Interaction of prostanoid EP₃ and TP receptors in guinea-pig isolated aorta: contractile self-synergism of 11-deoxy-16,16-dimethyl PGE₂.
OBJECTIVE
Surprisingly 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.


METHODS
Contraction of guinea-pig trachea (EP₁ system) and aorta (EP₃ and TP systems) was measured in conventional organ baths.


RESULTS
Strong 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 PGF(2α) 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 ≥3 µM.


CONCLUSIONS
EP₃/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.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. robert.l.jones@strath.ac.uk
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Woodward
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D058990:Molecular Targeted Therapy; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000819:agonists / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects / Q000502:physiology
C481059:11-deoxy,16,16-dimethyl prostaglandin E(2); D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D017482:Receptors, Thromboxane; D015232:Dinoprostone