Mineralocorticoid Receptor Blockade Attenuates Proliferative Changes in the Rat Pulmonary Artery in Monocrotaline-Induced Pulmonary Hypertension

Abstract

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. We hypothesized that mineralocorticoid receptor （MR） signaling plays a significant role in the remodeling, and that antagonizing MR could ameliorate the vascular impairments in PAH.
Methods: Male rats were divided into two groups one day after a single subcutaneous injection of monocrotaline （60 mg/kg）: one group received oral eplerenone （EPL, 100 mg/kg per day, N = 6） and the other received vehicle （N = 8）. Animals in another group with saline injection and no medication served as control （N = 8）. After three weeks of treatment, right ventricular （RV） function was assessed and RV pressure was measured. The mRNA levels for the MR, angiotensin II type 1a receptor and transforming growth factor-β1 in the lungs were measured by quantitative RT-PCR.
Results: Peak RV pressure was significantly higher in the vehicle group compared to the control but significantly reduced in the EPL group （p < 0.01）. RV function （Tei-index） was significantly reduced in the vehicle group compared to the control but significantly preserved in the EPL group （p < 0.01）. The eplerenone group showed significantly greater reduction in % medial wall thickness of pulmonary arterioles compared to the vehicle group （20.7±7.4 vs. 43.5±7.5, p < 0.01）. All mRNA levels were significantly upregulated in the vehicle group, compared to the control. Eplerenone treatment resulted in significant reduction in these mRNA levels, compared to the vehicle group （p < 0.01）.
Conclusions: These results suggest that MR signaling plays at least a partial role in the proliferative vascular remodeling of PAH and that MR blockade may be an effective alternate treatment for PAH.