Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart.
We studied the role of aldosterone (aldo) in myocardial injury in a model of angiotensin (Ang) II-hypertension. Wistar rats were given 1% NaCl (salt) to drink and randomized into one of the following groups (n = 10; treatment, 21 d): 1) vehicle control (VEH); 2) Ang II infusion (25 ng/min, sc); 3) Ang II infusion plus the selective aldo blocker, eplerenone (epl, 100 mg/kg.d, orally); 4) Ang II infusion in adrenalectomized (ADX) rats; and 5) Ang II infusion in ADX rats with aldo treatment (20 micro g/kg.d, sc). ADX rats received also dexamethasone (12 micro g/kg.d, sc). Systolic blood pressure increased with time in all treatment groups except the VEH group (VEH, 136 +/- 6; Ang II/NaCl, 203 +/- 12; Ang II/NaCl/epl, 196 +/- 10; Ang II/NaCl/ADX, 181 +/- 7; Ang II/NaCl/ADX/aldo, 236 +/- 8 mm Hg). Despite similar levels of hypertension, epl and ADX attenuated the increase in heart weight/body weight induced by Ang II. Histological examination of the hearts evidenced myocardial and vascular injury in the Ang II/salt (7 of 10 hearts with damage, P < 0.05 vs. VEH) and Ang II/salt/ADX/aldo groups (10 of 10 hearts with damage, P < 0.05). Injury included arterial fibrinoid necrosis, perivascular inflammation (primarily macrophages), and focal infarctions. Vascular lesions were associated with expression of the inflammatory mediators cyclooxygenase 2 (COX-2) and osteopontin in the media of coronary arteries. Myocardial injury, COX-2, and osteopontin expression were markedly attenuated by epl treatment (1 of 10 hearts with damage, P < 0.05 vs. Ang II/salt) and adrenalectomy (2 of 10 hearts with damage, P < 0.05 vs. Ang II/salt). Our data indicate that aldo plays a major role in Ang II-induced vascular inflammation in the heart and implicate COX-2 and osteopontin as potential mediators of the damage.
Rocha
Ricardo
R
Pharmacia Corporation, Cardiovascular and Metabolic Diseases, Skokie, Illinois 60077 and St. Louis, Missouri 63167, USA. ricardo.rocha@pharmacia.com
Martin-Berger
Cynthia L
CL
Yang
Pochang
P
Scherrer
Rachel
R
Delyani
John
J
McMahon
Ellen
E
D000315:Adrenalectomy; D000450:Aldosterone / Q000097:blood / Q000502:physiology; D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001835:Body Weight; D003327:Coronary Disease / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000737:chemistry / Q000473:pathology; D003345:Corticosterone / Q000097:blood; D051546:Cyclooxygenase 2; D004231:Diuresis / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D000077545:Eplerenone; D006321:Heart / Q000033:anatomy & histology; D006973:Hypertension / Q000139:chemically induced*; D007527:Isoenzymes / Q000032:analysis; D008264:Macrophages / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D009336:Necrosis; D009929:Organ Size / Q000187:drug effects; D053495:Osteopontin; D011188:Potassium / Q000097:blood / Q000652:urine; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood; D012795:Sialoglycoproteins / Q000032:analysis; D012964:Sodium / Q000097:blood / Q000652:urine; D012965:Sodium Chloride / Q000008:administration & dosage*; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014657:Vasculitis / Q000139:chemically induced / Q000517:prevention & control*
D007527:Isoenzymes; D000451:Mineralocorticoid Receptor Antagonists; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D000804:Angiotensin II; D013148:Spironolactone; D012965:Sodium Chloride; D000450:Aldosterone; D000077545:Eplerenone; D012964:Sodium; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D012083:Renin; D011188:Potassium; D003345:Corticosterone