Abstract-Angiotensin II plays an important role in vascular remodeling. We investigated the role of aldosterone, which is stimulated by angiotensin II, as a mediator of angiotensin II-induced vascular structural and functional alterations. Sprague-Dawley rats (nϭ8 to 12/group) received angiotensin II (120 ng/kg per minute, subcutaneously) for 14 days Ϯ spironolactone or hydralazine (25 mg/kg per day). An additional group received aldosterone (750 ng/h, subcutaneously) Ϯ spironolactone. Systolic blood pressure was increased by angiotensin II (PϽ0.001) and reduced by spironolactone and hydralazine (PϽ0.001). Aldosterone-induced increase of blood pressure was reduced by spironolactone (PϽ0.05).In mesenteric small arteries studied on a pressurized myograph, media/lumen ratio was increased (PϽ0.001) and acetylcholine-mediated relaxation was impaired in angiotensin II-infused rats (PϽ0.001); both were partially improved by spironolactone (PϽ0.05) but not by hydralazine. Aldosterone-induced increase of media/lumen ratio (PϽ0.001) and impaired response to acetylcholine (PϽ0.001) were normalized by spironolactone. Response to sodium nitroprusside was similar in all groups. Aortic NADPH oxidase activity was increased (PϽ0.01) by angiotensin II and reduced by spironolactone and hydralazine. Aldosterone also increased (PϽ0.05) activation of NADPH oxidase, an effect abolished by spironolactone. Plasma thiobarbituric acid-reactive substances (a marker of oxidative stress), higher in angiotensin II and aldosterone rats (PϽ0.001), were normalized by spironolactone. In conclusion, spironolactone, which inhibited aldosterone actions, partially corrected structural and functional angiotensin II-induced abnormalities. These effects were associated with reduced vascular NADPH oxidase activity and decreased plasma markers of oxidative stress. Our findings suggest that aldosterone may mediate some of angiotensin II-induced vascular effects in hypertension, in part via increased oxidative stress.

Background-Pioglitazone and rosiglitazone, thiazolidinedione peroxisome proliferator-activated receptor-␥ (PPAR␥) activators, reduce blood pressure (BP) in some hypertensive models by unclear mechanisms. We tested the hypothesis that pioglitazone or rosiglitazone would prevent BP elevation and vascular dysfunction in angiotensin (Ang) II-infused rats by direct vascular effects. Methods and Results-Sprague-Dawley rats received Ang II (120 ng · kg Ϫ1 · min Ϫ1 SC) with or without pioglitazone (10 mg · kg Ϫ1 · d

Background-Endothelin (ET)-1 is a potent vasoconstrictor that contributes to vascular remodeling in hypertension and other cardiovascular diseases. Endogenous ET-1 is produced predominantly by vascular endothelial cells. To directly test the role of endothelium-derived ET-1 in cardiovascular pathophysiology, we specifically targeted expression of the human preproET-1 gene to the endothelium by using the Tie-2 promoter in C57BL/6 mice. Methods and Results-Ten-week-old male C57BL/6 transgenic (TG) and nontransgenic (wild type; WT) littermates were studied. TG mice exhibited 3-fold higher vascular tissue ET-1 mRNA and 7-fold higher ET-1 plasma levels than did WT mice but no significant elevation in blood pressure. Despite the absence of significant blood pressure elevation, TG mice exhibited marked hypertrophic remodeling and oxidant excess-dependent endothelial dysfunction of resistance vessels, altered ET-1 and ET-3 vascular responses, and significant increases in ET B expression compared with WT littermates. Moreover, TG mice generated significantly higher oxidative stress, possibly through increased activity and expression of vascular NAD(P)H oxidase than did their WT counterparts. Conclusions-In this new murine model of endothelium-restricted human preproET-1 overexpression, ET-1 caused structural remodeling and endothelial dysfunction of resistance vessels, consistent with a direct nonhemodynamic effect of ET-1 on the vasculature, at least in part through the activation of vascular NAD(P)H oxidase.