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.