Background and purpose
Surprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E&sub2; (DX-DM PGE&sub2;) on pig cerebral artery when used as a selective EP&sub3; receptor agonist. This study investigated the selectivity profile of DX-DM PGE&sub2;, focusing on the interaction between its EP&sub3; and TP (thromboxane A&sub2;-like) agonist activities. Experimental approach: Contraction of guinea-pig trachea (EP&sub1; system) and aorta (EP&sub3; and TP systems) was measured in conventional organ baths. Key
Purpose
Surprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E&sub2; (DX-DM PGE&sub2;) on pig cerebral artery when used as a selective EP&sub3; receptor agonist. This study investigated the selectivity profile of DX-DM PGE&sub2;, focusing on the interaction between its EP&sub3; and TP (thromboxane A&sub2;-like) agonist activities. Experimental approach: Contraction of guinea-pig trachea (EP&sub1; system) and aorta (EP&sub3; and TP systems) was measured in conventional organ baths. Key
Results
Strong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE&sub2; (EP&sub3; agonists) was only seen under priming with a second contractile agent such as phenylephrine, histamine or U-46619 (TP agonist). In contrast, DX-DM PGE&sub2; induced strong contraction, which on the basis of treatment with (DG)-3ap (EP&sub3; antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP&sub3; and TP receptors. EP&sub3;/TP self-synergism also accounted for contraction induced by PGF(2α) and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE&sub2; also showed significant EP&sub1; agonism on guinea-pig trachea as defined by the EP&sub1; antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations ≥3 µM. Conclusions and implications: EP&sub3;/TP self-synergism, as seen with PGE/PGF analogues in this study, may confound EP&sub3; 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 EP&sub3; system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed.