Role of κ-opioid receptor in hypoxic pulmonary artery hypertension and its underlying mechanism.

The objective of this study were to determine the mechanism of action and role of the κ-opioid receptor (κ-OR) on hypoxic pulmonary artery hypertension (HPH) in the rat and its underlying mechanisms. The effect of U50,488H, a selective κ-OR agonist, on the proliferation of pulmonary arterial smooth muscle cells (PASMCs) under hypoxic conditions were measured by monotetrazolium assay and [H]-thymidine incorporation. Effects of U50,488H and nor-BNI, a highly selective κ-OR antagonist, on expression of κ-ORs were determined by Western blot technique. The results of our study demonstrated that U50,488H significantly lowered both mean pulmonary artery pressure and right ventricular pressure in HPH rats (P < 0.01). Further, this effect was abolished by nor-BNI (P < 0.01). Further, the effect of the agonist U50,488H was abolished by the antagonist nor-BNI (P < 0.01). mean pulmonary artery pressure and right ventricular pressure were both significantly upregulated in HPH rats treated with nor-BNI versus HPH control group rats (P < 0.01). Moreover, U50,488H inhibited proliferation of the PASMCs that were induced by hypoxia, and this inhibition lasted for 48 hours in a dose-dependent manner (P < 0.01). The inhibitory effect that U50,488H exerted on PASMC proliferation was also abolished by nor-BNI. During hypoxia, the expression of κ-ORs increased in the pulmonary artery. This increase of κ-OR expression was both enhanced by U50,488H and abolished by nor-BNI. The results demonstrate that U50,488H attenuates HPH through both the stimulation and upregulation of κ-ORs.