Targeting Nadph Oxidase 281011 PDE5 Inhibitors

PDE5 inhibitors, e.g., sildenafil citrate, tadalafil, vardenafil hydrochloride, promote penile erection in response to sexual stimulation by inhibiting PDE5-catalyzed degradation of cGMP. They are widely accepted as an efficacious option for the treatment of ED in most, but not all, cases [6]. Recently, interest has been generated in the additional effects of PDE5 inhibitors on preventing formation of ROS and inhibition of ROS-mediated PDE5 upregulation in the penis.

Several animal studies have demonstrated the beneficial effect of PDE5 inhibitors on reducing oxidative stress in the penis. Sildenafil citrate was found to decrease superoxide production in the penis of a mouse model of secondhand smoke-induced ED [91]. Sildenafil also decreases oxidative stress in rabbit penile vascular smooth muscle after exposure to several ROS-inducing agents such as nicotine [87], TNFa [87]. combination of homocysteine and copper [129], and vasoconstrictor thromboxane A2 mimetic [130]. This effect of sildenafil is apparently due to the inhibition of NADPH oxidase through the reduction in protein expression of its subunit p47phox [130]. Tadalafil also exerts a beneficial acute effect on the cardiovascular system by reducing serum levels of oxidative stress [131] in patients with ED. A vasorelaxant agent given in combination with PDE5 inhibitors proved more beneficial in reducing oxidative stress in the penis and improving penile erection compared to PDE5 inhibitors alone [77, 132]. In cavernosal tissue from hypercholesterolemic rabbits, sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil, inhibits NADPH-dependent superoxide formation in a more efficient way than sildenafil citrate [77]. This effect may be due to antioxidant properties of exogenous NO [133-136]. In addition to NO donors, a hydrogen sulfide-donating derivative of sildenafil, ACS6, also inhibits superoxide formation in cavernosal tissue from hypercholesterolemic rabbits [132] by inhibition of the p47phox subunit of NADPH oxidase and activation of PKA and PKG pathways.

An additional beneficial effect of PDE5 inhibitors in the penis is to prevent upreg-ulation of PDE5 by oxidative stress, which would further contribute to ED by depleting cGMP levels. Oxidative stress has been shown to increase PDE5 expression and activity in the vasculature [137], including that of the penis [87, 129, 138]. Animal studies demonstrated that, in response to increased oxidative stress, sildenafil prevents PDE5 upregulation by inhibition of NADPH oxidase [87, 129, 132]. It was therefore proposed that the therapeutic benefit of PDE5 inhibitors might be mediated, in part, through inhibition of NADPH oxidase-derived oxidative stress and inhibition of PDE5 upregulation, both of which impair normal erectile function. Angiotensin-Converting Enzyme Inhibitors and ATj Receptor Antagonists

Angiotensin II promotes endothelial dysfunction by inducing oxidative stress through activation of NADPH oxidase via AT j receptor [67]. ACE inhibitors and AT1 receptor antagonists decrease oxidative stress by preventing the activation of NADPH oxidase and enhancing clearance of ROS [139-141]. Indeed, some (but not all) clinical trials have demonstrated that blocking angiotensin II signaling improves endothelial function in patients with hypertension and metabolic syndrome, and reduces the incidence of death, myocardial infarction, and stroke [22, 142].

Several studies have demonstrated the beneficial effects of antihypertensive treatment with ACE inhibitors or AT , receptor antagonists on erectile function in men and animals with ED [143-149]. ATt receptor antagonists irbesartan and losar-tan decrease ROS production and increase NO production in the penis of hypercho-lesterolemic mice ] 78] and aged rats [147] independent from a blood pressure lowering effect. These limited data imply that an underlying mechanism for the beneficial effects of inhibition of the renin-angiotensin system on erectile function may be through prevention of ROS generation. Statins (3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors)

Beneficial pleiotropic effects of statins are due to the improvement of endothelial function at least in part by reducing oxidative stress and improving eNOS function independent from their cholesterol-lowering effect. Statins upregulate antioxi-dants SOD3 and catalase [150, 151] and inhibit endothelial superoxide formation. The latter effect is due to the inhibition of NADPH oxidase ] 152] and eNOS uncoupling [153],

Basic science studies demonstrate that several statins, such as rosuvastatin and atorvastatin, improve diabetes- [154, 155], metabolic syndrome- [156], and hypertension- [157] related ED and increase the responsiveness to sildenafil by inhibiting RhoA/ROCK signaling in the penis. A limited number of clinical studies which evaluated the effect of statin therapy in men with ED have produced mixed results. Some [158-162], but not all [163, 164], studies demonstrated a beneficial effect of atorvastatin on erectile function in men with and without concomitant sildenafil treatment. It remains to be determined whether this effect of statins is due to a reduction in cholesterol levels or non-lipid-lowering actions. The role of statins in preventing oxidative stress in the diseased penis has not been investigated. Future basic science and clinical studies are warranted to determine whether statins may improve erectile function by decreasing oxidative stress and improving endothelial function in the penis and define the underlying mechanism for this effect.

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