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.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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EW
Jonsson
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SE
Dahlén
D000707:Anaphylaxis / Q000503:physiopathology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000502:physiology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000502:physiology*; D008168:Lung / Q000502:physiology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D010047:Ovalbumin / Q000276:immunology; D010972:Platelet Activating Factor / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D002722:Chlorobenzenes
D001381:Azepines; D006632:Histamine; D007211:Indoles; D007213:Indomethacin; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D010047:Ovalbumin; D010972:Platelet Activating Factor; D011804:Quinolines; D014230:Triazoles; C060893:MK-886; D002722:Chlorobenzenes; C052518:WEB 2086; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid