NADPH Oxidase as a Mechanistic Link Between Erectile Dysfunction, Peripheral, and Coronary Endothelial Dysfunction in Obesity

Abstract

Cardiovascular complications involving both microvascular and macrovascular tissues are the major cause of morbidity and mortality in obese patients. Clinical and epidemiological studies suggest that erectile dysfunction and peripheral endothelial dysfunction may predict cardiovascular risk. The purpose of these studies was to investigate NADPH oxidase, a major source of vascular derived oxidative stress, as a common mechanism between erectile dysfunction and coronary artery endothelial dysfunction in rats fed a Western diet (WD), and peripheral endothelial dysfunction in an obese group of human subjects. Male Sprague-Dawley rats were fed a control diet (CD) or WD for 4, 8, or 12 weeks. Erectile function was evaluated by measuring intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve. Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of (ACh) applied to pre-constricted segments of the left anterior descending coronary artery. Erectile function was significantly attenuated following 8-weeks (P < 0.05) and 12-weeks (P < 0.05) of the WD, whereas CAEF was significantly attenuated following 12-weeks of the WD (P < 0.01). Larger groups of rats were then fed the CD or WD for 12 weeks, and erectile function and CAEF were evaluated following intracavernosal injection or vessel incubation with apocynin, an NADPH oxidase inhibitor. Apocynin improved erectile function (P < 0.01) and CAEF (P < 0.05) in WD, and had no effect on CD rats. Sedentary, young adults were recruited across a body mass index (BMI) range of 18-40, and split into BMI tertiles. Microdialysis probes were inserted into the vastus lateralis, and in vivo reactive oxygen species (ROS) production was measured, and microvascular endothelial function was assessed via local ACh-stimulated blood flow. ROS production (P < 0.05) was elevated and ACh-stimulated blood flow (P < 0.05) was attenuated in the highest BMI tertile compared to both other tertiles. Apocynin had a greater effect of attenuating ROS production (P < 0.05) and augmenting ACh-stimulated blood flow (P < 0.05) in the highest compared to lowest BMI tertile. These studies suggest that NADPH oxidase contributes to obesity associated erectile dysfunction, peripheral endothelial dysfunction, and coronary artery disease development.