BACKGROUND AND PURPOSESurprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E2 (DX-DM PGE2) on pig cerebral artery when used as a selective EP3 receptor agonist. This study investigated the selectivity profile of DX-DM PGE2, focusing on the interaction between its EP3 and TP (thromboxane A2-like) agonist activities.
EXPERIMENTAL APPROACHContraction of guinea-pig trachea (EP1 system) and aorta (EP3 and TP systems) was measured in conventional organ baths.
KEY RESULTSStrong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE2 (EP3 agonists) was only seen under priming with a second contractile agent such as phenylephrine, histamine or U-46619 (TP agonist). In contrast, DX-DM PGE2 induced strong contraction, which on the basis of treatment with (DG)-3ap (EP3 antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP3 and TP receptors. EP3/TP self-synergism also accounted for contraction induced by PGF2a and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE2 also showed significant EP1 agonism on guinea-pig trachea as defined by the EP1 antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations Ն3 mM.
CONCLUSIONS AND IMPLICATIONSEP3/TP self-synergism, as seen with PGE/PGF analogues in this study, may confound EP3 agonist potency comparisons and the characterization of prostanoid receptor systems. The competitive profile of a TP antagonist may be distorted by variation in the silent/overt contraction profile of the EP3 system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed.
AbbreviationsFA, free acid form of a C1-ester or C1-amide prostanoid; nH, Hill slope for a sigmoidal log concentration-response curve; pA2, negative logarithm of the molar concentration of antagonist producing a dose ratio of 2; pEC50, negative logarithm of the agonist concentration inducing 50% maximum response; PGE2, prostaglandin E2; pIC50, negative logarithm of the molar concentration producing 50% inhibition of an established response; TXA2, thromboxane A2
IntroductionProstaglandin E2 (PGE2) has a broad range of actions including excitation of smooth muscle cells mediated by prostanoid EP1 and EP3 receptors and inhibition mediated by EP2 and EP4 subtypes (see Coleman et al., 1994; receptor nomenclature follows Alexander et al., 2009). Its contractile action on pig BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 British Journal of Pharmacology (2011) isolated cerebral artery has been linked to activation of both EP1 and EP3 receptors operating through the phosphatidyl inositol pathway (Jadhav et al., 2004). We had two major concerns about this study. First, very high concentrations (30-300 mM) of the EP1 antagonist AH-6809 (Coleman et al., 1985;1987) were used to identify the EP1 component and also to gauge the selectivity of 11-deoxy-16,16-dimethyl PGE2 (DX-DM PGE...