Mineralocorticoid receptor antagonism in experimental atherosclerosis.
BACKGROUND
Aldosterone has been implicated in the effects of angiotensin II in the vasculature. We hypothesized that there is local expression of the mineralocorticoid receptor (MR) in the vasculature and that the use of a selective aldosterone receptor antagonist (SARA) improves endothelial function in early atherosclerosis.


RESULTS
New Zealand rabbits were placed on normal chow or 1% cholesterol diets, randomized to placebo or SARA (eplerenone, 50 mg/kg twice daily), and killed at the end of 6 weeks for various studies. In the hyperlipidemic (HL) chow group, there was a 2.3-fold increase in superoxide (O2*-)) generation. SARA normalized O2*- generation in intact aortas and reduced NADH and NADPH oxidase activity to basal levels (0.31+/-0.04 and 0.27+/-0.02 in HL versus 0.16+/-0.05 and 0.07+/-0.02 in HL-SARA, respectively; P<0.01 by ANOVA). This was associated with improvements in peak relaxations to the endothelial-dependent agonist acetylcholine (82+/-6% in HL-SARA versus 61+/-4 in HL; P<0.01 by ANOVA; ED(50) 6.8x10(-8) mol/L in HL-SARA and 1.2x10(-7) mol/L in HL; P=NS) to near-normal levels. Vessels from the HL group demonstrated hyperreactivity to angiotensin II that could not be corrected with SARA. Plasma aldosterone levels by radioimmunoassay demonstrated a 4- to 5-fold increase in response to SARA but no differences with lipid feeding. Real-time reverse transcriptase-polymerase chain reaction studies revealed expression of MR in the aorta of HL rabbits and those of controls.


CONCLUSIONS
MR antagonism improves endothelial function and reduces O2*- generation in diet-induced atherosclerosis. Targeting aldosterone by blocking its receptor has potential antiatherosclerotic effects.
Rajagopalan
Sanjay
S
Department of Internal Medicine, University of Michigan, Ann Arbor, Mich, USA. srajagop@ umich.edu
Duquaine
Damon
D
King
Steven
S
Pitt
Bertram
B
Patel
Paresh
P
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001161:Arteriosclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000503:physiopathology; D000077545:Eplerenone; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014666:Vasomotor System / Q000187:drug effects
D000451:Mineralocorticoid Receptor Antagonists; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013481:Superoxides; D013148:Spironolactone; D000077545:Eplerenone; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases