(530) NADPH Oxidase Inhibition Relieves Cavernosal Dysfunction Related to Aging and Insulin Resistance in Rats

Abstract Introduction Aging is a main risk factor for erectile dysfunction (ED), which is also more prevalent when metabolic alterations such as insulin resistance (IR) are present. In turn, IR is related to unhealthy lifestyle and aging populations Objective Our aim was to evaluate the impacts of aging and IR on endothelial and neurogenic relaxations of corpus cavernosum in rats and to determine the role of NADPH oxidase inhibition in reducing such impacts Methods Fructose (20% w/v) was administered in drinking water for 8-weeks to young 6 weeks-old (3M-IR, n=19) and to aged 18 months-old (20M-IR, n=17) male rats, as a previously validated model to induce IR. Young (3M, n=21) and aged (20M, n=26) control animals were age-matched rats drinking only water. After control or fructose treatments, rats were euthanized and corpus cavernosum strips were obtained. Acetylcholine (ACh) exposure and electrical field stimulation (EFS) application were used to evaluate endothelial and neurogenic relaxations, respectively, in organ chambers. Nitroprusside (SNP)-induced endothelium-independent relaxations were also determined. Protein expressions of endothelial NO synthase (eNOS), NADPH-oxidases 2 (NOX2) and 4 (NOX4) in cavernosal tissues were assessed by immunoblotting Results IR caused a significant impairment of ACh- (area under the curve (AUC) of the relaxation percentages: 325.2±14.7% in 3M vs. 247.0±20.5% in 3M-IR, p0.05) and EFS-induced relaxations (AUC: 213.0±20.6% in 3M vs. 156.9±23.3% in 3M-IR, p0.05) in young rats. Aging significantly impaired endothelial (AUC: 207.6±17.7% in 20M, p0.001; 165.9±24.7% in 20M-IR, p0.001) and neurogenic relaxations (AUC: 108.3±13.0% in 20M, p0.001; 95.6±11.9% in 20M-IR, p0.001) in both control and IR rats. Endothelial impairment in aged rats with IR was significantly deeper than in aged control rats. SNP-induced relaxations were not significantly modified by aging or IR. Significantly lower cavernosal expression of eNOS was detected in both aged groups while NOX2 expression was augmented in 3M-IR (+93.1±68.9%) and 20M (+90.6±48.4%) but only 20M-IR group displayed a significant overexpression of NOX2 (+416.0±137.0%, p0.01). NOX4 expression was only increased in cavernosal tissues from 20M-IR rats but this elevation was not significant (+52.2±30.4%). Exposure to the inhibitor of NOXs, VAS2870 (10 μM) resulted in significantly improved endothelial and neurogenic relaxations in cavernosal tissues from 3M-IR, 20M and 20M-IR but not in those from young control rats (3M) Conclusions IR and aging independently caused cavernosal dysfunction in rats yielding an exacerbated impact in aged animals with IR. NOX2 upregulation seems to contribute to this impairment and NOX inhibition could represent a therapeutic target to relieve cavernosal dysfunction related to aging and metabolic alterations, potentially improving erectile function Disclosure No