POTENT CONTRACTILE ACTIONS OF PROSTANOID EP(3)-RECEPTOR AGONISTS ON HUMAN ISOLATED PULMONARY-ARTERY

1 In 13 of 15 experiments, prostaglandin E(2) (PGE(2)) and sulprostone (a prostanoid EF(1)/EF(3)-receptor agonist) contracted isolated rings of human pulmonary artery at low concentrations (greater than or equal to 5 and greater than or equal to 0.5 nM respectively). Tissue was obtained from patients undergoing surgery mainly for carcinoma of the lung. Characterization of the receptors involved was complicated by loss of sensitivity to the contractile PGE action over the experimental period. In contrast, contractile responses to KCl, phenylephrine and the specific thromboxane (TP-) receptor agonist, U-46619, did not decrease with time. 2 The relative contractile potencies for seven PGE analogues, measured during the first few hours after setting up the preparations, were as follows: sulprostone > misoprostol = gemeprost greater than or equal to PGE(2) greater than or equal to GR 63799X > 17-phenyl-omega-trinor PGE(2) greater than or equal to 11-deoxy PGE(1). This ranking indicates that an EP(3)-receptor is involved. 3 The contractile action of sulprostone was not blocked by the TP-receptor antagonists, EP 169 and GR 32191, and the EP(1)-receptor antagonist, AH 6809. 4 In two experiments, PGE(2) (50 nM) reduced basal tone and sulprostone was a weak contractile agent. Phenylephrine-induced tone was also inhibited by PGE(2) (EC(50) = 5-20 nM), 11-deoxy PGE(1) and butaprost (a selective EP(2)-receptor agonist); the latter prostanoids were about 2 and 4 times less potent than PGE(2) respectively. Interactions with phenylephrine were different in experiments where PGE(2) alone was contractile: PGE(2) induced contraction superimposed on the phenylephrine response and 11-deoxy PGE(1) induced either further contraction or had no effect. Butaprost produced relaxation at high concentrations; this may not be an EP(2) action since preparations were highly sensitive to relaxant actions of prostacyclin (IP-) receptor agonists (cicaprost and TEI-9063). 5 The study has shown that in the majority of experiments on the human isolated pulmonary artery, the contractile EF(3) system outweighed the relaxant EP(2) system. However, in two experiments the reverse was true. It is not clear to what extent these differences are due to disease processes affecting the tissues. The findings are discussed in relation to the adverse cardiovascular responses occasionally encountered during treatment of postpartum haemorrhage with sulprostone, and more generally to the clinical use of EP-receptor agonists in man.