Spironolactone improves angiotensin-induced vascular changes and oxidative stress.
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 (n=8 to 12/group) received angiotensin II (120 ng/kg per minute, subcutaneously) for 14 days +/- spironolactone or hydralazine (25 mg/kg per day). An additional group received aldosterone (750 ng/h, subcutaneously) +/- spironolactone. Systolic blood pressure was increased by angiotensin II (P<0.001) and reduced by spironolactone and hydralazine (P<0.001). Aldosterone-induced increase of blood pressure was reduced by spironolactone (P<0.05). In mesenteric small arteries studied on a pressurized myograph, media/lumen ratio was increased (P<0.001) and acetylcholine-mediated relaxation was impaired in angiotensin II-infused rats (P<0.001); both were partially improved by spironolactone (P<0.05) but not by hydralazine. Aldosterone-induced increase of media/lumen ratio (P<0.001) and impaired response to acetylcholine (P<0.001) were normalized by spironolactone. Response to sodium nitroprusside was similar in all groups. Aortic NADPH oxidase activity was increased (P<0.01) by angiotensin II and reduced by spironolactone and hydralazine. Aldosterone also increased (P<0.05) 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 (P<0.001), 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.
D000450:Aldosterone / Q000097:blood / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001158:Arteries / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D046508:Culture Techniques; D004730:Endothelium, Vascular / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D013148:Spironolactone / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014655:Vascular Resistance
D000451:Mineralocorticoid Receptor Antagonists; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D019255:NADPH Oxidases; D012083:Renin