title: Antagonising EP1 and EP2 receptors reveal that the TP receptor mediates a component of antigen-induced contraction of the guinea pig trachea.
abstract: The role of different cyclooxygenase (COX) metabolites released after antigen exposure has been difficult to assess due to simultaneous release of dominant constrictors such as histamine and cysteinyl-leukotrienes (CysLT). In addition prostaglandin E2 (PGE2) also has a powerful effect on basal tone. The aim was to exclude PGE2, histamine and CysLTs from the antigen-induced contraction to define the possible involvement of remaining COX metabolites. Isometric force was measured in guinea pig trachea after exposure to cumulatively increasing concentrations of ovalbumin (OVA; 0.1 ng/ml to 0.1 mg/ml) in the absence or presence of biosynthesis inhibitors and receptor antagonists. Challenge with OVA induced a concentration-dependent contraction that reached 75% of maximal tissue response. COX-inhibition or a combination of EP1 and EP2 receptor antagonism (ONO-8130 and PF-04418948) completely abolished the tone, resulting in an augmented antigen response. COX inhibition in combination with either antihistamines or antileukotrienes (FLAP inhibitor or CysLT1-2 receptor antagonist) displayed no difference compared to COX inhibition alone. However, a combination of all three classes reduced the contraction to 30%, revealing an unknown contractile component. Exchanging COX inhibition with EP1-2 receptor antagonists together with antihistamines and antileukotrienes could not decrease the contraction more than to 50%. However, when a TP receptor antagonist (SQ-29,548) was further included, the maximal antigen contraction reached 30%, similar as previously, clearly revealing a TP-mediated contractile component. PGE2 primarily regulate the basal tone via EP1 and EP2, whereas prostanoids, such as TXA2 and PGD2, contribute as mediator of the antigen-response by activation of the TP receptor.
authors.affiliation: Unit for Experimental Asthma and Allergy Research, Centre for Allergy Research, The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Säfholm
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
mesh_terms: D000818:Animals; D000941:Antigens / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003545:Cysteine / Q000037:antagonists & inhibitors; D015232:Dinoprostone / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism; D006633:Histamine Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D015289:Leukotrienes; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D010047:Ovalbumin / Q000494:pharmacology; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*
chemical_list: D000941:Antigens; D016861:Cyclooxygenase Inhibitors; D006633:Histamine Antagonists; D015289:Leukotrienes; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D017482:Receptors, Thromboxane; C112381:cysteinyl-leukotriene; D006632:Histamine; D010047:Ovalbumin; D015232:Dinoprostone; D003545:Cysteine
keywords: EP receptor; Eicosanoids; Guinea pig trachea; Organ bath; Ovalbumin; TP receptor