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Interactions among three classes of mediators explain antigen-induced bronchoconstriction in the isolated perfused and ventilated guinea pig lung.
J Pharmacol Exp Ther. 2003 Oct; 307(1):408-18.JP

Abstract

Intravascular challenge of isolated perfused and ventilated guinea pig lung (IPL) from actively sensitized guinea pigs, with cumulatively increasing (10-10,000 microg) doses of ovalbumin (OVA), resulted in dose-dependent and reproducible reductions in lung conductance. The antihistamines mepyramine (1 microM) and metiamide (1 microM), the leukotriene antagonist zafirlukast (0.1 microM), or the cyclooxygenase enzyme (COX) inhibitor diclofenac (10 microM) each caused a parallel and rightward shift in the dose-response relation for OVA, providing evidence for contributions of histamine, cysteinyl-leukotrienes, and COX products to the OVA-induced bronchoconstriction in the IPL. Moreover, when all three drugs were combined there was a complete abolishment of the response to OVA. When two antagonists or inhibitors were combined, the results, however, were more complex. The 5-lipoxygenase inhibitor BAY x1005 (30 microM) and the thromboxane (TP) receptor antagonist BAY u3405 (1 microM) given as single treatment did not inhibit the response to OVA. However, combinations of different antagonists/inhibitors, including BAY x1005 and BAY u3405, caused pronounced inhibitions of the antigen responses, suggesting synergism in action. On the basis of these data it was concluded that although histamine and cysteinyl-leukotrienes mediate the major part of the bronchoconstriction, one or several prostanoids other than thromboxane contribute to the bronchoconstriction evoked by OVA. Moreover, the effect of diclofenac involved a dual action because it also made the IPL less sensitive to histamine and LTD4. The findings resemble and extend recent observations in clinical studies of patients with asthma and support the usefulness of this particular model in airway pharmacology.

Authors+Show Affiliations

Division of Physiology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12954791

Citation

Sundström, Ewa, et al. "Interactions Among Three Classes of Mediators Explain Antigen-induced Bronchoconstriction in the Isolated Perfused and Ventilated Guinea Pig Lung." The Journal of Pharmacology and Experimental Therapeutics, vol. 307, no. 1, 2003, pp. 408-18.
Sundström E, Låstbom L, Ryrfeldt A, et al. Interactions among three classes of mediators explain antigen-induced bronchoconstriction in the isolated perfused and ventilated guinea pig lung. J Pharmacol Exp Ther. 2003;307(1):408-18.
Sundström, E., Låstbom, L., Ryrfeldt, A., & Dahlén, S. E. (2003). Interactions among three classes of mediators explain antigen-induced bronchoconstriction in the isolated perfused and ventilated guinea pig lung. The Journal of Pharmacology and Experimental Therapeutics, 307(1), 408-18.
Sundström E, et al. Interactions Among Three Classes of Mediators Explain Antigen-induced Bronchoconstriction in the Isolated Perfused and Ventilated Guinea Pig Lung. J Pharmacol Exp Ther. 2003;307(1):408-18. PubMed PMID: 12954791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interactions among three classes of mediators explain antigen-induced bronchoconstriction in the isolated perfused and ventilated guinea pig lung. AU - Sundström,Ewa, AU - Låstbom,Lena, AU - Ryrfeldt,Ake, AU - Dahlén,Sven-Erik, Y1 - 2003/09/03/ PY - 2003/9/5/pubmed PY - 2003/10/24/medline PY - 2003/9/5/entrez SP - 408 EP - 18 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 307 IS - 1 N2 - Intravascular challenge of isolated perfused and ventilated guinea pig lung (IPL) from actively sensitized guinea pigs, with cumulatively increasing (10-10,000 microg) doses of ovalbumin (OVA), resulted in dose-dependent and reproducible reductions in lung conductance. The antihistamines mepyramine (1 microM) and metiamide (1 microM), the leukotriene antagonist zafirlukast (0.1 microM), or the cyclooxygenase enzyme (COX) inhibitor diclofenac (10 microM) each caused a parallel and rightward shift in the dose-response relation for OVA, providing evidence for contributions of histamine, cysteinyl-leukotrienes, and COX products to the OVA-induced bronchoconstriction in the IPL. Moreover, when all three drugs were combined there was a complete abolishment of the response to OVA. When two antagonists or inhibitors were combined, the results, however, were more complex. The 5-lipoxygenase inhibitor BAY x1005 (30 microM) and the thromboxane (TP) receptor antagonist BAY u3405 (1 microM) given as single treatment did not inhibit the response to OVA. However, combinations of different antagonists/inhibitors, including BAY x1005 and BAY u3405, caused pronounced inhibitions of the antigen responses, suggesting synergism in action. On the basis of these data it was concluded that although histamine and cysteinyl-leukotrienes mediate the major part of the bronchoconstriction, one or several prostanoids other than thromboxane contribute to the bronchoconstriction evoked by OVA. Moreover, the effect of diclofenac involved a dual action because it also made the IPL less sensitive to histamine and LTD4. The findings resemble and extend recent observations in clinical studies of patients with asthma and support the usefulness of this particular model in airway pharmacology. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12954791/Interactions_among_three_classes_of_mediators_explain_antigen_induced_bronchoconstriction_in_the_isolated_perfused_and_ventilated_guinea_pig_lung_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12954791 DB - PRIME DP - Unbound Medicine ER -