Commonly used leukotriene B4 receptor antagonists possess intrinsic activity as agonists in human endothelial cells: Effects on calcium transients, adhesive events and mediator release

Leukotriene B4 (LTB4), a potent chemotactic and immune-modulating lipid mediator, signals via two receptors, BLT1 and BLT2, leading to pro-inflammatory responses in phagocytes. Recently, we reported that BLT1 is the predominating BLT on human umbilical vein endothelial cells (HUVEC) and transmits a variety of functional responses. Here, we demonstrate that, in HUVEC, two BLT1 antagonists (U75302, CP105696) and one BLT2 antagonist (LY255283) possess intrinsic but varying agonist activity for adhesion of neutrophils, up-regulation of E-selectin, ICAM-1 and VCAM-1, and release of MCP-1. These effects were observed after exposure of HUVEC for the drugs for 0.25–6 h, persisted for several hours, and were less potent in magnitude as those elicited by LPS. Our findings may have consequences for interpretation of in vitro BLT blockade experiments.