Abstract 16510: Mineralocorticoid Receptor Blockade Attenuates Proliferative Changes in the Rat Pulmonary Artery in Monocrotaline-Induced Pulmonary Hypertension
Background: Pulmonary arterial hypertension (PAH) is recognized as a spectrum of pulmonary vascular remodeling that leads to lumen obstruction induced by a nexus of unregulated proliferative signaling. Inhibition of proliferative changes is likely to become a new cornerstone in treatment of PAH, in addition to use of current pulmonary vasodilators.
Hypothesis: We hypothesized that coupling of mineralocorticoid receptor (MCR) signaling and downstream signals, such as angiotensin II and others, plays a role in the proliferative changes in PAH, and that a selective antagonist of MCR, eplerenone, could ameliorate the vascular impairments in PAH.
Methods: Male rats aged 7 weeks were given a single subcutaneous injection of monocrotaline (60 mg/kg). The animals were divided into two groups one day after the injection: one group received oral eplerenone (100 mg/kg per day, N=8) and the other received a similar volume of vehicle (N=8). After three weeks of treatment, cardiac function was assessed by echocardiography and peak right ventricular pressure was measured by cardiac catheterization. The lungs were then harvested for histological and biological analysis.
Results: Peak right ventricular pressure was significantly lower in the eplerenone group compared to the vehicle group (37.3±3.9 vs. 60.2±4.7 mmHg, p<0.01) and right ventricular function expressed as the Tei-index was significantly better preserved in the eplerenone group (0.58±0.03 vs. 0.70±0.07, p<0.01). The eplerenone group showed significantly greater reduction in % medial wall thickness of intra-acinar pulmonary arteries compared to the vehicle group (20.7±7.4 vs. 43.5±7.5, p<0.01). Quantitative RT-PCR showed two-fold upregulation of mRNA levels for the MCR, angiotensin II type 1a receptor and transforming growth factor-β1 in the lungs following monocrotaline injection in the vehicle group, compared to controls that did not receive an injection. Eplerenone treatment resulted in significant reduction in these mRNA levels in monocrotaline-induced PAH, compared to the vehicle group (p<0.01).
Conclusions: These results suggest that MCR signaling plays at least a partial role in the proliferative pathogenesis of PAH and that MCR blockade may be an effective alternate treatment for PAH.
- © 2010 by American Heart Association, Inc.