Interaction of prostanoid EP? and TP receptors in guinea-pig isolated aorta: contractile self-synergism of 11-deoxy-16,16-dimethyl PGE?.

ABSTRACT: BACKGROUND AND PURPOSE: Surprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E? (DX-DM PGE?) on pig cerebral artery when used as a selective EP? receptor agonist. This study investigated the selectivity profile of DX-DM PGE?, focusing on the interaction between its EP? and TP (thromboxane A?-like) agonist activities. EXPERIMENTAL APPROACH: Contraction of guinea-pig trachea (EP? system) and aorta (EP? and TP systems) was measured in conventional organ baths. KEY RESULTS: Strong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE? (EP? 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? induced strong contraction, which on the basis of treatment with (DG)-3ap (EP? antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP? and TP receptors. EP?/TP self-synergism also accounted for contraction induced by PGF(2?) and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE? also showed significant EP? agonism on guinea-pig trachea as defined by the EP? antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations ?3 µM. CONCLUSIONS AND IMPLICATIONS: EP?/TP self-synergism, as seen with PGE/PGF analogues in this study, may confound EP? 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? system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed.

SUBMITTER: Jones RL 

PROVIDER: S-EPMC3031070 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature