Hypertension, Angiotensin II, and Oxidative Stress

The New England Journal of Medicine

Renovascular hypertension is a potentially curable form of secondary hypertension generally due to either atherosclerosis or fibromuscular dysplasia of one or both renal arteries. The critical element promoting hypertension in this disorder is reduced arterial perfusion to one or both kidneys, leading to increased production of renin, which elevates circulating angiotensin II levels. The resultant high-renin hypertensive state is associated with moderate-to-severe elevation of blood pressure, with an attendant high risk of cardiovascular disease and progressive loss of renal function in the flow-deprived kidney. Treatment of renovascular hypertension with angioplasty, stenting, or surgery affords an opportunity to reduce blood pressure and to prevent the progression of renal dysfunction and cardiovascular disease.

In this issue of the Journal, Higashi and colleagues report that patients with unilateral renovascular hypertension have impaired endothelium-dependent vasodilatation of the brachial artery and that this impairment is corrected by angioplasty or administration of the antioxidant ascorbic acid (vitamin C). Furthermore, the improvement in endothelial function correlates with two indexes of oxidative stress. The authors suggest that patients with unilateral renal- artery stenosis have a form of hypertension that is characterized by systemic and vascular-tissue enhancement of the renin–angiotensin system. As detailed in a review by Dzau, activation of the renin–angiotensinn system in cardiovascular tissue often accompanies systemic activation of this system and may be the principal contributor to cardiovascular disease. Indeed, in the report by Higashi et al., angioplasty did significantly reduce plasma renin activity and angiotensin II levels as well as blood pressure and indexes of oxidative stress.


There is accumulating evidence that angiotensin II increases vascular oxidative stress as well as vasoconstriction. Activation of the renin–angiotensin system in tissue, as well as increases in the systemic renin–angiotensin system, enhances the vascular production of reactive oxygen species, in part through the activation of membrane-bound NADH and NADPH oxidases (Fig. 1). These oxidase enzymes are present in endothelial cells, vascular smooth-muscle cells, fibroblasts, and phagocytic mononuclear cells. The increased vascular activity of NADH and NADPH oxidase enhances the production of reactive oxygen species by several pathways, including the increased activation of xanthine oxidase, the auto-oxidation of NADH, and the inactivation of superoxide dismutase. There is increasing evidence that the resultant increase in nitric oxide degradation or inactivation by reactive oxygen species, rather than reduced nitric oxide production itself, plays the principal part in the impairment of endothelium-dependent vasodilatation in diabetes and other vascular diseases characterized by enhanced tissue activation of the renin–angiotensin system. Thus, enhanced production of reactive oxygen species (including oxygen radicals) causes a loss of bioavailability of nitric oxide, which impairs endothelium-dependent vasodilatation. The reaction of oxygen radicals with nitric oxide leads to the production of peroxynitrite, a potent oxidant that further contributes to vasoconstriction and vascular injury.

In the study by Higashi et al., infusion of ascorbic acid, an antioxidant, improved endothelium-dependent forearm vasodilatation before, but not after, angioplasty. Others have shown that the vasoconstriction induced by an acute infusion of angiotensinII was attenuated by coinfusion of ascorbic acid, an observation thought to be consistent with the notion that angiotensin II induces vasoconstriction, in part, through activation of NADPH oxidases and increased production of superoxide anions. Furthermore, these observations provide additional evidence of the role of angiotensin II–induced oxidative stress in mediating impaired endothelium-dependent vasodilatation in renovascular hypertension. The seminal role of angiotensin II in generating vascular reactive oxygen species through activation of NADPH oxidases is further evidenced by the observation that this effect can be abrogated experimentally by angiotensin II–receptor blockers and in essential hypertension by therapy with angiotensin II–receptor blockers and angiotensin-converting–enzyme inhibitors.


Although the reduction in markers of oxidative stress and the associated improvement in endothelium-dependent vasodilatation after angioplasty may be due to reductions in tissue and circulating angiotensin II, the reduction in blood pressure after angioplasty may also have an important role (Fig. 1). Studies in animals with hypertension and in humans with essential hypertension have shown that endothelial dysfunction is associated with an excess of oxygen
radicals and increased production of reactive oxygen species. It has been suggested that in essential hypertension there is an imbalance between enhanced production of oxygen radicals and decreased antioxidant activity. Indeed, the levels of free-radical scavengers, such as glutathione, superoxide dismutase, and vitamin E, have been reported to be depressed in patients with hypertension.

Furthermore, ascorbic acid normalizes endothelial function by restoring the nitric oxide–mediated vasodilatation of the endothelium in patients with essential hypertension. In addition, the mechanical forces generated by hypertension are capable of stimulating the autocrine and paracrine renin–angiotensin systems within the vessel. Angiotensin II is generated in the arterial wall in response to increased vascularwall tension.This mechanical stress has also been shown to increase the protein levels of the type 1 angiotensin II receptor. Thus, in the study by Higashi et al., reductions in blood pressure after renal-artery angioplasty may have further reduced the local vascular renin–angiotensin system, contributing to improved endothelium-dependent vasodilatation. Accordingly, some of the improvement in endothelial function and associated reductions in oxidative stress after angioplasty may have been due to reductions in blood pressure, even though the changes were not statistically correlated. Further studies will be needed to ascertain the importance of the vascular renin– angiotensin system as compared with that of blood pressure in promoting oxidative stress and endothelial dysfunction in patients with unilateral renal- artery stenosis.