Abstract
BackgroundAldosterone is a mineralocorticoid hormone critically involved in arterial blood pressure regulation. Although pharmacological aldosterone antagonism reduces mortality and morbidity among patients with severe left-sided heart failure, the contribution of aldosterone to the pathobiology of pulmonary arterial hypertension (PAH) and right ventricular (RV) heart failure is not fully understood.MethodsThe effects of Eplerenone (0.1% Inspra® mixed in chow) on pulmonary vascular and RV remodeling were evaluated in mice with pulmonary hypertension (PH) caused by Sugen5416 injection with concomitant chronic hypoxia (SuHx) and in a second animal model with established RV dysfunction independent from lung remodeling through surgical pulmonary artery banding.ResultsPreventive Eplerenone administration attenuated the development of PH and pathological remodeling of pulmonary arterioles. Therapeutic aldosterone antagonism – starting when RV dysfunction was established - normalized mineralocorticoid receptor gene expression in the right ventricle without direct effects on either RV structure (Cardiomyocyte hypertrophy, Fibrosis) or function (assessed by non-invasive echocardiography along with intra-cardiac pressure volume measurements), but significantly lowered systemic blood pressure.ConclusionsOur data indicate that aldosterone antagonism with Eplerenone attenuates pulmonary vascular rather than RV remodeling in PAH.
Highlights
Aldosterone is a mineralocorticoid hormone critically involved in arterial blood pressure regulation
pulmonary artery banding (PAB)-challenged animals were randomly assigned for either placebo or Eplerenone (0.1% mixed in chow, hereafter referred to as Epl) therapy starting one week after disease commencement for additional two weeks
Eplerenone attenuates Sugen5416 injection with concomitant chronic hypoxia (SuHx)-induced pulmonary hypertension (PH) and pulmonary vascular remodeling Oral Eplerenone administration (0.1% mixed in chow) for three consecutive weeks significantly attenuated the development of PH in the SuHx mouse model (Sugen5416 injection followed by chronic hypoxia) demonstrated by reduced right ventricular (RV) hypertrophy (1.2 ± 0.1 vs. 1.4 ± 0.1, p < 0.05) (RV/BW, Fig. 1a) and reduced RV systolic pressure (33.8 ± 4.3 vs. 39.5 ± 4.0 mmHg, p < 0.05) (RVSP, Fig. 1b) as compared with controls
Summary
Aldosterone is a mineralocorticoid hormone critically involved in arterial blood pressure regulation. Pharmacological aldosterone antagonism reduces mortality and morbidity among patients with severe left-sided heart failure, the contribution of aldosterone to the pathobiology of pulmonary arterial hypertension (PAH) and right ventricular (RV) heart failure is not fully understood. Pulmonary arterial hypertension (PAH) is a devastating disorder characterized by aberrant remodeling of pulmonary arteries that results in sustained pulmonary vasoconstriction, progressively increases pulmonary vascular resistance (PVR) and right ventricular (RV) afterload [1,2,3]. PH rat models demonstrate increased plasma and lung tissue aldosterone concentrations that correlate with cardio-pulmonary hemodynamics as well as pulmonary vascular remodeling [8, 9] pointing towards a causative role for aldosterone signaling in mediating adverse lung remodeling as seen in PAH development. Pharmacological aldosterone antagonism by the FDA approved drugs Spironolactone or Eplerenone, respectively, directly reduced the pathologic pulmonary vascular remodeling in PAH animal models [10]
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