Humoral and Metabolic Factors Many of the mechanisms that initiate and maintain hyper- tension also damage target organs, including the coronary arteries and the myocardium. Angiotensin II elevates BP and promotes target-organ damage, including atherosclerosis, by mechanisms that include direct effects on constriction and remodeling of resistance vessels, stimulation of aldosterone synthesis and release, enhancement of sympathetic outflow from the brain, and facilitation of catecholamine release from the adrenals and peripheral sympathetic nerve terminals.1 Aldosterone can mimic or potentiate the vasotoxic properties of angiotensin II and norepinephrine. Angiotensin II promotes cardiac and vascular smooth muscle cell hypertrophy directly via activation of the angiotensin II type 1 (AT1) receptor and indirectly by stimulating expression of a number of growth factors, cytokines, and adhesion molecules. AT1 receptor activation also contributes to endothelial damage and athero- genesis by inhibiting the mobilization of endothelial progeni- tor cells from the bone marrow, thus impairing endothelial regeneration and vascular repair processes.78 There is also a link between RAAS activation and fibrinolysis. Angiotensin II induces the formation of plasminogen activator inhibitor-1 via an AT1 receptor dependent effect on endothelial cells, whereas ACE downregulates tissue plasminogen activator production by degrading bradykinin, a potent stimulator of endothelial tissue plasminogen activator expression. ACE inhibitors and ARBs limit oxidative reactions in the vasculature by blocking the activation of NAD(P)H oxi- dase, supporting the concept that these RAAS blockers may have important vasoprotective effects beyond BP lowering.79 Furthermore, there is evidence of interaction between the RAAS and dyslipidemia: Hypercholesterolemia upregulates the RAAS, particularly vascularAT1 receptor density and func- tional responsiveness, and systemic angiotensin II peptide syn- whereas the RAAS stimulates the accumulation of low-density lipoprotein cholesterol in the arterial wall. These findings suggest that these antihypertensive drug classes may have clinically important vasoprotective effects beyond BP lowering. 