form of glutathione in erythrocytes of diabetics is brought about by impaired glutathione synthesis and that the increase in the levels of glutathione disulfide is brought about by the decreased transport activity of glutathione disulfide through the erythrocyte membrane together with a decrease in the activity of glutathione reductase. These data also suggest that the impairment of glutathione metabolism weakens the defense mechanism against oxidative stress in erythrocytes of diabetics.
During the past decade, our appreciation of the original experiments with myo-inositol supplementation in diabetic rats has greatly expanded. The effects of myo-inositol on nerve conduction are now explained by concepts that were largely unappreciated in 1976, including the fundamental role of phosphoinositide metabolism in cell regulation and the importance of the activity of sodium-potassium-ATPase in nerve conduction. Aldose reductase inhibitors firmly link defects in myo-inositol metabolism to activation of the polyol pathway in diabetes; the resulting "sorbitol-myo-inositol hypothesis" has been extended from its application to the lenses and peripheral nerves to most of the tissues involved with diabetic complications. These biochemical mechanisms provide a new framework within which to explore the complex interactions between hyperglycemia and the vascular, genetic, and environmental variables in the pathogenesis of diabetic complications. It is anticipated that these endeavors will result in the appearance of new classes of therapeutic agents, the first of which--the aldose reductase inhibitors--has emerged from the laboratory and is now undergoing extensive clinical testing. These efforts are very likely to result in the appearance of new treatment methods that may dramatically lighten the burden of chronic complications in patients with diabetes.
The time-dependent relationship between the levels of the reduced form of glutathione (GSH) and thromboxane A2 (TXA2) synthesis, as measured by the accumulation of TXB2, in platelets from human diabetic and control subjects was investigated during aggregation. In platelets from control subjects, the GSH level decreased to 21% of the initial level within 30 sec in response to arachidonic acid (1.65 mM) and rapidly recovered to 91% by 1 min. In platelets from diabetic subjects, the GSH level decreased to 3% of the initial level within 30 sec and recovered to only 41% by 1 min. During collagen (20 ug/ml) aggregation, platelets from control subjects had a 15 sec lag phase which was followed by a decrease in the GSH level to 21% of the initial level within 1 min and a recovery to 74% by 2 min. Platelets from diabetic subjects in response to collagen showed no lag phase and decreased to 10% of the initial level within 1 min which was followed by a recovery to 34% by 2 min. In all aggregations, the initial GSH level was significantly (p less than .001) lower in platelets from diabetic subjects and remained significantly (p less than .01) lower than GSH in platelets from control subjects throughout the aggregation. The amount of TXB2 formed by platelets from control subjects reached a maximum in response to arachidonic acid and collagen by 1 min and 2 min, respectively, whereas, the TXB2 continued to increase up to 4 min when platelets from diabetic subjects were aggregated. These data indicate that TXA2 synthesis occurs during the decrease in GSH and ceases when the GSH level recovers. The continued synthesis of TXA2 by platelets from diabetic subjects coincides with the gradual recovery of the GSH level.
In a survey of 541 diabetic males, aged 20-59 years, 190 (35%) had erectile impotence. Using linear logistic regression models for analysis the five most significant associations with impotence were age (p < 0.001), treatment with either insulin or oral hypoglycaemic agents (p < 0.001), retinopathy (p < 0.001), symptomatic peripheral neuropathy (p < 0.001) and symptomatic autonomic neuropathy (p < 0.005). The greatest correlations were found in patients with severe microangiopathy, as demonstrated by proliferative retinopathy and symptomatic autonomic neuropathy. In addition the duration of diabetes and the presence of ischaemic heart disease, nephropathy and poor diabetic control may also be associated with diabetic impotence. It is concluded that diabetic impotence is still a common problem and may have a multifactorial aetiology.
Psychological issues are salient in every case of erectile dysfunction because sexual function is a psychosomatic process. The best overall assessment is made through separate psychosocial interviews of patient and partner. Interview technique requires comfort and a nonjudgmental attitude. A combination of psychological and physiological treatments offer the best outcome for many cases.
We designed this study to examine whether uncontrolled hyperglycemia, duration of diabetes, or race (black v white) have any effect on glutathione levels in erythrocytes of type I diabetic patients. Hyperglycemia was assessed by measuring the level of hemoglobin A1c (HbA1c). Results show that erythrocytes of diabetic patients have a significantly lower glutathione level compared with those of age-matched normal subjects (P < .004). We found a significant negative correlation (r = -.59, P < .001) between the degree of hyperglycemia and the level of reduced glutathione (GSH) in erythrocytes of diabetic patients. There was no significant relationship (r = -.29, P > .12) between the level of GSH in erythrocytes and the duration of diabetes. Erythrocytes of black diabetic patients had significantly lower levels of GSH (P < .05) than those of white diabetic patients. Using erythrocytes as a model, this study suggests that a lower level of GSH may have a role in the cellular damage and impaired insulin secretion in uncontrolled diabetic patients.
Human endothelial cells cultured from umbilical vein (HUVEC) were tested for their ability to synthesize nitric oxide (NO), which has been identified as an endothelium-derived relaxing factor. The synthesis of this free radical (detected as citrulline, which is produced stoichiometrically with NO from arginine) in HUVEC is Ca2+ dependent, is increased sevenfold by the calcium ionophore ionomycin, and accounts for most basal and ionomycin-induced guanosine 3',5'-cyclic monophosphate (cGMP) production. Loading of cells with reduced glutathione (GSH), but not with N-(2-mercaptopropionyl)- glycine (MPG), led to increased citrulline production, both basally and after ionomycin stimulation. When the cells were depleted of GSH by incubation with 1-chloro-2,4-dinitrobenzene (CDNB), citrulline synthesis and cGMP production were inhibited in a concentration-dependent way. CDNB was not cytotoxic and did not inhibit cGMP increase elicited by sodium nitroprusside; cell loading with GSH (but not with MPG) relieved the block of citrulline synthesis. These results suggest that GSH is necessary in HUVEC for NO synthesis rather than for the NO effect on guanylate cyclase.
We provide current, normative data on the prevalence of impotence, and its physiological and psychosocial correlates in a general population using results from the Massachusetts Male Aging Study. The Massachusetts Male Aging Study was a community based, random sample observational survey of noninstitutionalized men 40 to 70 years old conducted from 1987 to 1989 in cities and towns near Boston, Massachusetts. Blood samples, physiological measures, socio-demographic variables, psychological indexes, and information on health status, medications, smoking and lifestyle were collected by trained interviewers in the subject's home. A self-administered sexual activity questionnaire was used to characterize erectile potency. The combined prevalence of minimal, moderate and complete impotence was 52%. The prevalence of complete impotence tripled from 5 to 15% between subject ages 40 and 70 years. Subject age was the variable most strongly associated with impotence. After adjustment for age, a higher probability of impotence was directly correlated with heart disease, hypertension, diabetes, associated medications, and indexes of anger and depression, and inversely correlated with serum dehydroepiandrosterone, high density lipoprotein cholesterol and an index of dominant personality. Cigarette smoking was associated with a greater probability of complete impotence in men with heart disease and hypertension. We conclude that impotence is a major health concern in light of the high prevalence, is strongly associated with age, has multiple determinants, including some risk factors for vascular disease, and may be due partly to modifiable para-aging phenomena.
The purpose of this report is to examine the prevalence of erectile dysfunction and relationships to other characteristics in men with younger-onset diabetes.
In a population-based cohort study in southern Wisconsin, prevalence of erectile dysfunction was measured based on self reports in men who were 21 years of age or older, were < 30 years of age at diagnosis of diabetes, had 10 or more years of diabetes, and were taking insulin (n = 365).
Of the study group, 20% reported a history of erectile dysfunction. The prevalence of erectile dysfunction increased with increasing age (from 1.1% in those 21-30 years of age to 47.1% in those 43 years of age or older, P for trend < 0.0001) and with increasing duration of diabetes (P for trend < 0.0001). Erectile dysfunction was associated with presence of severe diabetic retinopathy, a history of peripheral neuropathy, amputation, cardiovascular disease, a higher glycosylated hemoglobin, use of antihypertensive medications, and higher BMI.
These data suggest that tighter glycemic control and careful selection of antihypertensive medications might prove beneficial.
Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although prospective randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between diabetic hyperglycemia and the development of secondary complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that the generation of reactive oxygen species (oxidative stress) may play an important role in the etiology of diabetic complications. This hypothesis is supported by evidence that many biochemical pathways strictly associated with hyperglycemia (glucose autoxidation, polyol pathway, prostanoid synthesis, protein glycation) can increase the production of free radicals. Furthermore, exposure of endothelial cells to high glucose leads to augmented production of superoxide anion, which may quench nitric oxide, a potent endothelium-derived vasodilator that participates in the general homeostasis of the vasculature. In further support of the consequential injurious role of oxidative stress, many of the adverse effects of high glucose on endothelial functions, such as reduced endothelial-dependent relaxation and delayed cell replication, are reversed by antioxidants. A rational extension of this proposed role for oxidative stress is the suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status.
Erectile impotence is more common in the diabetic than the general population, occurs at a younger age, and is often associated with ejaculatory problems. For these, and possibly for other more subtle reasons, fertility may be a problem for men with diabetes. The symptoms of erectile and ejaculatory dysfunction are frequently not discussed between patient and doctor. Psychological factors are important but the vast majority of diabetic patients have an organic basis for their impotence. Both neurogenic and vascular factors are important in the pathogenesis of erectile failure. Autonomic neuropathy is almost certainly the cause of the ejaculatory failure that may be present in up to 40% of men with diabetes. The final biochemical mediator of erection within the penile erectile tissue is nitric oxide and a key enzyme in its degradation is phosphodiesterase (type V). Drugs that affect the metabolism of this enzyme are being developed to treat erectile failure. At present, the self injection of intra-cavernosal erectogenic agents (such as prostaglandin E1) provide the main form of therapy for erectile failure. Vacuum devices are a simple alternative and venous ligation surgery may be effective for a properly selected cohort of patients. Prosthetic implants are a final option for patients in whom all else has failed. Fertility problems, particularly when associated with ejaculatory failure can be overcome with modern assisted reproductive techniques. Nowadays, these will frequently involve gamete micro-manipulation.
Blood samples were analyzed for GSH and GSH redox state in 40 age-related macular degeneration (ARMD) patients (> 60 y), 33 non-ARMD diabetic patients (> 60 years), 27 similarly aged non-ARMD and nondiabetic individuals (> 60 years), and 19 younger individuals (< 60 years) without ARMD or diabetes. Results showed a significantly lower plasma GSH in older individuals (ARMD, diabetes, and controls) than in younger individuals (p < .01). Total GSH (GSHt) obtained following treatment with dithiothreitol was significantly lower only in diabetic cases (p < .05) but also approached significance for ARMD cases (p = .089). Estimation of redox potential indicated that the plasma GSH pool is considerably more oxidized in all of the older groups. Analyses of whole blood GSH showed that GSH was significantly lower in diabetic cases compared to the other groups, but did not reveal any difference associated with age or ARMD. In contrast, GSSG in whole blood was significantly higher in the older groups compared to the younger controls. The results suggest that in studies of age-related pathologies, oxidation of GSH may be a more important parameter than a decline in pool size, while in specific pathologies such as diabetes, both oxidation and a decline in pool size may be important.
There is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unclear. Using transgenic mice that overexpress aldose reductase (AR) in their lenses, we found that the flux of glucose through the polyol pathway is the major cause of hyperglycemic oxidative stress in this tissue. The substantial decrease in the level of reduced glutathione (GSH) with concomitant rise in the level of lipid peroxidation product malondialdehyde (MDA) in the lens of transgenic mice, but not in the nontransgenic mice, suggests that glucose autoxidation and nonenzymatic glycation do not contribute significantly to oxidative stress in diabetic lenses. AR reduction of glucose to sorbitol probably contributes to oxidative stress by depleting its cofactor NADPH, which is also required for the regeneration of GSH. Sorbitol dehydrogenase, the second enzyme in the polyol pathway that converts sorbitol to fructose, also contributes to oxidative stress, most likely because depletion of its cofactor NAD+ leads to more glucose being channeled through the polyol pathway. Despite a more than 100% increase of MDA, oxidative stress plays only a minor role in the development of cataract in this acute diabetic cataract model. However, chronic oxidative stress generated by the polyol pathway is likely to be an important contributing factor in the slow-developing diabetic cataract as well as in the development of other diabetic complications.--Lee, A. Y. W., Chung, S. S. M. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J. 13, 23-30 (1999)
To develop Patient and Partner versions of a psychometrically sound questionnaire, the EDITS (Erectile Dysfunction Inventory of Treatment Satisfaction), to assess satisfaction with medical treatments for erectile dysfunction.
Treatment satisfaction differs from treatment efficacy as it focuses on a person's subjective evaluation of treatment received. Twenty-nine items representing the domain of treatment satisfaction for men and 20 representing partner satisfaction were generated. Two independent samples of 28 and 29 couples completed all items at two points in time. Spearman rank-order correlations were derived to assess test-retest reliability and couple coefficients of validity. Internal consistency coefficients were calculated for both Patient and Partner versions and a content validity panel was used to analyze content validity.
Only items that met all the following criteria were selected to comprise the final questionnaires: (a) range of response four or more out of five; (b) test-retest reliability greater than 0.70; (c) ratings by at least 70% of the content validity panel as belonging in and being important for the domain; and (d) significant correlation between the subjects' and partners' responses. Eleven patient items met criteria and formed the Patient EDITS; five partner items met criteria and formed the Partner EDITS. Scores on the two inventories were normally distributed with internal consistencies of 0.90 and 0.76, respectively. Test-retest reliability for the Patient EDITS was 0.98; for the Partner EDITS, it was 0.83.
Reliability and validity were well established, enabling the EDITSs to be used to assess satisfaction with treatment modalities for erectile dysfunction and to explore the impact of patient and partner satisfaction on treatment continuation.
We estimated the incidence of erectile dysfunction in men 40 to 69 years old at study entry during an average 8.8-year followup, and determined how risk varied with age, socioeconomic status and medical conditions.
Data from a randomly sampled population based longitudinal study of Massachusetts men were analyzed. A total of 1,709 men completed the baseline interview during 1987 to 1989 and 1,156 survivors completed followup from 1995 to 1997. The analysis sample consisted of 847 men without erectile dysfunction at baseline and with complete followup information. Erectile dysfunction was assessed by discriminant analysis of 13 questions from a self-administered sexual function questionnaire and a single global self-rating question.
The crude incidence rate for erectile dysfunction was 25.9 cases per 1,000 man-years (95% confidence interval [CI] 22.5 to 29.9). The annual incidence rate increased with each decade of age and was 12.4 cases per 1,000 man-years (95% CI 9.0 to 16.9), 29.8 (24.0 to 37.0) and 46.4 (36.9 to 58.4) for men 40 to 49, 50 to 59 and 60 to 69 years old, respectively. The age adjusted risk of erectile dysfunction was higher for men with lower education, diabetes, heart disease and hypertension. Population projections for men 40 to 69 years old suggest that 17,781 new cases of erectile dysfunction in Massachusetts and 617,715 in the United States (white males only) are expected annually.
Although prevalence estimates and cross-sectional correlates of erectile dysfunction have recently been established, incidence estimates were lacking. Incidence is necessary to assess risk, and plan treatment and prevention strategies. The risk of erectile dysfunction was about 26 cases per 1,000 men annually, and increased with age, lower education, diabetes, heart disease and hypertension.
Atherosclerosis and microvascular complications in patients with non-insulin-dependent diabetes have been linked to increased oxidative stress. The glutathione redox cycle is a major determinant of the antioxidative capacity of plasma and its constituents.
We attempted to investigate plasma oxidation and plasma and erythrocyte glutathione and glutathione enzymes in 20 patients with NIDDM, compared with euglycemic matched controls. Plasma oxidation was analyzed both basally (without) and as induced by 2,2'-azobis,2-amidopropane hydrochloride measured by the generation of thiobarbituric acid reactive substances and lipid peroxides.
There was a significant increase in oxidation both basally (without) and as induced by AAPH. Plasma glutathione was lowered by 50% (P < 0.01) and erythrocyte glutathione peroxidase, glutathione s-transferase and glutathione reductase activities were lower by 30%, 27% and 46%, respectively (P < 0.01) in the patients with NIDDM.
Confronted by increased oxidation, patients with NIDDM show an abnormal plasma and erythrocyte antioxidative capacity, which may result in an accelerated rate of complications.
Many men with erectile dysfunction have been successfully treated with intracavernosal injection of prostaglandin E(1) (PGE(1)) but this treatment is ineffective in 30 to 40% of patients. The goals of this study were to characterize PGE(1)-induced relaxation of isolated human penile smooth muscle (penile arteries and trabecular strips), correlating this in vitro response with the clinical response to this drug, and to evaluate the effects of the combination of PGE(1) with S-nitrosoglutathione (SNO-Glu) on relaxation of isolated human penile smooth muscle. Large variability in the EC(50) and maximal relaxation induced by PGE(1) was observed between tissues of different patients. Patients with poor clinical response to intracavernosal alprostadil (PGE(1)) had significantly larger EC(50) values and smaller maximal relaxation compared with patients with partial or complete clinical response to this drug. SNO-Glu consistently produced complete or near complete relaxation of human corpus cavernosum strips and penile arteries, even when the tissue responded poorly to PGE(1). In trabecular strips, the combination of PGE(1) and SNO-Glu in a 1:100 ratio demonstrated a synergistic relaxation effect. The combination of PGE(1) and SNO-Glu simultaneously increased the levels of both cAMP and cGMP in human corpus cavernosum tissue. Our results suggest that the clinical effectiveness of intracavernosal administration of PGE(1) is related to the variability of the relaxation responses of human trabecular tissue and penile arteries to this drug. The synergistic interaction of PGE(1) and SNO-Glu makes this combination an effective method to cause penile smooth muscle relaxation, a necessary step to initiate and maintain penile erection.
Several studies suggest that nitric oxide (NO) production is impaired in diabetes mellitus. Reduced levels of NO could contribute to cardiovascular mortality. Furthermore, NO synthesis is impaired in glutathione (GSH)-depleted human umbilical vein endothelial cells and GSH is reduced in patients with type 2 diabetes mellitus (T2DM). We tested the hypothesis that treatment with GSH may improve platelet constitutive NO sinthase (cNOS) activity in patients with T2DM. Fifteen patients with T2DM underwent a treatment with GSH 600 mg/day i.m. for 10 days. With respect to the basal values on the 10th day of treatment, the red blood cell GSH concentration and platelets cNOS increased (1.4+/-0.1 vs 1.9+/-0.1 micromol/10(10) RBC, p<0.001 and 0.7+/-0.1 vs 2.9+/-0.2 fmol x min(-1) x 10(-9) PLTs, p<0.001, respectively) and the plasma PAI-1 levels diminished (81.4+/-3.7 vs 68.7+/-4.0 ng/ml, p<0.002). A negative correlation between the cNOS and the PAI-1 was found on the basal values. After a wash-out of 30 days the values of red blood cell GSH concentration, platelet cNOS activity and PAI-1 Ag returned to the basal levels. These data suggest that the administration of GSH, in patients with T2DM, is able to improve platelet cNOS activity together with a reduction of PAI-1.
Erectile dysfunction affects 31% to 52% of all men. Although considerable advances have been made in the diagnosis and management of erectile dysfunction, the inadequate knowledge of erectile dysfunction by health care providers still precludes them from initiating candid discussions with their patients. This article provides the health care professional with the ability to establish comfortable doctor-patient dialogue and to clinically evaluate erectile dysfunction in a goal-directed manner. The goal of evaluation is to find the appropriate treatment for the individual, dictated primarily by factors like the patients' preferences, comfort, cost, and the availability of treatment modalities.
Our aim was to evaluate oxidative stress parameters on three groups of diabetic patients, insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), and insulin-treated type 2 diabetes mellitus (ITDM2), with similar HbA1c value and to determine if insulin's impact on these parameters was the same for IDDM and ITDM2.
This study has been conducted on 18 IDDM, 55 NIDDM, 27 ITDM2, compared to 12 healthy subjects. Plasmatic concentrations of thiobarbituric acid reactive substances (TBARS), fatty acids, total antioxidant status (TAS), alpha-tocopherol, and erythrocyte reduced glutathione (GSH) were measured as well as enzymatic activities of superoxide dismutase (SOD), and glutathione peroxidase/reductase.
Diabetic patients have significant increase of SOD activity, of TBARS concentration (concomitant with low levels of unsaturated fatty acids) and significant decrease of GSH and alpha-tocopherol. NIDDM have significantly lower levels of GSH and higher levels of TBARS compared to IDDM. ITDM2 values are intermediate between IDDM and NIDDM but are far from reaching those of IDDM.
Diabetic patients undergo an important oxidative stress that is nearly corrected for IDDM, but only partially improved for ITDM2, although length of insulin treatment and HbA1c values are similar, suggesting metabolic differences between the two types of diabetes.
The aim of the present study was to examine the susceptibility of glutathione (GSH) and glutathione related antioxidant enzymes to oxidation in type 2 diabetic patients with and without glycemic control.
Erythrocyte glutathione level and activities of glutathione peroxidase (G-Px), glutathione reductase (G-Red) and glutathione S-transferase (GST) in controls, well controlled and poorly controlled type 2 diabetics were measured by spectrophotometric assays before and after the incubation in vitro with H2O2.
GSH level, G-Px and G-Red activities decreased but GST activity increased in the erythrocytes from all the groups after the incubation with H2O2. Percentage of decrease in GSH was independent from glycemic control, whereas the percentage of decreases in G-Px and G-Red was related to glycemic control. The percentage of increase in GST was found to be independent from diabetes.
GSH and GSH-related antioxidant enzymes in human erythrocytes are susceptible to oxidation, particularly, G-Px and G-Red which were found to be more susceptible to oxidation in erythrocytes from poorly controlled type 2 diabetic patients.
The discovery of nitric oxide (NO) as one of the major effectors in penile erectile function has led to the development of various drugs which are able to elevate intracellular levels of cGMP. Recently, a novel class of NO donors have been developed, exemplified by S-nitroso-glutathione (GSNO) and S-nitroso-N-acetylcysteine-ethylester (SNACET), as well as compounds combining both phosphodiesterase inhibitory and NO donating activity, such as NCX 911 (sildenafil nitrate). In our study, we assessed the effects of GSNO, SNACET and NCX 911 on adrenergic tension and electrically induced relaxation of isolated human corpus cavernosum (HCC) and the in vitro formation of cGMP. Effects were compared to those of sodium nitroprusside (SNP) and sildenafil citrate.
Using the organ bath technique, drug effects were investigated on norepinephrine-induced tension and electrically induced relaxation of HCC. HCC strips were exposed to increasing concentrations of the compounds (0.01/0.1-10/100 microM) and the accumulation of cGMP was determined by means of a radioimmunoassay.
Relaxation of HCC induced by means of electrical field stimulation (EFS) was abolished by tetrotodoxin, guanylyl cyclase inhibitor ODQ and nitric oxide synthase inhibitor L-NNA. Adrenergic tension of HCC strips was dose-dependently reversed by the drugs. The rank order of potency was: SNP > GSNO > NCX911 > sildenafil > SNACET. Compounds also dose-dependently increased EFS-induced amplitudes of relaxation (SNP > NCX911 > sildenafil > SNACET/GSNO). Relaxing effects of the drugs were paralleled by an increase in tissue levels of cGMP.
Our results provide a rationale for future use of NCX 911 and S-nitrosothiols in the pharmacotherapy of erectile dysfunction (ED). Since the compounds are assumed to exert no considerable hemodynamic effects, they might be developed into new oral treatments for ED.
Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. These consequences of oxidative stress can promote the development of complications of diabetes mellitus. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes, and their consequences, are discussed in this review. In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed. There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.
Diabetes mellitus affects more than 6.2% of the population in the United States. Therefore, more than 8 million American men have the potential of being affected by diabetes mellitus induced erectile dysfunction (DMED).1 An association between diabetes mellitus and the development of erectile dysfunction has been documented in the literature since 1798.2 In fact, DMED represents one of the largest groups of erectile dysfunction. Between 25% and 75% of men with type 2 diabetes will complain of erectile dysfunction.3 In numerous epidemiological studies the odds ratio of having erectile dysfunction if a man is diabetic is 1.9 to 4 times greater than a population without diabetes, making diabetes one of the greatest risk factors for erectile dysfunction.4, 5 The incidence of DMED has been shown to be age associated. By the age of 30 years approximately 15% of diabetic men have erectile dysfunction, whereas by the age of 60 years 55% will have it. 6–8 Not only does erectile dysfunction occur at a higher frequency in younger patients with diabetes, but also DMED occurs at a greater frequency across all age groups. As the treatment of diabetes improves and patient life spans increase, the importance of quality of life issues in the treatment of diabetes becomes more prominent. Diabetic patients with erectile dysfunction have a significantly poorer quality of life demonstrated by self-reported quality of life indexes. The focus of diabetic therapy in the year 2002 is now directed toward decreasing the sequela of diabetes mellitus, including erectile dysfunction. A review of the mechanisms responsible for causing DMED and a focus on the clinical manifestations of diabetic erectile dysfunction will lead us to improved prevention and treatment of DMED. The purpose of this article is to review research, and preclinical and clinical information related to DMED, and discuss possible treatment, prevention strategies and future goals needed to improve our understanding of the unique pathophysiological attributes of diabetes and erectile dysfunction. MECHANISM OF DMED
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.
The aim of this study is to investigate the role of nitric oxide (NO) stabile end products, membrane lipid peroxidation and antioxidant defensive mechanism in diabetic erectile dysfunction (ED) and compare these parameters with non-diabetic ED groups. We examined the penile cavernosal tissues, obtained from 22 patients who had undergone surgery of penile prostheses implantation, for the nitrite, nitrate, malondialdehyde (MDA) and glutathione (GSH) levels. Eight patients were suffering from diabetic erectile dysfunction (ED) and 14 patients had non-diabetic ED. Nitrite and nitrate levels were lower; MDA and GSH levels were higher in the diabetic group. There were statistically significant differences between diabetic and non-diabetic groups amongst the nitrite (p<0.001), nitrate (p<0.01), MDA (p<0.001) and GSH (p<0.01) levels. Our data provide evidence that NO deficiency, possibly due to the membrane lipid peroxidation and defective antioxidant defensive mechanism, may contribute to the development of diabetic ED and thus is involved in the pathogenesis of ED in diabetic patients.
Erectile dysfunction in diabetic subjects in Italy
- D Fedele
- C Coscelli
- F Santeusanio
- A Bortolotti
- L Chate-Noud
- E Colli
- M Landoni
- F Parazzini
Fedele, D., Coscelli, C., Santeusanio, F., Bortolotti, A., Chate-noud, L., Colli, E., Landoni, M. & Parazzini, F. (1998) Erectile dysfunction in diabetic subjects in Italy. Gruppo Italiano Studio Deficit Erettile nei Diabetici Diabetes Care 21, 1973–1977.
In: The Handbook of Sexual Dysfunction
- Man
man, woman, and couple. In: The Handbook of Sexual Dysfunction (ed. W. J. Hellstrom). The American Society of Andrology, San Francisco.
AACE medical guidelines for clinical practice for the diagnosis and treatment of dyslipidemia and prevention of atherogenesis
- AACE Lipid Guidelines Committee. The American Association of Clinical Endocrinologists