Effects of Zafirlukast, a Cysteinyl-Leukotriene Receptor Antagonist, in a Low Dose Endotoxin Infusion Model of Feline Sepsis
Cysteinyl-leukotrienes (cys-LT) are important inflammatory mediators contributing to systemic inflammation and hemodynamic instability during sepsis and there is experimental evidence that inhibiting the effects of leukotrienes ameliorates these sequelae. We hypothesized that the cys-LT receptor antagonist, zafirlukast, an inexpensive and readily available cys-LT receptor antagonist, would attenuate systemic inflammation and hemodynamic derangement in a low-dose endotoxin infusion model of feline sepsis.
This was a randomized, blinded, placebo-controlled cross over design, utilizing 6 adult cats. The cats were given a priming dose of lipopolysaccharide (LPS) (1 mcg/kg, IV) at time 0 and then either placebo (flour) or zafirlukast 10 mg, orally at 6 and 12 hours. The cats were challenged at 14 hours with LPS (2 mcg/kg/h x 6h, IV). There was a 30 day washout period between evaluations. Rectal temperature, heart rate (HR), systolic arterial blood pressure (BP), plasma interleukin-6 (IL-6) concentration and tumor necrosis factor (TNF) activity were evaluated. Repeated measures ANOVA with post-hoc Tukey's test or paired t-test were used for statistical analysis with a p-value < 0.05 considered significant.
LPS administration induced significant systemic inflammation and hemodynamic derangement as indicated by increased mean±SD rectal temperature at 4, 5 and 6 hours (baseline, 39.1±0.5; 4h, 39.9±0.4; 5h, 40.0±0.3; 6h, 39.8±0.4 °C; p<0.001), increased IL-6 concentrations at 3 hours (baseline, 68.8±194.8; 3h, 883.7±492.2 pg/mL; p<0.004), increased TNF activity at 1.5 hours (baseline, ND; 1.5 h, 151±49 ng/ml; p<0.001) and relative hypotension at 6 hours (baseline, 145.7±19.8; 6h, 110±27.54 mmHg; p=0.03), when compared to baseline regardless of treatment group. There was no significant difference between the placebo and zafirlukast treatment groups in regards to rectal temperature, HR, BP, IL-6 concentrations or TNF activity at any time point.
These data indicate that antagonism of cys-LT with zafirlukast has neither beneficial nor deleterious effects in this model of feline sepsis.