l-663536 and Anaphylaxis

The aim of the study was to investigate if antigen-induced contraction of guinea pig lung parenchyma (GPLP) was an appropriate model for the study of antileukotriene drugs. Antileukotrienes have recently shown antiasthmatic effects in humans. Challenge of GPLP with a cumulatively increasing concentration of antigen evoked a graded contractile response. The antigen response could be divided into an immediate peak phase and a plateau phase of long duration. Histamine antagonism alone (mepyramine, H1, and metiamide, H2) had no effect on the response, whereas 5-lipoxygenase (5-lox) inhibitors (BAY x1005, MK-886 or BWA4C) depressed the plateau phase. When 5-lipoxygenase inhibition (BAY x1005 or MK-886) or cysteinyl-leukotriene receptor antagonism (ICI 198,615) was combined with histamine antagonism, there was a major attenuation of both components of the antigen response, leaving only a small residual response. In contrast, cyclooxygenase inhibition (diclofenac or indomethacin), antagonism of platelet-activating factor (WEB 2086) and thromboxane receptor antagonism combined with inhibition of thromboxane synthesis (BAY u3405 and CS-518) failed to inhibit the antigen response. In conclusion, cysteinyl-leukotrienes and histamine synergistically mediated the major part of the Schultz-Dale response in GPLP. The characteristics of GPLP anaphylaxis closely resembled those of antigen-challenged human bronci, supporting that antigen challenge of GPLP is a suitable model in experimental asthma research.

Topics: Anaphylaxis; Animals; Azepines; Guinea Pigs; Histamine; In Vitro Techniques; Indoles; Indomethacin; Leukotriene Antagonists; Leukotrienes; Lung; Male; Muscle Contraction; Ovalbumin; Platelet Activating Factor; Quinolines; Triazoles

Leukotriene C4 (LTC4) underwent rapid elimination from the circulating blood and was extensively converted to LTD4 within the vascular space of the guinea pig. To mimic the elimination and metabolism of endogenous LTC4 generated during anaphylaxis, 14,15-3H-labeled LTC4 was infused intravenously over a period of 15 min, leading to a recovery in bile of 85% of the infused LT radioactivity within 2 h. Corresponding to the tracer studies, LTD4 and, to a lesser extent, LTC4 were the predominant endogenous cysteinyl LTs in guinea pig bile. The biliary production rate of endogenous LTD4 increased from 0.3 +/- 0.1 to 6.2 +/- 1.8 pmol x min-1 x kg-1 (p less than 0.001) during anaphylactic shock induced by intravenous injection of OVA (0.2 mg/kg) into sensitized guinea pigs. A novel LT biosynthesis inhibitor (MK-886; 10 mg/kg, i.v., 15 min before antigen challenge) suppressed the antigen-induced cysteinyl LT production by greater than 92% (p less than 0.001). This inhibition of systemic LTC4 formation was associated with a complete protection against lethal anaphylactic shock in animals pretreated in addition with the H1 receptor antagonist pyrilamine. Pretreatment with either the inhibitor of LT synthesis or the histamine receptor antagonist reduced the lethality during anaphylactic shock from 100 to 60 and 78%, respectively. In artificially ventilated, pyrilamine-pretreated animals, the antigen-induced decrease in dynamic lung compliance and the rise in hematocrit were significantly reduced (p less than 0.05) by pretreatment with the inhibitor of LT synthesis. Dexamethasone at high doses (10 mg/kg, i.p., once daily for 7 d, or in a single dose of 10 mg/kg, i.v., 3.5 h before challenge) had no inhibitory effect on LT generation during anaphylaxis in vivo. However, in resident peritoneal macrophages, harvested from these dexamethasone-treated sensitized guinea pigs and stimulated with zymosan, both cysteinyl LT and 6-keto-PGF1 alpha formation were strongly suppressed. These studies indicate an important role of cysteinyl LTs in systemic anaphylaxis in vivo and demonstrate the blockade of anaphylactic LT generation by a novel inhibitor of LT biosynthesis (MK-886) but not by dexamethasone.

Topics: Anaphylaxis; Animals; Dexamethasone; Guinea Pigs; Hemodynamics; Indoles; Leukotriene Antagonists; Male; Ovalbumin; Respiration; SRS-A