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

1. In 13 of 15 experiments, prostaglandin E2 (PGE2) and sulprostone (a prostanoid EP1/EP3-receptor agonist) contracted isolated rings of human pulmonary artery at low concentrations (> or = 5 and > or = 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 > or = PGE2 > or = GR 63799X > 17-phenyl-omega-trinor PGE2 > or = 11-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 EP1-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), 11-deoxy PGE1 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 PGE1 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.

Pathophysiology of transient cranial diabetes insipidus during pregnancy.

OBJECTIVE: We investigated the possible mechanisms underlying transient cranial diabetes insipidus during pregnancy. DESIGN AND PATIENTS: A woman who developed clinical diabetes insipidus during the third trimester of pregnancy was studied through a total of three pregnancies and postpartum. MEASUREMENTS: Plasma AVP, urine and plasma osmolality, urine volume and specific gravity were measured during water deprivation tests and hypertonic saline infusion. Plasma and urine osmolality were measured after subcutaneous injection of AVP. The water deprivation and AVP test were repeated after proven inhibition of urinary PGE2 with aspirin. Serum vasopressinase activity was measured during one of the pregnancies affected with diabetes insipidus and compared with that obtained between 26 and 38 weeks from 13 normal pregnancies. RESULTS: The patient was found to have cranial diabetes insipidus which responded to low dose intranasal 1-desamino-8-D-arginine vasopressin. Inhibition of PGE2 with aspirin did not enhance urine concentrating ability or the response to a test dose of subcutaneous AVP. Plasma levels of vasopressinase remained within the physiological range for normal pregnancy. CONCLUSIONS: These studies indicate that subclinical cranial diabetes insipidus may be unmasked in late pregnancy. This effect is not related to AVP resistance resulting from PGE2 production or excessive vasopressinase activity, but may be due to a combination of physiological vasopressinase secretion with reduced AVP secretory capacity and reduction in the thirst threshold that accompanies normal pregnancy. We relate these findings to a previously described group of women with transient diabetes insipidus during pregnancy who had impaired liver function.