NADPH Oxidase Activation: A Mechanism of Hypertension-Associated Erectile Dysfunction

Abstract

Hypertension is a risk factor for erectile dysfunction (ED). The pathophysiologic basis of ED in hypertension remains largely unknown. The goal of this study was to test the hypothesis that increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity contributes to the development of hypertension-associated ED. Male Sprague-Dawley rats were implanted with osmotic pumps containing saline or angiotensin II (Ang II, 70 ng/min) for 28 days and treated with or without the NADPH oxidase inhibitor apocynin (10 mM) in the drinking water. Erectile function was examined by measuring the mean arterial blood pressure (MAP) and intracavernosal pressure (ICP) upon electrical stimulation of the cavernous nerve. Protein expression levels of NADPH oxidase subunits were analyzed by Western blot. Reactive oxygen species production was determined by dihydroethidium (DHE) staining and thiobarbituric acid reactive substances (TBARS) assay. Maximum ICP (MaxICP) and ICP area under the curve, which were normalized by MAP, were significantly reduced in Ang II-infused hypertensive rats compared to that of normotensive rats (P < 0.05). Protein expression of NADPH oxidase subunit p47(phox) was significantly increased by 30% in Ang II-infused hypertensive rat penes along with increased DHE staining and TBARS levels (P < 0.05) when compared to that of controls. There were no significant changes in p67(phox) or gp91(phox) protein expression. Apocynin reduced NADPH oxidase protein expression and TBARS levels as well as improved MaxICP and ICP area under curve in Ang II-infused hypertensive rats (P < 0.05). These data suggest that activation of NADPH oxidase is a molecular mechanism for hypertension-associated ED. Apocynin treatment exerted protective effects on erectile function through inhibition of NADPH oxidase activity, thereby reducing oxidative stress in Ang II-infused hypertensive rats. This is the first study to identify the importance of NADPH oxidase in the regulation of erectile function in vivo.