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Reactive oxygen species (ROS) decreases bioavailability of nitric oxide (NO) and impairs NO-dependent relaxations. Like NO, hydrogen sulfide (H 2 S) is an antioxidant and vasodilator; however, the effect of ROS on H 2 S-induced relaxations is unknown. Here we investigated whether ROS altered the effect of H 2 S on vascular tone in mouse aorta and determined whether resveratrol (RVT) protects it via H 2 S. Pyrogallol induced ROS formation. It also decreased H 2 S formation and relaxation induced by l-cysteine and in mouse aorta. Pyrogallol did not alter sodium hydrogensulfide (NaHS)-induced relaxation suggesting that the pyrogallol effect on l-cysteine relaxations was due to endogenous H 2 S formation. RVT inhibited ROS formation, enhanced l-cysteine-induced relaxations and increased H 2 S level in aortas exposed to pyrogallol suggesting that RVT protects against "H 2 S-dysfunctions" by inducing H 2 S formation. Indeed, H 2 S synthesis inhibitor AOAA inhibited the protective effects of RVT. RVT had no effect on Ach-induced relaxation that is NO dependent and the stimulatory effect of RVT on H 2 S-dependent relaxation was also independent of NO. These results demonstrate that oxidative stress impairs endogenous H 2 S-induced relaxations and RVT offers protection by inducing H 2 S suggesting that targeting endogenous H 2 S pathway may prevent vascular dysfunctions associated by oxidative stress., (Copyright © 2016. Published by Elsevier Inc.)

There are few discoveries with the magnitude of the impact that NO has had on biology during the 25 years since its discovery. There is hardly a disease today not associated with altered NO homeostasis. In fact, despite numerous other endothelial functions, endothelial dysfunction has become synonymous with reduced biological activity of NO. Translating the preclinical discoveries in NO biology to new modalities for disease management has not been as impressive. Beyond the success of drugs for erectile dysfunction, clinical trials of nitric oxide synthase inhibitor have been proven either ineffective or wrought with side effects. NO donors (e.g., nitroglycerine) remain frequently used cardiovascular agents, but were discovered before 1980. Gene therapy studies have yet to become clinically useful. There is no doubt that endothelial- and NO-dysfunction is a hallmark of cardiovascular disease, including diseases which are considered as major current public health concerns: hypertension, obesity, diabetes, malnutrition. In many cases, cardiovascular disease (CVD) can be prevented by identifying and controlling modifiable risk factors. One conceivable approach to the management of multiple risk factors in CVD could be to treat endothelial dysfunction (e.g., by enhancing eNOS expression), since many CVD risk factors are related to endothelial dysfunction. In this regard one goal may include optimizing eNOS function. This can be realized by supplementing co-factors, e.g., BH4, or substrate, L-arginine, by increasing cGMP availability via phosphodiesterase inhibitors or sGC activators or by increasing NO bioavailability via antioxidants. The association of other proteins with the nitric oxide synthase (NOS) isoforms and sGC could also serve as experimental and potentially therapeutic targets to modulate NO bioactivity. There is tremendous promise behind NO itself as well as the numerous other molecules and processes associated with the L-arginine-NO-cGMP pathway. Collaborative efforts among bench scientists, clinical investigators and epidemiologists are the key in realizing this promise.