Characterization of a prostanoid EP3-receptor in guinea-pig aorta:: partial agonist action of the non-prostanoid ONO-AP-324

1 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 (EC(50)similar to 23 nM) 1.0, SC-46275 0.11, misoprostol 2.2, gemeprost 3.3, PGE(2) 5.4, 17-phenyl PGE(2) 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. 2 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. 3 Sulprostone contractions are markedly suppressed in zero-Ca2+ bathing fluid containing either 2 mM EDTA or 50 mu M EGTA, and by Cd2+ (500 mu M), but are usually unaffected by nifedipine (0.3 mu M) and verapamil (4.44 mu M). Influx of Ca2+, but not through L-type Ca2+-channels, appears to be the major contractile mechanism. 4 The guinea-pig aorta is a valuable addition to the vascular EP3 preparations available and may increase our knowledge of the mechanisms whereby G(i)-coupled receptors mediate vasoconstriction (c.f. 5-HT1B/D- and alpha(2)-receptors). The possibility of certain EP3 agonists distinguishing EP3-receptor isoforms is discussed.