Resveratrol prevents endothelial nitric oxide synthase uncoupling and attenuates development of hypertension in spontaneously hypertensive rats.

Endothelial dysfunction is a hallmark of hypertension and vascular oxidative stress can contribute to endothelial dysfunction and hypertension development. Resveratrol is an antioxidant polyphenol which improves endothelium dependent relaxation, the mechanisms of which are unknown. Also, the role of resveratrol in hypertension remains to be established. The purpose of this study was to investigate the mechanisms of resveratrol induced improvement of endothelial function and establish its role in hypertension. SHR and WKY rats, 3-4 weeks old, were treated with resveratrol in drinking water for 10 weeks, untreated SHR and WKY rats served as controls. At the end of the treatment, control SHR exhibited increased blood pressure, oxidative stress and attenuated endothelium dependent relaxation in comparison to WKY rats. The impaired endothelium function in SHR was associated with lower nitrite/nitrate levels, elevated nitrotyrosine content and eNOS uncoupling. Resveratrol treatment attenuated hypertension development in SHR as indicated by lower blood pressure in resveratrol treated SHR (SHR-R) compared to control SHR. SHR-R also exhibited reduced H(2)O(2) content and elevated superoxide dismutase activity. Resveratrol treatment normalized endothelium dependent vasorelaxation in SHR. In parallel, resveratrol restored nitrite/nitrate levels and normalized nitrotyrosine content in SHR. SHR exhibited increased l-arginine dependent superoxide production which was blocked by NOS inhibitor l-NNA, suggesting eNOS uncoupling. eNOS uncoupling was prevented by resveratrol treatment. In conclusion, early treatment with resveratrol lowers oxidative stress, preserves endothelial function and attenuates development of hypertension in SHR. More importantly, prevention of eNOS uncoupling and NO scavenging could represent novel mechanisms for resveratrol-mediated antihypertensive effects.