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

Abstract

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 (EC₅₀∼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.

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 μM EGTA, and by Cd²⁺ (500 μM), but are usually unaffected by nifedipine (0.3 μM) and verapamil (4.44 μM). 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-HT_1B/D- and α₂-receptors). The possibility of certain EP₃ agonists distinguishing EP₃-receptor isoforms is discussed.

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