Immediate hypersensitivity reactions in the guinea-pig conjunctiva: studies with a second-generation leukotriene D4 receptor antagonist, MK-571.
The role of leukotriene D4 (LTD4) as a mediator of immediate hypersensitivity reactions in the guinea-pig conjunctiva was examined using a potent, second-generation LTD4 receptor antagonist, MK-571 (also known as L-660,711). The microvascular permeability changes in the guinea-pig conjunctiva following challenge with either LTD4 or antigen were measured through accumulation of intravenously administered 99mtechnetium-labeled albumin. Topical application of MK-571 (up to 2 h pretreatment) significantly inhibited the conjunctival responses to LTD4 (ED50 of 18-60 ng/eye) but not to histamine. The responses to a single topical antigen challenge in ovalbumin-sensitized guinea pigs were significantly inhibited (44%) by topical treatment with MK-571, in contrast to the lack of effect previously observed with prototypic antagonists. The inhibitory effects of MK-571 did not involve an action on conversion of [3H]LTC4 to LTD4 and LTE4. Following a second antigen challenge (24 h after the first), MK-571 inhibited the resultant permeability changes by 78%. Specific histamine H1 and H2 antagonists similarly inhibited the responses to the first and second challenges (63 and 74%, respectively). The present study suggests that LTD4 is involved in conjunctival hypersensitivity reactions and that potent LTD4 receptor antagonists may be of therapeutic value in the treatment of allergic conjunctivitis.
Chan
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CC
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Qué., Canada.
Dagenais
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F
Firby
P
P
Foster
A
A
Ford-Hutchinson
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AW
D000818:Animals; D003228:Conjunctiva / Q000276:immunology*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006969:Hypersensitivity, Immediate; D017999:Leukotriene E4; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D011422:Propionates / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology
D011422:Propionates; D011804:Quinolines; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C059141:verlukast; D017999:Leukotriene E4; D006632:Histamine; D010047:Ovalbumin