Potent contractile actions of prostanoid EP₃‐receptor agonists on human isolated pulmonary artery

Abstract

1In 13 of 15 experiments, prostaglandin E2 (PGE2) and sulprostone (a prostanoid EPI/EP3-receptor agonist) contracted isolated rings of human pulmonary artery at low concentrations () 5 and > 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 KCI, 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 > PGE2 > GR 63799X> 17-phenyl-w-trinor PGE2 1 1 1-deoxy PGE1. This ranking indicates that an EP3-receptor is involved. 3 The contractile action of sulprostone was not blocked by the TP-receptor antagonists, EP 169 and GR 32191, and the EPI-receptor antagonist, AH 6809.4 In two experiments, PGE2 (50 nM) reduced basal tone and sulprostone was a weak contractile agent.Phenylephrine-induced tone was also inhibited by PGE2 (EC50 = 5-20 nM), 1 1-deoxy PGEI and butaprost (a selective EP2-receptor agonist); the latter prostanoids were about 2 and 4 times less potent than PGE2 respectively. Interactions with phenylephrine were different in experiments where PGE2 alone was contractile: PGE2 induced contraction superimposed on the phenylephrine response and 11-deoxy PGE, induced either further contraction or had no effect. Butaprost produced relaxation at high concentrations; this may not be an EP2 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 EP3 system outweighed the relaxant EP2 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.

Prostacyclin release and receptor activation: differential control of human pulmonary venous and arterial tone

“…The potentiation effect of the EP 1 -receptor antagonist AH6809 on the exogenous PGI 2 -induced relaxations suggests the activation of the EP 1 -receptor described in the human pulmonary veins (Walch et al, 2001) but not in the arteries (Qian et al, 1994). The results obtained in human pulmonary veins suggest that exogenous PGI 2 induced vasorelaxation via the IP-receptors and this effect is counterbalanced by the activation of the EP 1 -receptors.…”

“…Similarly, PGE 2 would also not be a candidate to explain the difference in ACh-induced relaxation between these vessels. PGE 2 may activate EP 1 (contractant) and an EP (relaxant) receptors in human pulmonary veins (Walch et al, 1999;2001) as well as EP 3 (contractant) receptor in the arteries (Qian et al, 1994). In addition, the quantities of PGE 2 released are the same in both pulmonary preparations (Carter et al, 1984; Release of 6-keto-PGF 1a by isolated human pulmonary vessels stimulated with AA.…”

Sulprostone‐induced reduction of myocardial infarct size in the rabbit by activation of ATP‐sensitive potassium channels

“…However, a higher dose of sulprostone increased, rather than decreased, mean arterial blood pressure (unpublished observation). Similarly, higher doses of sulprostone cause vasoconstriction in the human isolated pulmonary artery, and this effect is due to activation of EP3 receptors (Qian et al, 1994 tivation of platelets and particularly polymorphonuclear neutrophils (PMN's). This is, however, extremely unlikely as these effects are due to activation of EP2 receptors.…”

Acute myocardial infarction due to vasospasm induced by prostaglandin

“…All four EP receptors are relevant to the regulation of vascular tone by PGE 2 . EP 1 and EP 3 receptors induce vasoconstriction, and EP 2 and EP 4 receptors mediate vasodilation (3,4). Sulprostone has a selective agonist profile: EP 3 > EP 1 >> EP 2 = EP 4 (5).…”