Effect of Y-24180, a Platelet-Activating Factor-Receptor Antagonist, on the Antigen-Induced Airway Microvascular Leakage in Guinea Pigs

Abstract

ABSTRACT-The inhibitory effect of Y-24180 ((±)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H-thieno [3,2-on platelet-activating factor (PAF)-or antigen-induced airway microvascular leakage was studied in guinea pigs by oral administration. The tissue content of extravasated Evans blue dye was used as an index of plasma exudation in the trachea, main bronchi, central intrapulmonary airways and peripheral intrapulmonary airways. In all of these tissues, Y-24180 potently inhibited the leakage induced by PAF. The ED50 value of Y-24180 determined in each of the tissues was approximately 0.02 mg/kg, demonstrating that the inhibitory potency of Y-24180 is 4-6 times that of WEB 2086, another PAF antagonist. Even at a dose of 10 mg/kg, however, Y-24180 showed no inhibitory effect on the leakage induced by leukotriene (LT) D4, histamine or bradykinin. In the antigeninduced model of guinea pigs sensitized with aerosolized ovalbumin, Y-24180 (0.1-10 mg/kg) and WEB 2086 (1-100 mg/kg) potently inhibited the microvascular leakage in all of the examined airway tissues except for the trachea. At 1-100 mg/kg, however, both ONO-1078, an LT-receptor antagonist, and OKY-046, a thromboxane A2 synthetase inhibitor, prevented partially but not significantly the antigen-induced leakage. These results provide evidence that endogenous PAF partially mediates the antigen-induced airway microvascular leakage in guinea pigs.

Effect of Y-24180 on Ca2+ movement and proliferation in renal tubular cells

“…The novel finding of this study is that Y-24180, a chemical conventionally thought to exert its in vivo and in vitro actions purely via acting as a specific antagonist of PAF receptors (Cailleaux et al, 1999;Cunningham, 1990;Iwahisa et al, 1996;Kagoshima et al, 1997;Kawaguchi et al, 2001;Komatsu and Amano, 1997;Kuitert and Barnes, 1995;Kusuhara et al, 2000;Michel and Dubertret, 1992;Mizuki et al, 1999;Okamoto et al, 1992;Oshiro et al, 2000;Prozialeck and Niewenhuis, 1991;Stafforini, 2001;Stewart et al, 1990;Suzuki et al, 1998;Terasawa et al, 1990;Watanabe et al, 1991;Yamaguchi et al, 1997Yamaguchi et al, , 1999Yamaguchi et al, , 2000 induces significant increases in [Ca 2 + ] i in renal tubular cells. An increase in [Ca 2 + ] i may cause numerous cellular events including protein activation, gene expression, cell growth (Bootman et al, 1997), just to name a few.…”

“…In vivo, evidence demonstrates that Y-24180 suppresses the allergic cutaneous reactions including eosinophilia (Yamaguchi et al, 1999), cytokine production (Yamaguchi et al, 1999), edema and erythema in actively and passively sensitized mice. Y-24180 also suppresses the allergic airway reactions including eosinophilia , microvascular leakage (Iwahisa et al, 1996), bronchoconstriction (Terasawa et al, 1990) and airway hyperresponsiveness in sensitized animal models. Additionally, Y-24180 inhibits the cyclosporine-induced reduction in renal clearance and the increase in calculated renal vascular resistance in rat (Kawaguchi et al, 2001).…”

Effect of Y-24180, an antagonist at platelet-activating factor (PAF) receptors, on IgE-mediated cutaneous reactions in mice

“…4C). Both Y-24180 and WEB2086 suppress PAF-induced airway microvascular leakage in guinea pigs, and the ED 50 values are reported to be 0.02 and 0.1 mg/kg, respectively [19], indicating that Y-24180 is approximately 5 times more potent than WEB2086. Therefore, the doses of WEB2086 in the single administration used in the present study would be sufficient for its PAF-antagonism.…”