sq-29548 and Asthma

Inhaled prostaglandin (PG) E2 might inhibit asthmatic responses, but the mechanisms involved remain undefined.. We sought to characterize the direct and indirect effects of PGE2 on human small airways with particular reference to the receptors mediating the responses.. Contraction and relaxation were studied in isolated human bronchi with an inner diameter of 1 mm or less.. Low concentrations of PGE2 (0.01-1 μmol/L) relaxed the bronchi precontracted by histamine. The bronchodilator response was inhibited by the E prostanoid (EP) subtype 4 receptor antagonist ONO-AE3-208 but unaffected by the EP2 receptor antagonist PF-04418948. Higher concentrations of PGE2 (10-100 μmol/L) contracted the small airways. However, the TP receptor agonists U-46,619, PGF2α, and PGD2 were more potent than PGE2. Moreover, the bronchoconstrictor responses to PGE2 and all other tested prostanoids, including the EP1/EP3 receptor agonist 17-phenyl trinor PGE2 and the partial FP receptor agonist AL-8810, were uniformly abolished by the TP receptor antagonist SQ-29,548. In the presence of TP and EP4 antagonists, PGE2 inhibited the mast cell-mediated bronchoconstriction resulting from anti-IgE challenge. Measurement of the release of histamine and cysteinyl leukotrienes documented that this bronchoprotective action of PGE2 was mediated by the EP2 receptor, unrelated to bronchodilation, and increased with time of exposure.. The pharmacology of PGE2 in isolated human small airways was different from its profile in animal models. This first demonstration of powerful EP2 receptor-mediated inhibition of IgE-dependent contractions in human airways introduces a new selective target for the treatment of asthma. This EP2 control of mast cell-mediated bronchoconstriction is presumably exaggerated in patients with aspirin-exacerbated respiratory disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Asthma; Azetidines; Bridged Bicyclo Compounds, Heterocyclic; Bronchi; Bronchoconstriction; Cells, Cultured; Dinoprost; Dinoprostone; Fatty Acids, Unsaturated; Histamine; Humans; Hydrazines; Immunoglobulin E; In Vitro Techniques; Mast Cells; Molecular Targeted Therapy; Naphthalenes; Phenylbutyrates; Prostaglandin D2; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Thromboxane

Asthma and chronic obstructive pulmonary disease are airway inflammatory diseases characterised by airflow obstruction. Currently approved bronchodilators such as long-acting β(2) adrenoceptor agonists are the mainstay treatments but often fail to relieve symptoms of chronic obstructive pulmonary disease and severe asthma and safety concerns have been raised over long-term use. The aim of the study was to identify the receptor involved in prostaglandin E(2) (PGE(2))-induced relaxation in guinea pig, murine, monkey, rat and human airways in vitro.. Using an extensive range of pharmacological tools, the relaxant potential of PGE(2) and selective agonists for the EP(1-4) receptors in the presence and absence of selective antagonists in guinea pig, murine, monkey, rat and human isolated airways was investigated.. In agreement with previous studies, it was found that the EP(2) receptor mediates PGE(2)-induced relaxation of guinea pig, murine and monkey trachea and that the EP(4) receptor mediates PGE(2)-induced relaxation of the rat trachea. These data have been confirmed in murine airways from EP(2) receptor-deficient mice (Ptger2). In contrast to previous publications, a role for the EP(4) receptor in relaxant responses in human airways in vitro was found. Relaxant activity of AH13205 (EP(2) agonist) was also demonstrated in guinea pig but not human airway tissue, which may explain its failure in clinical studies.. Identification of the receptor mediating PGE(2)-induced relaxation represents a key step in developing a novel bronchodilator therapy. These data explain the lack of bronchodilator activity observed with selective EP(2) receptor agonists in clinical studies.

Topics: Alprostadil; Animals; Asthma; Bridged Bicyclo Compounds, Heterocyclic; Bronchodilator Agents; Dinoprostone; Fatty Acids, Unsaturated; Guinea Pigs; Humans; Hydrazines; Macaca fascicularis; Methyl Ethers; Mice; Mice, Inbred C57BL; Naphthalenes; Phenylbutyrates; Prostanoic Acids; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Regression Analysis; Species Specificity; Trachea; Xanthones

The effect of lung macrophages stimulated with calcium ionophore on parasympathetic contractile response of canine bronchial rings was studied. Macrophages augmented the contraction induced by electrical field stimulation, an effect that was inhibited by indomethacin and by SQ29548, a thromboxane A2 receptor antagonist, but had no effect on the contractile response to exogenous acetylcholine. These results suggest that macrophage-derived thromboxane A2 facilitates cholinergic neurotransmission prejunctionally in airway smooth muscle.

Topics: Animals; Asthma; Bridged Bicyclo Compounds, Heterocyclic; Bronchi; Dogs; Electric Stimulation; Fatty Acids, Unsaturated; Hydrazines; In Vitro Techniques; Indomethacin; Macrophages; Muscle Contraction; Parasympathetic Nervous System; Thromboxane A2