Abstract 11690: Mineralocorticoid Receptor Antagonists Prevent or Reverse Abnormal Cardiopulmonary Hemodynamics in Two Animal Models of Pulmonary Arterial Hypertension
Hyperaldosteronism (ALDO) associated with systemic hypertension contributes to vascular dysfunction by increasing vascular collagen deposition and fibrosis. In pulmonary arterial hypertension (PAH), the role of ALDO in mediating pulmonary vascular remodeling and dysfunction, however, is unknown. We hypothesized that in PAH, ALDO increases pulmonary arteriolar collagen levels to increase pulmonary vascular resistance and promote pulmonary hypertension. To test this hypothesis, we first demonstrated that plasma ALDO levels are elevated 4.2-fold (p<0.05) and 4.1-fold (p<0.05) in the rat Sugen-5416/Hypoxia (SU/Hyp) and monocrotaline (MCT) models of PAH, respectively. In a prevention study, rats were randomized to regular chow or the mineralocorticoid receptor antagonist eplerenone (0.6 gm/gm chow) initiated immediately following SU/Hyp initiation. Cardiac catheterization was performed 21 days later. Without affecting cardiac index (CI) or mean aortic pressure (MAP), eplerenone decreased pulmonary artery systolic pressure (PASP) (80.5 ± 4.9 vs. 61.5 ± 6.5 mm Hg, p=0.048, n=5) and indexed pulmonary vascular resistance (PVRi) (64.6 ± 21.4 vs. 43.9 ± 8.7 mm Hg*min*gm/ml, n=3-4, p=NS). To assess the generalizability of these findings, we tested the effect of spironolactone in reversing MCT-induced PAH. Rats were randomized to spironolactone (25 mg/kg/d) or vehicle control (V) beginning 14 days following MCT (50 mg/kg) injection. At day 24, spironolactone decreased PVRi (35.9 ± 3.2 vs. 21.5 ± 3.2 mm Hg*min*g/ml, p<0.05) and PASP (60.3 ± 5.2 vs. 39.5 ± 4.1 mm Hg, p<0.05) without affecting CI or MAP. Gomori trichrome staining showed that spironolactone or eplerenone decreased pulmonary arteriolar collagen levels by 71% (p<0.05) and 81% (p<0.05) in rats with MCT- and SU/Hyp-induced PAH, respectively, compared to control rats with PAH. These findings demonstrate a mineralocorticoid receptor antagonist class effect for attenuating pulmonary vascular remodeling and pulmonary hypertension in PAH. Identifying ALDO and/or the mineralocorticoid receptor as novel therapeutic targets to decrease pulmonary vascular collagen deposition and improve cardiopulmonary hemodynamics in PAH may have important implications for patients with this disease.
- © 2012 by American Heart Association, Inc.