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Interaction of prostanoid EP 3 and TP receptors in guinea‐pig isolated aorta: contractile self‐synergism of 11‐deoxy‐16,16‐dimethyl PGE 2
Author(s) -
Jones RL,
Woodward DF
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01039.x
Subject(s) - agonist , prostanoid , chemistry , thromboxane , medicine , receptor , contraction (grammar) , phenylephrine , endocrinology , guinea pig , prostaglandin e , antagonist , prostaglandin , thromboxane a2 , pharmacology , biology , biochemistry , platelet , blood pressure
BACKGROUND AND PURPOSE Surprisingly high contractile activity was reported for 11‐deoxy‐16,16‐dimethyl prostaglandin E 2 (DX‐DM PGE 2 ) on pig cerebral artery when used as a selective EP 3 receptor agonist. This study investigated the selectivity profile of DX‐DM PGE 2 , focusing on the interaction between its EP 3 and TP (thromboxane A 2 ‐like) agonist activities. EXPERIMENTAL APPROACH Contraction of guinea‐pig trachea (EP 1 system) and aorta (EP 3 and TP systems) was measured in conventional organ baths. KEY RESULTS Strong contraction of guinea‐pig aorta to sulprostone and 17‐phenyl PGE 2 (EP 3 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 2 induced strong contraction, which on the basis of treatment with (DG)‐3ap (EP 3 antagonist) and/or BMS‐180291 (TP antagonist) was attributed to self‐synergism arising from co‐activation of EP 3 and TP receptors. EP 3 /TP self‐synergism also accounted for contraction induced by PGF 2α and its analogues (+)‐cloprostenol and latanoprost‐FA. DX‐DM PGE 2 also showed significant EP 1 agonism on guinea‐pig trachea as defined by the EP 1 antagonists SC‐51322, (ONO)‐5‐methyl‐1 and AH‐6809, although AH‐6809 exhibited poor specificity at concentrations ≥3 µM. CONCLUSIONS AND IMPLICATIONS EP 3 /TP self‐synergism, as seen with PGE/PGF analogues in this study, may confound EP 3 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 3 system in different studies. The relevance of self‐synergism to in vivo actions of natural prostanoid receptor agonists is discussed.