Interactions between leukotrienes and histamine in the anaphylactic contraction of guinea pig lung parenchyma.

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.