Role of Oxidative Stress in the Pathophysiological Mechanism of Erectile Dysfunction

Erectile dysfunction (ED) is defined as the inability to achieve or maintain erections sufficient for satisfactory sexual intercourse (NIH Consensus Conference, 1993). It is estimated that the prevalence of ED will double in the next 25 years. Normal erectile function depends on a precise balance between psychological, hormonal, neurological, vascular, and cavernosal factors. Therefore, an alteration in any one or combination of these factors may lead to ED. For many years, the complex interaction between the origin of impulse and the normal erectile response was not clearly understood. It was not until the early 1990s when the roles of central and peripheral phenomena in the normal erectile response was proposed. The identification of the roles of various mediators, as well as their interactions, in normal erectile function is a major development in the study of ED. Production of nitric oxide (NO) plays a central physiological role in erections. The endothelium is the primary source of NO (Burnett, 1997). The pathophysiological mechanism of endothelial dysfunction is multifactorial, and the major outcome is impaired release of NO, which leads to ED. Although NO-mediated relaxation plays a central role in erections, other mediators, such as prostaglandins, endothelin, and bradykinins, are also important in maintaining penile tone. Researchers have made great strides in the past two decades in identifying the pathophysiological mechanism in ED. However, the precise pathophysiological mechanism is still unclear. There is a growing interest among researchers regarding the role of oxidative stress in the pathophysiological mechanism of ED. Oxidative stress occurs when there is an imbalance between pro-oxidants and the ability of the antioxidants to scavenge excess reactive oxygen species. The role of oxidative stress and reactive oxygen species has been extensively evaluated in the pathophysiological mechanisms of male and female infertility. However, its role in ED has not been investigated comprehensively. Initial reports from both in vitro and in vivo studies have shown a significant association between the production of reactive oxygen species and erectile dysfunction, especially in diabetic animal models. In this article, we discuss the role of oxidative stress in the pathophysiological mechanism of ED and the therapeutic interventions and preventive strategies that may be beneficial in restoring endothelial function and normal erectile function. ED is a highly prevalent and often underreported condition. The prevalence of ED varies in different countries (NIH Consensus Conference, 1993). Approximately 20–30 million men in the United States and approximately 0.5 million men in the UK have ED of varying severity (NIH Consensus Conference, 1993). According to the Massachusetts Male Aging Study, 52% of men in the United States between the ages of 40 and 70 years have ED (Feldman et al, 1994). The incidence is approximately 32% in the United Kingdom (Spector and Boyle, 1986), 26% in Japan (Melman and Gingell, 1999), and 19% in Denmark (Solstad and Davidsen, 1993). However, some men are unwilling to report the problem, because of their social and cultural backgrounds. This makes it difficult to determine the precise prevalence of ED. Furthermore, the paucity of epidemiological studies reported in the literature from developing and underdeveloped countries further compound this problem. Additional studies are needed to estimate the worldwide prevalence of ED. The available literature suggests that ED is a mounting problem. The etiology of ED is multifactorial and can be classified as organic, neurogenic, and mixed. In organic ED, vasculogenic causes are common. The major risk factors implicated in the pathophysiological mechanism of organic ED are diabetes mellitus, hypercholesterolemia, smoking, and chronic medical illness. All of these factors increase the risk of atherosclerosis, which is the predominant predisposing cause of vasculogenic ED. Kaiser et al (1988) reported that atherosclerotic disease was the cause of ED in approximately 40% of men more than 50 years old (Kaiser et al, 1988). Atherosclerosis, along with other risk factors, is associated with endothelial dysfunction, which plays a crucial role in vasculogenic ED (Zeiher et al, 1993). The physiological mechanism of erection is a complex neurovascular phenomenon that depends on neural, vascular, hormonal, and psychological factors. Integrated function of these factors is essential for production of a normal erectile response. Recent advances in the understanding of functional anatomy and of neurovascular interactions have improved our understanding of the pathophysiological mechanism of ED. NO has been implicated in diverse physiological functions, including regulation of neural transmission in vascular tissue and immune system function (Moncada et al, 1991). The vasodilator effects in most vascular beds are mediated by endothelial derived relaxing factor (EDRF). NO has been established as an EDRF (Palmer et al, 1987) and shown to play central role in the physiological mechanism of penile erection by initiating smooth-muscle relaxation (Burnett, 1997). Penile erectile tissue is formed by 2 dorsal corporal bodies known as the corpora cavernosa. The cavernosal bodies are composed of sinusoidal spaces with a trabecular meshwork. These spaces are lined by endothelium. Neural transmitters, such as acetylcholine, are released from cavernosal nerve endings and stimulate the neuronal NOS (nNOS) enzyme, which leads to the release of NO from the endothelium. Erectile function is mediated by both nNOS and endothelial NOS (eNOS) (Burnett et al, 1995). This was reported in studies involving transgenic mice lacking the gene encoding nNOS, which showed preserved erectile function, suggesting a possible alternative source of NOS from the endothelium (Huang et al, 1993). Later studies identified inducible NOS (iNOS), which also plays an important role in normal erectile response. The regulation of NOS is a complex phenomenon and is regulated by numerous factors. Inhibitors of inducible NOS (iNOS) that are more selective than those of eNOS and nNOS have been identified. Some of these have the potential to treat a range of inflammatory and noninflammatory conditions in which iNOS has been implicated (Alderton et al, 2001). Inflammatory cytokines, high levels of oxidized cholesterol, hypertension, and steroids down regulate the expression of eNOS (Maas et al, 2002). In the genitouriniary tract, NO is a neurotransmitter involved in nonadregenic, noncholinergic neurotransmission (Sanez de Tezada et al, 1989; Ignarro et al, 1990; Kim et al, 1991; Knispel et al, 1991; Andersson et al, 1992; Burnett et al, 1992; Rajfer et al, 1992; Burnett et al, 1993, 1995) and is a vasodilator produced by endothelial cells (Sanez de Tezada et al, 1989; Knispel et al, 1991). NO is an epithelial-derived factor (Burnett et al, 1995). It has been implicated in regional blood flow (Heaton et al, 1990; Holmquist et al, 1991; Burnett et al, 1992; Trigo-Rocha et al, 1993; Finberg et al, 1993), smooth-muscle function (Sanez de Tezada et al, 1989; Ignarro et al, 1990; Holmquist et al, 1991; Kim et al, 1991; Pickard et al, 1991; Burnett et al, 1992, 1993; Finberg et al, 1993; Trigo-Rocha et al, 1993; Burnett et al, 1995), and secretory responses in genitourinary tissues (Burnett et al, 1995). NO is derived from the amino acid L-arginine via the L-arginine-NO pathway (Palmer et al, 1987). The synthesis of NO from L-arginine is catalyzed by the enzyme NOS (Palmer et al, 1988). In mammalian cells, L-arginine is used as a substrate by both NOS and arginase. In patients with uremia, arginine transport into the cell is inhibited, which could be a factor in ED in uremic patients (Xiao et al, 2001). Thus, arginase may down regulate NO production by competing with NOS for L-arginine (Bivalacqua et al, 2001). Arginase catalyzes the hydrolysis of L-arginine to form L-ornithine and urea, thus limiting the availability of L-arginine to form NO (Mori and Gotoh, 2000). Specifically, the L-arginine-NO pathway has been shown to play a significant role in mediating smooth-muscle relaxation of several nongenitourinary tissues (Calignano et al, 1992; Shuttleworth et al, 1993; Thirlby et al, 1993). NO is the principal mediator of penile erection (Burnett et al, 1992). Erectile function is dependent on relaxation of the cavernous smooth muscle, and its mechanism of action is dependent on penile smooth-muscle relaxation mediated by NO. Immunohistochemical localization of NOS activity in the penile tissue provides confirmatory evidence that NO activity is important in erectile function (Burnett et al, 1992, 1993). NO is synthesized by NOS. NO is a postganglionic neurotransmitter released from autonomic nerve terminals that diffuses into the vascular and cavernosal smooth muscle. In smooth muscle, NO activates guanyl cyclase and the increases cyclic guanosine monophosphate (cGMP) concentration. cGMP activates certain intracellular protein kinases that phosphorylate receptor proteins. Activated protein kinases open the potassium channels and increase the influx of potassium (Seftel et al, 1996) and block the influx of calcium by inhibiting calcium channels (Figure 1). This leads to hyperpolarization and relaxation of smooth muscle. Reduced arteriolar resistance leads to sinusoidal spaces filled with blood. These enlarged sinusoids further increase the intracavernosal by the and a cGMP is to by which is by mechanism of normal oxide (NO) is synthesized from the endothelial cells by the enzyme NO It diffuses into the smooth and guanyl increase in the cyclic (cGMP) the release of protein This causes the potassium channels to open and the calcium channels to hyperpolarization smooth-muscle endothelial guanosine nNOS, neuronal The of and the for ED. has the of for any form of ED. These to increase the NO by the of For a certain of the not to may be by NO to endothelial The precise pathophysiological mechanism of ED is still unclear. However, production of NO or the of NO may play a major Production when the availability of substrate for NOS is NO is a highly reactive that with the of or that with such as to form and This the of oxidative stress in ED. Oxidative stress occurs when cells are to levels of reactive oxygen species as a of an imbalance between pro-oxidants and the mechanisms by antioxidants et al, 2000). are formed to the of oxygen is the most important among the acid and are other important implicated in the pathophysiological mechanism of vascular The vascular endothelium is the major source for these and are the other important of and are because of oxygen in the transport such as are the major source of in cells and have reported that regulation of these is associated with an risk of vascular disease et al, et al, 2001). is an important enzyme that the from the There are of and plays a role in maintaining the of vascular and the pathophysiological effects of in the to The interaction between NO and is one of the important mechanisms implicated in the pathophysiological of ED et al, 2002). NO with to form which has been reported to play a central role in and with the of which and leads to of et al, 1997). This further increases the of and the available NO concentration. causes smooth-muscle relaxation and is than NO. et al the of NO and on cavernosal tissue from reported that relaxation by NO is and in with that to which is and in the tissues to with NO, with the tissues to their These mechanisms an relaxation in cavernosal which ED. and have been reported to increase the incidence of in the endothelium. This leads to of endothelium and further of available NO and et al, 2001). is reported to have a of calcium and This can ED. According to the the availability of NO is the pathophysiological that leads to ED et al, 2000). NO is reported to the of and to the vascular endothelial cells (Figure NO the of these cells to the endothelium and and that cause These further ED. The by et al the of oxidative stress in the endothelium and in ED and has a of This also has lead many to the role of antioxidants in oxidative between reactive oxygen species and erectile dysfunction, on the that stimulate form and endothelial smooth-muscle and increases to endothelium. dysfunction and of nitric oxide (NO) leads to erectile In to the production of NO has also been implicated as a possible cause of cavernosal NO can be in the corpora especially in inflammatory such as penile and This increases the of to effects on cavernosal et al, In vitro studies that cavernosal to high of NO and synthesis et al, 2001). the cavernosal smooth tissue is to high levels of NO in vivo to effects is unclear. These studies that to increase NO can of oxidative stress reported to have a more on cavernosal smooth than high which cell et al, production of and the NO available for cavernosal The availability of NO in disease and endothelial are the 2 most important causes of ED. is important in the Oxidative to the to oxidative by plays a role in the et al, 1993; et al, 1995). The prevalence and severity of ED increase with The Massachusetts Male Aging reported that 52% of men between the ages of 40 and 70 years have some form of This study also that is the most important factor associated with ED (Feldman et al, 1994). Aging is to endothelial cell function, and the in erectile function has been to in NOS impaired smooth-muscle and NO et al, et al, et al, The of is multifactorial in and dependent on several factors, including not to and conditions 1999), suggesting that is an risk the initiating the is to smooth-muscle cells and an increase in the of which the vasodilator response. This of with has been in both and corporal smooth et al, The increase in leads to a in blood flow as by There is interest among researchers to cavernosal by of various Although there is evidence the role of vasodilator in oxidative tissue is an important factor in initiating oxidative be a factor in oxidative stress and These the effects of in patients ED for The patients to of the 50 of 2 of on and not a a of patients with normal erectile function and The that ED in the by penile blood Aging not increases the prevalence of ED also increases the Although the development of ED is multifactorial in it is associated with vascular and risk factors, such as hypertension, diabetes mellitus, and (Feldman et al, et al, et al, 2000). studies that hypertension, and are known risk factors for ED et al, et al, et al, 2001). The risk of ED also to be for patients with et al, 1994). These factors increase the risk of is associated with of NO, which has been to be one of the most important causes of with risk factors, such as hypertension, hypercholesterolemia, and to have a availability of NO, because of of ED is more among men with diabetes than in the Approximately of men with diabetes have ED, which occurs an early and cavernosal smooth-muscle relaxation mediated by endothelial and neuronal mechanisms has been in and animal diabetic de et al, Oxidative neurovascular alteration to play an role in the development of ED in the diabetic NO activity in diabetic was reported in de et al, However, et al reported that in NO levels could be to the of essential for NOS This was further by the that cavernosal smooth-muscle are by of L-arginine substrate for et al, 2000). However, studies involving the and cavernosal that than activity of is the major cause of NO levels and et al, 2000). In a by et al in with the that the intracavernosal NO was in the with diabetes than in the with diabetes The was in diabetic with et al, Furthermore, levels also in diabetic than in These further the between oxidative stress and ED in diabetic patients and evidence that the of diabetes increases the risk of ED. The role of in diabetic is further by the of et al reported that production is in the of with with in diabetic produced a of relaxation than in the and 1992). This was further by the that an the of in These studies that an play a role in cavernosal smooth-muscle other mechanisms have been implicated in diabetic of protein and of is an enzyme that several and levels of this enzyme are associated with production of and levels of NO, which can be by of antioxidants and 2000). NO, and their production is associated with production et al, is the major of implicated in cavernosal dysfunction in diabetic Burnett et al investigated increases the of eNOS in with reported a significant increase in the of eNOS and the of eNOS by and in diabetic with also reported that the in with diabetes a response to This study suggests that a mechanism eNOS function in diabetic (Burnett et al, It is from studies animal that or NO availability in cavernosal smooth muscle, which smooth-muscle levels of amino or are associated with which in endothelial This phenomenon has been implicated in the development of and impaired relaxation of vascular which to disease et al, and and has been to a in cavernosal smooth in animal models. of levels was associated with production of levels and significant in cGMP levels et al, The precise mechanism of in patients with is still unclear. However, this study suggests that oxidative stress may be a cause of ED in patients with is associated with to and cavernosal smooth-muscle relaxation et al, 1994). of levels cavernosal smooth-muscle relaxation et al, 1994). tissue levels are in that for 2 et al, 1997). cavernosal levels in may the availability of NO, which may lead to ED. The of on cavernosal smooth was not in models. However, further studies are essential to the role of in ED and its with oxidative is one of the important risk factors for vascular (Feldman et al, 1994). This vascular is a major cause of ED in However, in the pathway may also play a role in et al, NO has been the vasodilator involved in cavernosal smooth-muscle However, there is some evidence suggesting that alternative such as also have vasodilator et al, and impaired has been implicated in ED. et al reported the role of and NO in ED in cavernosal smooth-muscle relaxation in with that in The and NO-mediated impaired in the and associated with activity of have a blood and levels of is formed from the of on than In a significant is between blood and oxidative stress in et al, 2002). to the role of of reactive oxygen species and in patients with essential to endothelial dysfunction vasodilator activity et al, 2001). These the that ED in may from impaired relaxation by and NO. is also a of chronic et al, and is associated with studies have evidence of oxidative stress in chronic and of et al, 1997). studies have shown that certain of or are associated with oxidative stress et al, et al, et al, et al, et al, 2001). of endothelial NO has been implicated in some of (Huang et al, and et al, of reactive oxygen species et al, levels of levels of catalyzed and levels of have been reported in chronic et al, 2002). increase in the is one of the factors for an increase in blood and for of levels have also been reported to be associated with oxidative stress and These effects could be mediated by a in the of NO, along with the of and and and NO in has been shown to be in to oxidative stress et al, production in both the and the has been extensively reported in various of in and in et al, 1992; et al, et al, et al, is one of the most prevalent significant of the has ED. It is essential to the to the incidence ED in this The role of antioxidants in the prevalence of ED to be established in further the by oxygen can be or and antioxidants and and are the of antioxidants that The role of in has been extensively investigated in animal in the of is an important that et al, 1991). It more than with Thus, it is known as a It has been shown to endothelial function by In vivo studies that improved NO-mediated et al evaluated the role of in the of in the diabetic and reported that This study the role of in reactive oxygen species. studies that and release et al, and and by a protein mechanism et al, et al, This protein mechanism has been used to vascular dysfunction in patients with diabetes in vivo and in vitro evidence that the of a can protein and endothelial The of has been one of the major advances in the of ED. has the for of ED. of these are used as in the of ED. However, are in of the and in of the diabetic et al, The precise for this of response are many that in the NO may be a levels of NO may be the of of such as levels of NO, increase penile blood with the potential for a when with a This was in an animal et al, In this male with diabetes into the 2 of of and of and of The for Erectile function was as an increase in an of significant increase in was in the with and Immunohistochemical of the cavernosal tissue an increase in the nNOS endothelial cell and smooth-muscle cell the therapeutic of the in the animal of This study suggests a potential of erectile function for patients are to In the reported of a of cavernosal between diabetic and et al, with diabetes into the 2 of of and of and of These also Penile tissue was evaluated for nNOS smooth-muscle and endothelial cell and and levels a a significant in cavernosal was between the and the combination and in diabetic in the and the significant increase in the was in the of that the therapeutic of the the potential of antioxidants in erectile function in diabetic The of these animal studies to be in with on of can be used in The role of such as acid and in the of cavernosal dysfunction was in vivo in a diabetic et al, has both and of was associated with of and noncholinergic cavernosal relaxation in diabetic animal models. when with produced a of cavernosal relaxation and noncholinergic nerve NO-mediated relaxation of smooth muscle, which is to be the organic for and of cavernosal dysfunction by the of reactive oxygen species and suggests a potential therapeutic However, the role of these antioxidants to be further in both animal and can be used in the of interest in ED has to NO that increase NO synthesis in the cavernosal et al investigated the effects of to a of NO on of and cavernosa. reported that guanyl cyclase activity and in smooth-muscle relaxation in both and cavernosal et al, et al reported that a the relaxation of cavernosal smooth by the of NO. These 2 may be for patients with impaired NO release from the endothelium. However, the of these to be in is the reactive oxygen species involved in the pathophysiological mechanism of ED. plays an important role in is one of the most important implicated in the pathophysiological mechanism of vascular dysfunction in hypertension, atherosclerosis, and diabetes It a major and the is to play a role in the of the vascular the pathophysiological effects of in the The of gene involving some of penile erection to erectile response in animal has for gene in the of erection et al, et al, have used an as a for the gene encoding eNOS to the gene can be in the to erectile also reported that that the the eNOS to the and that the gene encoding eNOS was in intracavernosal in response to and nerve in These important for the functional of eNOS in the regulation of erectile function, and that in vivo of the gene encoding eNOS could a therapeutic for the of ED. This of gene is for strategies involving possible factors associated with penile There is a growing interest in gene of (Bivalacqua et al, et al with the gene encoding This in expression of and cyclic guanosine monophosphate In their in vivo et al that with in a significant increase in erectile response to cavernosal nerve The to be more in that cavernosal dysfunction associated with is in to an increase in This study the of a in restoring erectile function. as an important therapeutic in the of ED, especially in the However, the and of these to be in The between reactive oxygen species and ED was derived from in vitro studies animal It is difficult to from these as the are not in the of various to which the tissues are may not be to that in This for studies the role of It is difficult to the of the that to be in to et al, It is not possible to the NO because of its which that we on such as the of cavernosal smooth-muscle This has further the of the of such However, these studies have the role of oxidative stress in ED and have a to the until on the of Normal penile erection is dependent on the of the endothelium. NO plays an important role in the physiological mechanism of in the of NO, to to endothelium or to to be the most important causes for ED, especially in the of vascular In vitro studies showed that production of reactive oxygen species is associated with normal erectile because of NO production of reactive oxygen species in such as diabetes and be an important cause of an risk of ED. strategies and interventions are needed to and treat endothelial The the for and for