Although the effectiveness of CysLT receptor antagonists on asthma has been clinically established, the effects of CysLT receptor antagonists are still unclear. The purpose of this study was to develop a new CysLT and CysLT receptors-mediated anaphylaxis guinea pig model using S-hexyl GSH, a γ-glutamyl transpeptidase (GTP) inhibitor, to suppress conversion of LTC to LTD. 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 CysLT receptor antagonist, but not by the CysLT receptor antagonist BayCysLTRA. However, under treatment with S-hexyl-GSH, the inhibitory effect of motelukast was dramatically diminished, whereas that of BayCysLTRA was markedly increased. The dual CysLT 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 LTC metabolism in the blood and lung tissues. Using S-hexyl GSH, we developed a novel CysLT and CysLT receptors-mediated anaphylaxis guinea pig model that can be useful for not only screening both CysLT and CysLT receptors antagonists, but also for functional analysis of CysLT receptors.
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