Biomaterial Database

Competition of leukotrienes and ICI-198,615 for [3H]LTD4 binding sites in guinea pig lung membranes suggests the involvement of two LTD4 receptor subtypes. 1991

J T Shirley, and J B Cheng

Department of Immunology and Infectious Diseases, Pfizer Inc., Groton, Connecticut.

Pharmacological analysis of the effects of leukotriene D4 (LTD4) antagonists on contraction of guinea pig airway smooth muscle to leukotrienes reveals the presence of two subtypes of the LTD4 receptor. This finding is, however, inconsistent with [3H]LTD4 equilibrium binding results, which show no evidence of a heterogeneity of pulmonary [3H]LTD4 binding sites. It is possible that LTD4 binds to the two receptor subsets with equal affinity, and the pharmacological difference between them lies in the relative ability of leukotriene (LT) agonists and antagonists to interact at the receptor sites. This study was, therefore, undertaken to determine the rank order of potency of LTs and ICI-198,615 in competing with [3H]LTD4 for their respective binding sites in guinea pig lung membranes. To determine precisely the inhibitory constant (Ki) of LTC4, we used the irreversible gamma-glutamyl transpeptidase inhibitor, acivicin (AT-125), to prevent LTC4 metabolism. Incubation of lung membranes with 5 mM AT-125 for 120 min at 25 degrees C resulted in greater than 98% recovery of LTC4. Unlike L-serine-borate complex, AT-125 failed to inhibit pulmonary [3H]LTD4 binding. These results suggest that AT-125 can be used in this study. Nonlinear least squares analysis of the results of LTD4/[3H]LTD4 or ICI-198,615/[3H]LTD4 competitive binding reveals that either LTD4 (Ki = 0.49 nM) or ICI-198,615 (Ki = 6.89 nM) interacts at a single homogenous population of [3H]LTD4 binding sites. However, the data of competitive binding results of LTC4 (in the presence of AT-125) or LTE4 are best fitted for its interaction with high- and low-affinity [3H]LTD4 binding sites, designated as LTD4 alpha and LTD4 beta sites, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

UI	MeSH Term	Description	Entries
D007191	Indazoles	A group of heterocyclic aromatic organic compounds consisting of the fusion of BENZENE and PYRAZOLES.	Indazole
D007555	Isoxazoles	Azoles with an OXYGEN and a NITROGEN next to each other at the 1,2 positions, in contrast to OXAZOLES that have nitrogens at the 1,3 positions.	Isoxazole
D008168	Lung	Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood.	Lungs
D008274	Magnesium	A metallic element that has the atomic symbol Mg, atomic number 12, and atomic weight 24.31. It is important for the activity of many enzymes, especially those involved in OXIDATIVE PHOSPHORYLATION.
D011971	Receptors, Immunologic	Cell surface molecules on cells of the immune system that specifically bind surface molecules or messenger molecules and trigger changes in the behavior of cells. Although these receptors were first identified in the immune system, many have important functions elsewhere.	Immunologic Receptors,Immunologic Receptor,Immunological Receptors,Receptor, Immunologic,Receptors, Immunological
D006168	Guinea Pigs	A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research.	Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001667	Binding, Competitive	The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.	Competitive Binding
D013189	SRS-A	A group of LEUKOTRIENES; (LTC4; LTD4; and LTE4) that is the major mediator of BRONCHOCONSTRICTION; HYPERSENSITIVITY; and other allergic reactions. Earlier studies described a "slow-reacting substance of ANAPHYLAXIS" released from lung by cobra venom or after anaphylactic shock. The relationship between SRS-A leukotrienes was established by UV which showed the presence of the conjugated triene. (From Merck Index, 11th ed)	Slow Reacting Substance of Anaphylaxis
D015289	Leukotrienes	A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system.	Leukotriene