RT Journal Article
SR Electronic
T1 A Selective Cysteinyl Leukotriene Receptor 2 Antagonist Blocks Myocardial Ischemia/Reperfusion Injury and Vascular Permeability in Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 768
OP 778
DO 10.1124/jpet.111.186031
VO 339
IS 3
A1 Nathan C. Ni
A1 Dong Yan
A1 Laurel L. Ballantyne
A1 Alma Barajas-Espinosa
A1 Tim St. Amand
A1 Derek A. Pratt
A1 Colin D. Funk
YR 2011
UL http://jpet.aspetjournals.org/content/339/3/768.abstract
AB Cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators that predominantly exert their effects by binding to cysteinyl leukotriene receptors of the G protein-coupled receptor family. CysLT receptor 2 (CysLT2R), expressed in endothelial cells of some vascular beds, has been implicated in a variety of cardiovascular functions. Endothelium-specific overexpression of human CysLT2R in transgenic mice (hEC-CysLT2R) greatly increases myocardial infarction damage. Investigation of this receptor, however, has been hindered by the lack of selective pharmacological antagonists. Here, we describe the characterization of 3-(((3-carboxycyclohexyl)amino)carbonyl)-4-(3-(4-(4-phenoxybutoxy)phenyl)-propoxy)benzoic acid (BayCysLT2) and explore the selective effects of this compound in attenuating myocardial ischemia/reperfusion damage and vascular leakage. Using a recently developed β-galactosidase–β-arrestin complementation assay for CysLT2R activity (Mol Pharmacol 79:270–278, 2011), we determined BayCysLT2 to be ∼20-fold more potent than the nonselective dual CysLT receptor 1 (CysLT1R)/CysLT2R antagonist 4-(((1R,2E,4E,6Z,9Z)-1-((1S)-4-carboxy-1-hydroxybutyl)-2,4,6,9-pentadecatetraen-1-yl)thio)benzoic acid (Bay-u9773) (IC50 274 nM versus 4.6 μM, respectively). Intracellular calcium mobilization in response to cysteinyl leukotriene administration showed that BayCysLT2 was >500-fold more selective for CysLT2R compared with CysLT1R. Intraperitoneal injection of BayCysLT2 in mice significantly attenuated leukotriene D4-induced Evans blue dye leakage in the murine ear vasculature. BayCysLT2 administration either before or after ischemia/reperfusion attenuated the aforementioned increased myocardial infarction damage in hEC-CysLT2R mice. Finally, decreased neutrophil infiltration and leukocyte adhesion molecule mRNA expression were observed in mice treated with antagonist compared with untreated controls. In conclusion, we present the characterization of a potent and selective antagonist for CysLT2R that is useful for discerning biological activities of this receptor.