Endogenous PGE 2 contributes to antigen-induced contractions of guinea pig trachea

We have previously shown that PGE 2 via EP 1 receptors maintains basal tone of guinea pig trachea (GPT). Our aim was to assess if antagonism of PGE 2 also affected antigen-induced contractions. Isometric responses to administration of ovalbumin (OVA) were recorded in GPT from guinea pigs sensitized to OVA and expressed as% of the maximal contraction to histamine 100μM. Before challenge with OVA, the selective EP 1 (ONO-8130; 10nM) antagonist was given to naïve preparations as well as together with different combinations of inhibitors and antagonists of histamine (mepyramine and metiamide), leukotrienes (zileuton) and prostaonids (indomethacin). As shown previously, inhibition of one or two mediator classes, generally had no significant effects, whereas triple mediator antagonism (antihistamines+zileuton+indomethacin) abolished the response to OVA challenge. However, EP 1 antagonism partly reduced the antigen contraction. Moreover, when the EP 1 antagonist was given together with antihistamines and zileuton, the response to OVA was abolished (Table 1). Table 1. Contraction (% max) to highest OVA dose Control 75±5 M & M 72±7 INDO 84±5 ONO 59±4* ZIL 77±1 INDO + M & M 83±1 ONO + M & M 59±10 ZIL + M & M 65±7 ZIL + M & M + INDO 5±3* # ZIL + M & M + ONO 6±3* # *p<0.05 vs control, # p<0.05 vs ZIL + M & M. Effect of indomethacin together with antihistamines and anti-leukotrienes confirms that prostanoids mediate part of the antigen-induced contraction. The new finding is that EP 1 antagonism mimics the effect of indomethacin. This suggests that PGE 2 is the main prostanoid mediating the antigen-induced contractions of GPT, a preparation that is known to respond similarly to human airways where the effects of PGE 2 still await complete delineation.