Influence of inhaled iloprost on transpulmonary gradient of big endothelin in patients with pulmonary hypertension

Abstract

Background - The pulmonary circulation is an important site for the production and clearance of endothelin (ET)-1, a potent vasoactive and mitogenic peptide. In healthy individuals, 40% to 50% of circulating ET-1 is removed on each passage through the lungs resulting in an arteriovenous ratio of <1, whereas many patients with pulmonary arterial hypertension (PAH) have ratios >1, indicating reduced clearance or increased release of endothelin. The influence of inhaled prostanoids on endothelin clearance is unknown. Methods and Results - In a prospective investigation, plasma concentrations of big endothelin-1 (big ET-1, Elisa) were measured in 15 patients with pulmonary hypertension undergoing right heart catheterization with iloprost inhalation (4 m, 11 f, aged 35 to 75 years, mean pulmonary arterial pressure (PAPm) 54±2.3 mm Hg, pulmonary vascular resistance (PVR) 1061±141 dyn × sec × cm-5). There was a significant transpulmonary gradient for big ET-1 with 31% ± 11% higher concentrations in the radial artery than in the pulmonary artery (P<0.001). After inhalation of iloprost a significant decrease in the AV-ratio from 1.31±0.11 to 0.92±0.06 (P<0.007) was observed. The pulmonary net release of 3.10±0.65 pmol/min big ET-1 at baseline decreased to -1.24±1.32 pmol/min (P=0.013) within 15 minutes indicating a restored balance. Patients under long-term treatment with iloprost (n=7) tended to have a lower net release and AV-ratio for big ET-1 than patients without pretreatment. Conclusion - An increase in pulmonary clearance of big-ET could be a mechanism contributing to the beneficial effects of inhaled prostanoids in the treatment of PAH.