Erectile dysfunction is a common, multifactorial condition that has been associated to aging and a range of biological and psychological diseases, including depression, hypertension, diabetes mellitus, hypercholesterolemia, and cardiovascular disease. Penile erection is a complex process that involves neurovascular nonadrenergic, noncholinergic, hormonal, and psychogenic input. Nitric oxide (NO) is regarded to be the major vasoactive nonadrenergic, noncholinergic neurotransmitter and chemical mediator of penile erection. Endothelial and nerve cells in the corpora cavernosa of the penis emit NO. This NO activation raises 3′,5′-cyclic guanosine monophosphate (cGMP) levels. As a second messenger molecule, cGMP regulates intracellular contractile proteins and calcium channel activity, which influences smooth muscle relaxation in the corpus cavernosum. Impaired NO bioactivity is a major pathologic cause of erectile dysfunction. To treat erectile dysfunction, a combination of psychogenic and pharmacological therapy, many of which have previously had only poor success rates, is commonly required.
Erectile dysfunction (ED), a serious public health issue, is a common and complex ailment that has a significant negative impact on quality of life. 1, 3 ED, defined as the inability to obtain and maintain a sufficient erection for satisfying sexual interaction, is associated with aging, a growing number of systemic diseases such as hypertension, diabetes mellitus, cardiovascular disease (CVD), hypercholesterolemia, and depression, as well as lifestyle factors such as smoking, alcoholism, and drug abuse. 2 and 4 Evidence suggests that ED may be a general signal for concealed CVD as well as an indicator of overall physical and mental well-being. 3 , 5 , 6
Estimates of the prevalence of chronic ED in the United States have varied, owing in part to the use of different methodology and populations in epidemiologic research. 7 According to a global survey 8 of 9284 American men aged 20 to 75, the prevalence of ED was 22% in 2001, equating to about 20 million men. According to the Massachusetts Male Aging Study 9 conducted in Boston between 1987 and 1989, the cumulative incidence of minimum, moderate, and complete ED in males aged 40 to 70 was 52%, with the frequency of complete impotence increasing from 5% to 15% between those ages. In a larger research of more than 31,000 US health care professionals aged 53 to 90 years, the age-standardized prevalence of ED was found to be 33% using conservative criteria of poor to very poor function, ranging from roughly 25% in those under the age of 59 to 61% in those over the age of 70. 7 Overall, the prevalence of mild ED in adult males in the United States appears to be around 20%, rising to 30%-50% in those aged 40 to 70, and exceeding 60% in those over 70. More than 23 million men have obtained prescriptions for sildenafil citrate since its launch in 1998, reflecting the epidemiologic scope of this condition. 10
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The amazing intricacy of penile erection is primarily mediated by peripheral neurovascular, nonadrenergic, noncholinergic (NANC), and central nervous system pathways. The erectile response is mediated by androgens and psychosocial factors and can be induced by psychogenic or reflexogenic brain pathways (2, 15). Sympathetic responses govern detumescence by releasing norepinephrine, which induces smooth muscle constriction, vasoconstriction, and penile flaccidity (2, 15). 16,17 A penile erection occurs when penile blood flow exceeds penile blood flow outflow, and detumescence is both inhibited and stimulated. 16 , 17
The medial preoptic portion of the hypothalamus's paraventricular and supraoptic nuclei process external sexual input from the five senses and mental imaginations to generate psychogenic erections. 16,18 The hypothalamus responds by releasing a number of amines and neuropeptides that stimulate erections, including as substance P, gonadotropin-releasing hormone, oxytocin, and melanocyte-stimulating hormone. 16 These neurohormones' subsequent projects, which inhibit and encourage penile erection, are sent to the thoracolumbar sympathetic nerve fibers in the T11-L2 area and the sacral S2-S4 parasympathetic nerve fibers. 16
To activate the sacral parasympathetic nerves, the pelvic plexus, which is made up of two parallel columns of erectile tissue in the penis, as well as the cavernous nerves of the corpora cavernosa, are employed. 2 , 16 The cholinergic and NANC nerve fibers of the corpora cavernosa cause a multifold increase in blood flow to the corpora cavernosa as well as sinusoidal expansion. These nerve fibers then release vasoactive neurotransmitters like acetylcholine and NO. 16,18 Penile tumescence compresses the emissary veins in the tunica albuginea, a sheath-like tissue enveloping the corpora cavernosa; this compression hinders venous outflow, retaining the blood and causing rigidity. 2 Sexual action activates the bulbocavernosus reflex, which causes the ischiocavernous muscles to forcefully compress the base of the perfused corpora cavernosa, resulting in extra or full stiffness. 2
Erection Physiology: NO
NO is assumed to be the major vasoactive NANC neurotransmitter for erectile function in the corpora cavernosa. 2 , 4 , 15 The enzyme NO synthase (NOS), which catalyzes NO from the conversion of L-arginine to L-citrulline, has been localized to neural tissue, endothelium, and epithelium in the pelvic and urogenital tissues of humans and other animal species. 20 , 21 The autonomic NANC dilator nerve fibers that supply the corpora cavernosa and the vascular and sinusoidal endothelium trigger the erectile response by releasing NO. 2 Increased blood flow shear pressures lead the endothelium to release more NO. 22 Soluble guanylate cyclase (sGC), which is triggered by NO as it diffuses through the smooth muscle membrane, then catalyzes the creation of 3′,5′-cyclic guanosine monophosphate (cGMP).
The increased cGMP induces a protein kinase to phosphorylate specific proteins and ion channels, opening potassium channels and hyperpolarizing the muscle cell membrane. 2, 15 The endoplasmic reticulum sequesters intracellular calcium and blocks calcium channels and calcium influx, lowering cytosolic calcium levels, relaxing vascular smooth muscle, and dilating blood vessels. Although these roles have not been completely investigated, neuronal NO may also play a part in the neurotransmission of erectile cues from the brain to the spinal cord. 13 NO has been demonstrated to have erectile effects in both human penile tissue samples and a number of in vitro and in vivo animal tests. 23 , 24 , 25 , 26
a component of NOS Isoforms
Two of the three known NOS isoforms, neuronal NOS and endothelial NOS (eNOS), are constitutively present in the corpora cavernosa, albeit to varying degrees and in different cell types. 4 Although it is expressed in the brain's paraventricular nucleus, where it may interact with erectile response neurohormones such as oxytocin, and in the spinal cord, where the mechanisms of NO in erectile function are unknown, neuronal NOS is primarily localized to NANC cells of corpora cavernosa nerve fibers. 13 There is some dispute regarding whether eNOS can be found in cavernosal smooth muscle, but it is mostly located in the endothelium of the vasculature of the penis. 4 , 13 , 15 , 27 Inducible NOS has been detected in the corpora cavernosa, most likely in smooth muscle cells, in association with inflammatory effects or other pathologic abnormalities of the penis. 15 , 28
Neuronal NO is assumed to be the key element in promoting corpora cavernosa relaxation and activating increased blood flow to generate penile erection in comparison to the other NOS isoforms. 15 , 29 However, accumulating evidence suggests that endothelial NO is critical for achieving and maintaining a full erection, whereas neuronal NO favors initial cavernosal relaxation. 22 , 30 Intracavernosal delivery of an adenovirus expressing the eNOS gene to aged or diabetic rats with ED dramatically enhanced erectile function as determined by intracavernous pressure in response to cavernous nerve stimulation, demonstrating the physiological effects of eNOS in erectile function. 31 , 32 Intracavernosal administration of vascular endothelial growth factor, which promotes endothelial cell proliferation and migration in vitro and angiogenesis in vivo, has also been shown to restore erectile function and endothelium-dependent smooth muscle relaxation in rat and rabbit models of ED. 33 , 34 , 35 , 36
Modulators of NOS
Testosterone, whose active metabolite appears to be dihydrotestosterone, appears to modulate NO-mediated cavernosal relaxation in erection physiology in part, according to rat research. 37 , 38 Electrical field stimulation of the cavernous nerve resulted in a 50% reduction in erectile response in rats. 37 Giving castrated rats testosterone and dihydrotestosterone, on the other hand, has been shown to restore the erectile response and intracavernosal pressure mediated by NO. 37 , 38 However, it is unclear how androgens influence cavernosal NOS activity in humans. 39 Furthermore, experimental evidence suggests that NO-mediated relaxation of the corpora cavernosa is linked to physiological oxygen levels and that it might be diminished in hypoxic situations. 40 , 41
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ED is often classified as psychogenic, organic, or mixed, which is congruent with the complex physiology of penile erection, and can be caused by one or more of a number of psychologic, neurologic, vasculogenic, hormonal, or pharmaceutical factors (Table I). ED is frequently caused by both psychological and physiologic factors (2, 13). 4 After controlling for age, epidemiologic studies show that ED is associated with lower urinary tract symptoms, anger, depression, and fewer years of education, as well as CVD, hypertension, diabetes mellitus and associated medications, hypercholesterolemia, metabolic syndrome, obesity, and smoking. 8 , 9 , 42 , 43 , 44 , 45 , 46 Neurologic diseases such as Parkinson's disease are also recognized as causes of ED (Table I). 2 An examination of data from a managed-care claims database in the United States revealed that 68% of all ED patients (N=272,325) had one or more of the following four comorbidities: hypertension, hyperlipidemia, diabetes mellitus, or depression. 47
CONCLUSIONS
NO is an important regulator of erectile function, and ED is associated with decreased NO bioactivity. Organic and psychogenic therapy are widely used in the treatment of ED. PDE5 inhibitors are the primary first-line oral treatment for ED; they inhibit an enzyme that degrades cGMP and have been demonstrated to be quite effective and well tolerated in the majority of people with ED, regardless of the etiology. These drugs, however, are dependent on sufficient NO-stimulated cGMP production, which is reduced by severe underlying illnesses such as CHD or diabetes mellitus. Some people may require further ED medications, possibly in addition to a PDE5 inhibitor. NO donors, which promote NO-dependent relaxation of cavernosal smooth muscle, and sGC activators, which work through a NO-independent mechanism, are two possible therapies.
a component of NOS Isoforms
Two of the three known NOS isoforms, neuronal NOS and endothelial NOS (eNOS), are constitutively present in the corpora cavernosa, albeit to varying degrees and in different cell types. 4 Although it is expressed in the brain's paraventricular nucleus, where it may interact with erectile response neurohormones such as oxytocin, and in the spinal cord, where the mechanisms of NO in erectile function are unknown, neuronal NOS is primarily localized to NANC cells of corpora cavernosa nerve fibers. 13 There is some dispute regarding whether eNOS can be found in cavernosal smooth muscle, but it is mostly located in the endothelium of the vasculature of the penis. 4 , 13 , 15 , 27 Inducible NOS has been detected in the corpora cavernosa, most likely in smooth muscle cells, in association with inflammatory effects or other pathologic abnormalities of the penis. 15 , 28
Neuronal NO is assumed to be the key element in promoting corpora cavernosa relaxation and activating increased blood flow to generate penile erection in comparison to the other NOS isoforms. 15 , 29 However, accumulating evidence suggests that endothelial NO is critical for achieving and maintaining a full erection, whereas neuronal NO favors initial cavernosal relaxation. 22 , 30 Intracavernosal delivery of an adenovirus expressing the eNOS gene to aged or diabetic rats with ED dramatically enhanced erectile function as determined by intracavernous pressure in response to cavernous nerve stimulation, demonstrating the physiological effects of eNOS in erectile function. 31 , 32 Intracavernosal administration of vascular endothelial growth factor, which promotes endothelial cell proliferation and migration in vitro and angiogenesis in vivo, has also been shown to restore erectile function and endothelium-dependent smooth muscle relaxation in rat and rabbit models of ED. 33 , 34 , 35 , 36
Modulators of NOS
Testosterone, whose active metabolite appears to be dihydrotestosterone, appears to modulate NO-mediated cavernosal relaxation in erection physiology in part, according to rat research. 37 , 38 Electrical field stimulation of the cavernous nerve resulted in a 50% reduction in erectile response in rats. 37 Giving castrated rats testosterone and dihydrotestosterone, on the other hand, has been shown to restore the erectile response and intracavernosal pressure mediated by NO. 37 , 38 However, it is unclear how androgens influence cavernosal NOS activity in humans. 39 Furthermore, experimental evidence suggests that NO-mediated relaxation of the corpora cavernosa is linked to physiological oxygen levels and that it might be diminished in hypoxic situations. 40 , 41
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ED is often classified as psychogenic, organic, or mixed, which is congruent with the complex physiology of penile erection, and can be caused by one or more of a number of psychologic, neurologic, vasculogenic, hormonal, or pharmaceutical factors (Table I). ED is frequently caused by both psychological and physiologic factors (2, 13). 4 After controlling for age, epidemiologic studies show that ED is associated with lower urinary tract symptoms, anger, depression, and fewer years of education, as well as CVD, hypertension, diabetes mellitus and associated medications, hypercholesterolemia, metabolic syndrome, obesity, and smoking. 8 , 9 , 42 , 43 , 44 , 45 , 46 Neurologic diseases such as Parkinson's disease are also recognized as causes of ED (Table I). 2 An examination of data from a managed-care claims database in the United States revealed that 68% of all ED patients (N=272,325) had one or more of the following four comorbidities: hypertension, hyperlipidemia, diabetes mellitus, or depression. 47
CONCLUSIONS
NO is an important regulator of erectile function, and ED is associated with decreased NO bioactivity. Organic and psychogenic therapy are widely used in the treatment of ED. PDE5 inhibitors are the primary first-line oral treatment for ED; they inhibit an enzyme that degrades cGMP and have been demonstrated to be quite effective and well tolerated in the majority of people with ED, regardless of the etiology. These drugs, however, are dependent on sufficient NO-stimulated cGMP production, which is reduced by severe underlying illnesses such as CHD or diabetes mellitus. Some people may require further ED medications, possibly in addition to a PDE5 inhibitor. NO donors, which promote NO-dependent relaxation of cavernosal smooth muscle, and sGC activators, which work through a NO-independent mechanism, are two possible therapies.