The Selective TRPV4 Antagonist GSK2263095A Attenuates High Venous Pressure‐Induced Lung Injury In Murine And Canine Lung

Abstract

We have shown that the lung permeability response to high venous pressure (HiPv) is abrogated in mice lacking the vanilloid transient receptor potential channel TRPV4. The current study evaluated the efficacy of a novel selective TRPV4 antagonist GSK2263095A in limiting HiPv‐induced lung injury. Lungs isolated from anesthetized C57BL/6 mice or dogs were perfused with buffer/4% albumin or autologous blood, respectively, at constant flow. The filtration coefficient (Kf, an index of endothelial permeability) was measured at baseline (BL) and during 15‐min challenge with 25 or 40 cmH2O HiPv. In mouse lung, 25 cmH2O HiPv increased Kf 4.9‐fold, vs 2.9‐fold in lungs pretreated with 300 nM GSK2263095A (p<0.05). In canine lung, 25 cmH2O HiPv had no significant impact on Kf: 2.0‐ (vehicle) and 1.6‐fold BL (100 nM GSK2263095A). However, 40 cmH2O HiPv increased Kf significantly to 6.1‐fold baseline, an effect attenuated (final Kf 3.0‐ fold. baseline) by pretreatment with 100 nM GSK2263095A (both p<0.05). Further, the TRPV4 antagonist markedly attenuated the HiPv‐induced increase in extravascular lung water (p<0.05) and tended to blunt blood extravasation in canine lung. We conclude that TRPV4 is required for the permeability response to HiPv in both mouse and canine lung, and that the TRPV4 antagonist GSK2263095A is protective against lung injury induced by high pulmonary venous pressure. Supported by GlaxoSmithKline.