CHARACTERIZATION OF A PROSTANOID EP3-RECEPTOR IN GUINEA-PIG AORTA - PARTIAL AGONIST ACTION OF THE NONPROSTANOID ONO-AP-324

1 Contraction of guinea-pig isolated aorta induced by the prostaglandi n E analogue sulprostone (1-400 nM) has a lower maximum response (40%) than that of phenylephrine or U-46619 (TP-receptor agonist). A prosta noid 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 th an on the aorta. 2 ONO-AP-324, a relative of the non-prostanoid prosta cyclin mimetic series, behaves as an EP3 partial agonist on the aorta, inhibiting sulprostone responses but acting synergistically (in a sim ilar manner to sulprostone) with phenylephrine; it may be a useful pha rmacological tool for studying EP3-receptors. 3 Sulprostone contractio ns are markedly suppressed in zero-Ca2+ bathing fluid containing eithe r 2 mM EDTA or 50 mu M EGTA, and by Cd2+ (500 mu M), but are usually u naffected by nifedipine (0.3 mu M) and verapamil (4.44 mu M). Influx o f Ca2+, but not through L-type Ca2+-channels, appears to be the major contractile mechanism. 4 The guinea-pig aorta is a valuable addition t o the vascular EP3 preparations available and may increase our knowled ge of the mechanisms whereby G(i)-coupled receptors mediate vasoconstr iction (c.f. 5-HT1B/D- and alpha(2)-receptors). The possibility of cer tain EP3 agonists distinguishing EP3-receptor isoforms is discussed.