The Effects of Spironolactone on Inflammation in a Rodent Model of Pulmonary Arterial Hypertension

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Abstract

PAH encompasses a group of rare but lethal diseases characterized by progressive narrowing and occlusion of the small pulmonary arteries, stress on the right-side of the heart and eventually death from right-heart failure. New treatments are urgently needed because current therapy does not reverse this progressive disease and 50% of patients die within 7 years of their diagnosis. Inflammation has recently been recognized as an important part of the abnormal pulmonary arteries in patients with PAH, and therefore it has been hypothesized that drugs that block inflammation may have benefits in patients with PAH. Mineralocorticoid receptor (MR) antagonists improve patient outcomes in variety of cardiovascular diseases. Treatment with spironolactone or eplerenone, both MR antagonists, improves right heart function and pulmonary artery pressure in animal models of pulmonary hypertension. These effects are primarily believed to be a result of inhibiting the harmful effects of MR. However, MR-independent mechanisms and the effects of spironolactone on inflammation in PAH have not been previously studied in an animal model. Ongoing cell culture work by our group has uncovered an MR-independent mechanism whereby spironolactone suppresses inflammation in pulmonary artery endothelial cells. Part 1 of this study has been completed. Part 2 of the study began in May 2017 and will be completed in early September 2018.