Oxygen species in the microvascular environment: regulation of vascular tone and the development of hypertension.

Derangements of the three endothelium-related vasodilator systems (prostaglandins, endothelium-derived hyperpolarizing factor(s) and nitric oxide) cause the endothelial dysfunction observed in hypertension. Free radical-induced nitric oxide degradation plays a crucial role in hypertension. An increase in superoxide producing enzymes such as NAD(P)H oxidase and xanthine oxidase has been demonstrated. Superoxide dismutase may correct endothelial dysfunction in vitro and superoxide dismutase mimetics can lower blood pressure in experimental animals. Antioxidant agents and xanthine oxidase-inhibiting compounds have been used in humans. In addition, the synthesis of vasoconstrictor peroxides derived from the activity of cyclooxygenase in the endothelium and the vascular smooth muscle is stimulated by the OH. radical. Hydrogen peroxide levels are augmented in hypertension, but its role is unclear because recent investigations have shown that this substance may act as a hyperpolarizing factor. It is thought that the therapeutic benefit of anti-hypertensive drugs, such as calcium antagonists and angiotensin-converting enzyme inhibitors, could be in part due to an inhibition of free radical production. A role of superoxide in the endothelial dysfunction and hypertension of chronic renal failure has also been suggested by recent animal experiments.