A new CysLT1 and CysLT2 receptors-mediated anaphylaxis guinea pig model

Abstract

Although the effectiveness of CysLT₁ receptor antagonists on asthma has been clinically established, the effects of CysLT₂ receptor antagonists are still unclear. The purpose of this study was to develop a new CysLT₁ and CysLT₂ receptors-mediated anaphylaxis guinea pig model using S-hexyl GSH, a γ-glutamyl transpeptidase (GTP) inhibitor, to suppress conversion of LTC₄ to LTD₄. Actively sensitized guinea pigs were challenged with OVA in the absence or presence of S-hexyl GSH, and survival rate following anaphylactic response was monitored. OVA-induced fatal anaphylaxis in the absence of S-hexyl GSH was almost completely inhibited by montelukast, a CysLT₁ receptor antagonist, but not by the CysLT₂ receptor antagonist BayCysLT₂RA. However, under treatment with S-hexyl-GSH, the inhibitory effect of motelukast was dramatically diminished, whereas that of BayCysLT₂RA was markedly increased. The dual CysLT_1/2 receptor antagonist ONO-6950 effectively inhibited anaphylactic response in both S-hexyl GSH-treated and non-treated animals. LC/MS/MS analysis revealed that S-hexyl GSH treatment actually inhibited LTC₄ metabolism in the blood and lung tissues. Using S-hexyl GSH, we developed a novel CysLT₁ and CysLT₂ receptors-mediated anaphylaxis guinea pig model that can be useful for not only screening both CysLT₂ and CysLT_1/2 receptors antagonists, but also for functional analysis of CysLT₂ receptors.

Keywords: Anaphylaxis; Asthma; CysLT(1) receptors; CysLT(2) receptors; Cysteinyl leukotrienes; ONO-6950.