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Selective Aldosterone Blockade Prevents Angiotensin II/Salt-Induced Vascular Inflammation in the Rat Heart

Pharmacia Corporation, Cardiovascular and Metabolic Diseases, Skokie, Illinois 60077 and St. Louis, Missouri 63167

Address all correspondence and requests for reprints to: Ricardo Rocha, M.D., Pharmacia, 4901 Searle Parkway, Skokie, Illinois 60077. E-mail: ricardo.rocha{at}pharmacia.com.

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 µg/kg•d, sc). ADX rats received also dexamethasone (12 µg/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.

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