Interactive effects of peptidoleukotrienes and histamine on microvascular permeability and their involvement in experimental cutaneous and conjunctival immediate hypersensitivity.
The involvement of peptidoleukotrienes (LTs) in mediating the increase in microvascular permeability associated with experimental cutaneous immediate hypersensitivity was studied by examining the effect of SK&F 104353, a potent and selective LT-antagonist, on the response evoked by graded, intradermal injections of antigen. SK&F 104353, employed at doses that profoundly blocked LTC4, LTD4 and LTE4 responses, significantly reduced the response produced by experimental cutaneous immediate hypersensitivity. The response to the lowest antigen dose (0.1 microgram) was, however, entirely insusceptible to SK&F 104353. The effect of SK&F 104353 was also examined in combination with a pyrilamine-cimetidine dosing regimen sufficient to remove the histaminergic component of cutaneous immediate hypersensitivity. The non-histaminergic component associated with higher antigen doses (10 and 100 micrograms) was significantly reduced but not abolished by SK&F 104353; the non-histaminergic component associated with low antigen doses (0.1 and 1 microgram) was not susceptible to SK&F 104353. Thus, the increase in cutaneous microvascular permeability evoked by immediate hypersensitivity appears to comprise three components: (1) A histaminergic response apparent for all antigen doses; (2) a LT-mediated component which is manifest in response to high antigen doses; (3) a third, unidentified component that is present for the entire antigen dose-range but contributes less to the overall response when high antigen doses are used. A distinct non-histaminergic, non-leukotriene mediated component was not a feature of conjunctival immediate hypersensitivity. SK&F 104353 administered in combinatio with pyrilamine-cimetidine virtually abolished the response with a small residual remaining only for the highest antigen dose. In further contrast to cutaneous immediate hypersensitivity, SK&F 104353 alone was comparatively ineffective in type 1 allergic conjunctivitis. This difference in susceptibility to SK&F 104353 appears to reflect the type of histamine-LTD4 interactive effect on microvascular permeability. Histamine and LTD4 were additive in terms of cutaneous microvascular permeability. In the conjunctiva, histamine and LTD4 appeared mutually exclusive in that the level of response produced by the combination tended not to exceed that of the single component which caused the greater effect.
Department of Discovery Research, Allergan Inc., Irvine, CA 92715.
D F
DF
Woodward
A L
AL
Nieves
L S
LS
Williams
R K
RK
Gary
M A
MA
Wasserman
J G
JG
Gleason
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002860:Chromium Radioisotopes; D002927:Cimetidine / Q000494:pharmacology; D003228:Conjunctiva / Q000098:blood supply / Q000503:physiopathology; D003998:Dicarboxylic Acids / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology*; D006969:Hypersensitivity, Immediate / Q000503:physiopathology*; D007457:Iodine Radioisotopes; D015289:Leukotrienes / Q000494:pharmacology*; D008297:Male; D010047:Ovalbumin / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D012867:Skin / Q000098:blood supply / Q000503:physiopathology
D002860:Chromium Radioisotopes; D003998:Dicarboxylic Acids; D007457:Iodine Radioisotopes; D015289:Leukotrienes; D002927:Cimetidine; D006632:Histamine; D010047:Ovalbumin; D011738:Pyrilamine; C052393:pobilukast