Nintedanib relaxes human pulmonary arteries more potently than murine

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is common in patients with idiopathic pulmonary fibrosis and significantly impacts survival. We used human and murine pulmonary arteries (PAs) and veins (PVs) pre-contracted with endothelin-1 (ET-1) to determine the acute vasorelaxant effects of nintedanib. Methods: These effects were tested in precision-cut lung slices (PCLS) from man and mice, and in murine isolated perfused lungs (IPL). PCLS were prepared from agarose-filled lungs. Vessel area was used to quantify responses using an inverted microscope and digital camera. In the IPL, pulmonary arterial pressure (PPA) and left atrial pressure (PLA) were recorded. Capillary pressure, assessed by the double occlusion method, was used to calculate pre- and post-capillary resistance. Results: PAs and PVs were pre-contracted with 100 nM ET-1 in murine PCLS or 100 nM (PAs) or 1 µM (PVs) in human PCLS, and 32 nM ET-1 in murine IPL. Increasing concentrations of nintedanib (murine, 1 nM–10 µM; human, 1 nM–100 nM) were used to relax the vessels. In murine or human PCLS, incubation with ET-1 contracted PAs to 48% or 73% and PVs to 71% or 43% of their initial vessel area (IVA), respectively. Nintedanib (10 μM mice, 100 nM human) relaxed the pre-contracted PAs to 140% of the IVA; PVs did not relax. Even 32 nM nintedanib was effective in human PAs. In IPL, ET-1 increased PPA and pre-and post-capillary resistance. Nintedanib decreased PPA to 78% and pre-capillary resistance to 88%; post-capillary resistance was unaffected. Conclusions: In ET-1-pre-contracted pulmonary vessels, nintedanib relaxed human PAs more potently than murine PAs. The vasorelaxant properties of nintedanib might provide benefit in treating PAH.