title: Characterization of a prostanoid EP3-receptor in guinea-pig aorta: partial agonist action of the non-prostanoid ONO-AP-324.
abstract: Contraction of guinea-pig isolated aorta induced by the prostaglandin E analogue sulprostone (1-400 nM) has a lower maximum response (40%) than that of phenylephrine or U-46619 (TP-receptor agonist). A prostanoid EP3-receptor subtype is involved based on agonist potency ranking: equi-effective molar ratios (EMR) are sulprostone (EC50 approximately equal to 23 nM) 1.0, SC-46275 0.11, misoprostol 2.2, gemeprost 3.3, PGE2 5.4, 17-phenyl PGE2 6.0, GR-63799 8.9. GR-63799, which contains a bulky ester group, is relatively more potent on neuronal EP3 preparations than on the aorta. ONO-AP-324, a relative of the non-prostanoid prostacyclin mimetic series, behaves as an EP3 partial agonist on the aorta, inhibiting sulprostone responses but acting synergistically (in a similar manner to sulprostone) with phenylephrine; it may be a useful pharmacological tool for studying EP3-receptors. Sulprostone contractions are markedly suppressed in zero-Ca2+ bathing fluid containing either 2 mM EDTA or 50 microM EGTA, and by Cd2+ (500 microM), but are usually unaffected by nifedipine (0.3 microM) and verapamil (4.44 microM). Influx of Ca2+, but not through L-type Ca2+-channels, appears to be the major contractile mechanism. The guinea-pig aorta is a valuable addition to the vascular EP3 preparations available and may increase our knowledge of the mechanisms whereby Gi-coupled receptors mediate vasoconstriction (c.f. 5-HT1B/D- and alpha2-receptors). The possibility of certain EP3 agonists distinguishing EP3-receptor isoforms is discussed.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, New Territories.
authors.forename: R L
authors.initials: RL
authors.lastname: Jones
authors.forename: Y M
authors.initials: YM
authors.lastname: Qian
authors.forename: K M
authors.initials: KM
authors.lastname: Chan
authors.forename: A P
authors.initials: AP
authors.lastname: Yim
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure*; D010120:Oxytocics / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000085:Acetates; D001559:Benzhydryl Compounds; C117875:ONO AP 324; D010120:Oxytocics; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014662:Vasoconstrictor Agents; C016767:sulprostone; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015232:Dinoprostone; D002118:Calcium