ANGIOTENSIN-II, NITRIC-OXIDE, AND END-ORGAN DAMAGE IN HYPERTENSION

The adaptive changes that accompany hypertension and involve the kidne y, heart, and vessels, namely, muscle hypertrophy/hyperplasia, endothe lial dysfunction and extracellular matrix increase can, in fact, be ma ladaptive and eventually lead to endorgan disease, such as renal failu re, heart failure, and coronary disease. However, these changes vary m arkedly between individuals with similar levels of hypertension. Nitri c oxide (NO), an endogenous vasodilator and inhibitor of vascular smoo th muscle and mesangial cell growth, is synthesized in the endothelium by a constitutive NO synthase (NOS). NO antagonizes the effects of an giotensin II on vascular tone and growth and also downregulates the sy nthesis of angiotensin converting enzyme (ACE) and angiotensin II type 1 (AT-1) receptors. In hypertension, the physiologic response to the increased shear stress and cyclic strain is to upregulate NOS activity in endothelial cells. Upregulation of vascular NOS activity is a home ostatic adaptation to the increased hemodynamic workload that may help in preventing end-organ damage. Indeed, hypertension-prone salt-sensi tive rats manifest a decrease (instead of an increase) in vascular NOS activity when hypertensive; these rats develop severe vascular hypert rophy, left ventricular hypertrophy, and renal injury. Studies in hype rtensive humans suggest that, independent of the effects of salt on bl ood pressure, salt sensitivity may be a marker for susceptibility to t he development of endothelial dysfunction as well as cardiovascular an d renal injury. We hypothesize that in hypertension, recognition of ma rkers of cardiovascular susceptibility to injury and the understanding of the pathophysiological mechanisms involved may open new opportunit ies for therapeutic intervention. In this context, only those antihype rtensive agents that lower blood pressure and concomitantly restore th e homeostatic balance of vasoactive agents such as angiotensin II and NO within the vessel wall would be effective in preventing or arrestin g end-organ disease.