Abstract 651: Toll-like Receptor 4 (TLR4) Suppresses Nitric Oxide Contributing To AngiotensinII-induced Cavernosal Dysfunction.
AngiotensinII (AngII) is an important regulator of erectile dysfunction (ED), a vascular condition which has been described as an early marker for cardiovascular diseases. Recent evidence shows AngII modulates the expression of TLR4, resulting in augmented tumor necrosis factor α (TNF-α) cytokine associated to ED and nitric oxide synthase (NOS) suppression, effects that directly impact the vasculature. We investigate whether TLR4 plays a role in cavernosal dysfunction caused by AngII. Mice were infused with AngII (90ng/min, 28 days) in the presence or absence of anti-TLR4 antibody (0.1 mg/daily, i.p.) for the last 14 days. After blood pressure evaluation, corpus cavernosum (CC) tissue was used for functional studies and western blot. NOS activity was measured by conversion of [3H]-L-arginine to [3H]-L-citrulline and systemic TNF-α levels by ELISA. In AngII-infused mice increased adrenergic CC contraction was attenuated by blocking TLR4 (28±2.1%), which also ameliorated nitrergic (68.90±0.21 vs. 51.07±0.63, 8Hz) and endothelium-dependent relaxation (4.90±0.13 vs 2.45±0.19, AngII-infused mice treated vs. non-treated). Reduced NOS activity, augmented systemic levels of TNF-α and this cytokine overexpression were found in CC following AngII-infusion. However, these alterations were prevented by blocking TLR4, suggesting that inhibition of TLR4 ameliorates AngII-impaired cavernosal relaxation and restores NO availability, which is vital for normal penile erection and vascular function. Our data provides new insights into understanding the mechanisms leading to hypertension-associated ED.
Author Disclosures: K. Nunes: None. G. Bomfim: None. M. Carrilo-Sepulveda: None. T. Szasz: None. R. Webb: None.
- © 2014 by American Heart Association, Inc.