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; 0.1ng/ml to 0.1mg/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.