RESUMEN
BACKGROUND: The proinflammatory and vascular actions of cysteinyl leukotrienes (CysLTs) are mediated by 2 receptors: cysteinyl leukotriene 1 receptor (CysLT1R) and cysteinyl leukotriene 2 receptor (CysLT2R). However, the distinct contribution of CysLT2R to the vascular actions of CysLTs has not been addressed. METHODS AND RESULTS: We generated an endothelial cell-specific human CysLT2R (EC-hCysLT2R) transgenic (TG) mouse model using the Tie2 promoter/enhancer. Strong expression of hCysLT2R in TG lung and endothelial cells, detected by real-time polymerase chain reaction, markedly enhanced CysLT-stimulated intracellular calcium mobilization compared with endogenous expression in cells from nontransgenic mice. The permeability response to exogenous LTC4 and to endogenous CysLTs evoked by passive cutaneous anaphylaxis was augmented in TG mice. The rapid, systemic pressor response to intravenous LTC4 was also diminished in TG mice coincidentally with augmented production of nitric oxide. CONCLUSIONS: The development of EC-hCysLT2R mice has permitted detection of distinct vascular effects of CysLTs, which can be mediated via the CysLT2R in vivo.
Asunto(s)
Presión Sanguínea/fisiología , Células Endoteliales/fisiología , Endotelio Vascular/citología , Hipotensión/fisiopatología , Leucotrieno C4/farmacología , Pulmón/citología , Proteínas de la Membrana/fisiología , Receptores de Leucotrienos/fisiología , Animales , Señalización del Calcio/efectos de los fármacos , Permeabilidad Capilar , Oído Externo/irrigación sanguínea , Humanos , Hipotensión/etiología , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , Óxido Nítrico/sangre , Óxido Nítrico/fisiología , Anafilaxis Cutánea Pasiva/fisiología , Receptores de Leucotrienos/biosíntesis , Receptores de Leucotrienos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Glucocorticoids (GCs) are vital multi-faceted hormones with recognized effects on carbohydrate, protein and lipid metabolism. Previous studies with the steroid antagonist, RU486 have underscored the essential role of GCs in the regulation of these metabolic pathways. This article describes the discovery and characterization of novel GRalpha selective nonsteroidal antagonists (NSGCAs). NSGCAs 2 and 3 are spirocyclic dihydropyridine derivatives that selectively bind the GRalpha with IC(50s) of 2 and 1.5 nM, respectively. Importantly, these compounds are full antagonists of the induction by dexamethasone (Dex) of marker genes for glucose and glutamine metabolism; the tyrosine amino transferase (TAT) and glutamine synthetase (GS) enzymes, respectively. In contrast, GC-dependent transcriptional repression of the collagenase 1 (MMP-1) enzyme, an established GRalpha responsive proinflammatory gene; is poorly antagonized by these compounds. These NSGCAs might have useful applications as tools in metabolic research and drug discovery.
