Oxidative Stress And Antioxidant Therapy In Arteriogenic Erectile Dysfunction

Erectile dysfunction (ED) is defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Penile erection is a neurovascular phenomenon that requires dilation of penile vasculature, relaxation of smooth muscle, increased intracavernosal blood flow and normal veno-occlusive function. Most cases of erectile dysfunction are associated with oxidative stress risk factors such as diabetes mellitus, smoking, hypercholesterolaemia, atherosclerosis and hypertension. Vasculogenic ED consists of arteriogenic ED (cavernosal artery insufficiency) and veno-occlusive ED, which always coexist in the same patient. Arteriogenic ED results from haemodynamic impairment and chronic exposure of erectile tissue to ischemia and hypoxia, nutrient deficiency and a lack of metabolic waste clearance. These conditions are known to involve oxidative stress caused by dysfunction of antioxidant enzymes and excessive production of free radicals. Accumulation of these radicals results in lipid peroxidation, protein oxidation, DNA oxidation, decreased synthesis and bioavailability of endothelial and neuronal NO and upregulation of proinflammatory cytokines, growth factors and tissue-specific receptors. In the penis, endothelial cell injury and subsequent atherosclerosis and narrowing of the hypogastric-pudendal arterial bed result in diminished perfusion pressure, decreased arterial inflow to the lacunar spaces of the penile corpora cavernosa and lack of metabolic waste clearance. The clinical consequences of these changes are progressive prolongation of the time to achieve full erection, lowered rigidity of the erect penis and ultimately erectile failure. This initiates free radical accumulation and incursion of endothelial cells leading to smooth muscle dysfunction and erectile tissue fibrosis.An extensive, highly effective group of protective agents and defence mechanisms referred to collectively as the antioxidant defence system, acts to regulate oxidative reactions. The antioxidant defence system includes both enzymes and antioxidants to prevent the start of oxidative damage and control its spread. There are also enzymes to repair oxidative damage, and mechanisms to target damaged molecules for destruction and replacement. Essential antioxidants are either endogenous or exogenous. They are typically categorized as scavenger antioxidants and preventive antioxidants. Antioxidants such as vitamins E and C have been used widely in clinical practice to protect the body from harmful free radicals. Other families of antioxidants with a more potent free radical scavenging capacity, such as polyphenols, were shown to prevent cardiovascular oxidative injury. Consumption of dietary antioxidants with potent free radical scavenging capacities might also be effective in protecting the cardiovascular system.Our goal was to seek markers of oxidative stress in arteriogenic ED and examine the protective role of dietary antioxidants. Atherosclerosis-induced ED was developed in rabbits by balloon de-endothelialization of the iliac arteries. Ballooned and age-matched control animals were assigned into subgroups receiving pomegranate extract antioxidants in drinking water or tap water as placebo. After 8 weeks, penile blood flow and erectile activity were recorded. Erectile tissue relaxation, oxidative products, tissue structure and ultrastructural were examined using organ bath, enzyme immunoassay and transmission electron microscopy, respectively. Arterial ballooning caused diffused atherosclerosis, decreased intracavernosal blood flow and led to ED. Impairment of endothelium-dependent relaxation, diffused fibrosis, increased oxidative products, mitochondrial and endothelial structural damage and increased caveolae were evident in erectile tissues from atherosclerotic animals receiving placebo. Pomegranate extract antioxidant significantly improved intracavernosal blood flow, erectile activity, smooth muscle relaxation and fibrosis of the atherosclerotic group in comparison with the atherosclerotic group receiving placebo, but did not normalize them to the age-matched control levels. Pomegranate extract antioxidant appeared more effective in diminishing oxidative products, protecting mitochondrial, endothelial and caveolae structural integrity of the atherosclerotic group. Our data suggest the presence of oxidative stress in ED and a more efficient action of antioxidants on cellular, molecular and ultrastructural alterations than on distinct functional deficit and structural damage in the ischemic penis. Long-term consumption of dietary antioxidants may remove oxidative products and improve erectile function, possibly by protecting NO bioavailability and preserving endothelial and mitochondrial structural integrity. Therapies targeting free radical generation and basic mitochondrial processes may lead to newer strategies against smooth muscle dysfunction and erectile tissue fibrosis in arteriogenic ED.