Transition from post-capillary pulmonary hypertension to combined pre- and post-capillary pulmonary hypertension in swine: a key role for endothelin

Passive, isolated post-capillary pulmonary hypertension (IpcPH) secondary to left heart disease may progress to combined pre- and post-capillary or active' PH (CpcPH) characterized by chronic pulmonary vascular constriction and remodelling. The mechanisms underlying this activation' of passive pulmonary hypertension (PH) remain incompletely understood. Here we investigated the role of the vasoconstrictor endothelin-1 (ET) in the progression from IpcPH to CpcPH in a swine model for post-capillary PH. Swine underwent pulmonary vein banding (PVB; n=7) or sham-surgery (Sham; n=6) and were chronically instrumented 4weeks later. Haemodynamics were assessed for 8weeks, at rest and during exercise, before and after administration of the ET receptor antagonist tezosentan. After sacrifice, the pulmonary vasculature was investigated by histology, RT-qPCR and myograph experiments. Pulmonary arterial pressure and resistance increased significantly over time. mRNA expression of prepro-endothelin-1 and endothelin converting enzyme-1 in the lung was increased, while ETA expression was unchanged and ETB expression was downregulated. This was associated with increased plasma ET levels from week 10 onward and a more pronounced vasodilatation to in vivo administration of tezosentan at rest and during exercise. Myograph experiments showed decreased endothelium-dependent vasodilatation to Substance P and increased vasoconstriction to KCl in PVB swine consistent with increased muscularization observed with histology. Moreover, maximal vasoconstriction to ET was increased whereas ET sensitivity was decreased. In conclusion, PVB swine gradually developed PH with structural and functional vascular remodelling. From week 10 onward, the pulmonary ET pathway was upregulated, likely contributing to pre-capillary activation of the initially isolated post-capillary PH. Inhibition of the ET pathway could thus potentially provide a pharmacotherapeutic target for early stage post-capillary PH.