ABSTRACT
Reactive oxygen species (ROS) and reactive nitrogen (RNS) species are highly reactive byproducts of O2 metabolism that play an important physiological role in vascular biology and a pathophysiological role in hypertensive vascular disease.1,2 Normally the rate of ROS production is balanced by the rate of elimination. However, an imbalance between ROS production and the ability to defend against them by antioxidants results in increased bioavailability of ROS leading to oxidative excess.2,3 The pathogenic outcome of oxidative stress is oxidative damage, a major cause of vascular, renal, and cardiac injury in cardiovascular disease, including hypertension. Among the major ROS important in these processes are superoxide anion (•O2
−), hydrogen peroxide (H2O2), hydroxyl radical (•OH), and the RNS, nitric oxide (NO) and peroxynitrite (ONOO−). Under physiological conditions, ROS/RNS are produced in a controlled manner at low concentrations and function as signaling molecules to maintain vascular integrity by regulating vascular smooth muscle cell contraction-relaxation, vascular smooth muscle cell growth, and endothelial function.4,5 Under pathological conditions increased ROS production leads to endothelial dysfunction, increased contractility, vascular smooth muscle cell growth and apoptosis, monocyte migration, lipid peroxidation, inflammation and increased deposition of extracellular matrix proteins, major processes contributing to vascular injury in hypertension.6,7
Myriad experimental studies together with clinical investigations provide compelling evidence that oxidative stress is involved in the pathogenesis of cardiovascular diseases, including atherosclerosis, diabetes, cardiac failure, and hypertension. In experimental models of hypertension, production of cardiac, renal, neural and vascular ROS is increased.8-10 Mouse
models deficient in ROS-generating oxidases have lower blood pressure compared with wild-type counterparts and angiotensin (Ang) II infusion in these mice fails to induce hypertension.11 In human hypertension, plasma and urine levels of thiobarbituric acid-reactive substances (TBARS) and 8-epi-isoprostane, markers of systemic oxidative stress, are elevated.12,13 Treatment with antioxidants or superoxide dismutase (SOD) mimetics improves vascular function and structure and reduces blood pressure in experimental and human hypertension.14-16 Many of the adverse consequences of hypertension on endothelial function may be reversed by intra-arterial infusion of antioxidants, such as vitamin C.17 Furthermore, in cultured vascular smooth muscle cells (VSMCs) and isolated arteries from hypertensive rats and humans, production of ROS is enhanced and antioxidant capacity is reduced.18,19
Hence, evidence at multiple levels supports a role for oxidative excess in the pathogenesis of hypertension.
