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3 On other respiratory tissues known to contain mixtures of the 'X1,2,3'-and 'j'-receptors (guinea-pig trachea and lung strip, cat lung strip and human bronchial muscle), TR4979 consistently acted as a potent relaxant whereas PGE2 and to a lesser extent PGE1 had significant contractant activities. 4 Human pregnant uterus, guinea-pig and rat pseudo-pregnant uteri, rat colon and fundic strips and chick ileum are known to contain one or more of the three subclasses of the 'X'-receptor. TR4979 (l09-10-5M) was inactive on all these tissues whereas all of the reference prostanoids were contractants of varying potencies.5 PGEI and histamine-induced contractions of the guinea-pig isolated ileum were both noncompetitively antagonized by increasing concentrations of TR4979 suggesting that '*'-receptors also exist on this tissue. 6 TR4979 is a highly selective agonist of prostanoid '4' (relaxant/inhibitory)-receptors which at present have been demonstrated to exist mainly in the lung. This prostaglandin analogue is a useful new selective pharmacological tool for revealing as yet unidentified prostanoid '4'-receptors and actions in a wide range of non-respiratory tissues/organs such as the guinea-pig ileum.

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Mammalian serum and plasma contain an endogenous inhibitor of prostaglandin synthetase (EIPS). Human plasma fractions rich in EIPS show anti-inflammatory activity in vivo. In rats, glucocorticoids raise EIPS activity of plasma and serum. These findings suggest the existence of a natural mechanism of controlling prostaglandin synthesis, possibly related to corticosteroid action.

1 BAY u3405 (3(R)- [[(4-fluorophenyl) sulphonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid) has been evaluated on airway smooth muscle, from a number of species including man, for its thromboxane A2 (TXA2) antagonist activity. 2 BAY u3405 was a potent, and competitive, antagonist of the TXA2-mimetic U46619-induced contractions of human, guinea-pig, rat and ferret airway smooth muscle with pA2 values between 8.0 and 8.9 and with no inherent contractile activity (10 -IO-M). 3 The TXA2 antagonist activity of BAY u3405 was stereoselective. Its (S)-enantiomer, BAY u3406, was approximately 50 fold less effective against U46619 on guinea-pig and human airway smooth muscle. 4 BAY u3405 also competitively antagonized contractions of guinea-pig airway smooth muscle induced by prostaglandin D2 (PGD2) or its metabolite 9a, 1 lfl-PGF2. On human and ferret airway smooth muscle it abolished contractions induced by PGD2, PGF2. and 16, 5 A high concentration (10-6 M) of BAY u3405 had no effect on the contraction, or relaxation, of airway smooth muscle induced by a range of other agonists, nor did BAY u3405 have any effect on other prostanoid receptor types (DP, EP1, EP2, FP or IP). 6 BAY u3405, in contrast to some other TXA2 antagonists, is a potent and selective antagonist on a wide range of airways including human. This high affinity, and the oral activity of the compound described elsewhere, suggest it may be an appropriate tool to investigate the role of prostanoids in airway diseases such as asthma.

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1 Cysteinyl-leukotrienes cause contractions and/or relaxations of human isolated pulmonary vascular preparations. Although, the localization and nature of the receptors through which these effects are mediated have not been fully characterized, some effects are indirect and not mediated via the welldescribed LT1 receptor. 2 In human pulmonary veins (HPV) with an intact endothelium, leukotriene D4 (LTD4) induced contraction above basal tone. This response was observed at lower concentrations of LTD4 in the presence of nitric oxide synthase inhibitor N4-nitro-L-arginine (L-NOARG). Contractions (in the absence and presence of L-NOARG) were partially blocked by the LT, antagonists (MK 571 and ICI 198615). 3 LTD4 relaxed HPV previously contracted with noradrenaline. This relaxation was potentiated by LT1 antagonists, but was abolished by removal of the endothelium. LTD4 also relaxed human pulmonary arteries (HPA) precontracted with noradrenaline but this effect was not modified by LT, antagonists. 4 The results suggest that contraction of endothelium-intact HPV by LTD4 is partially mediated via LT, receptors. Further, in endothelium-intact HPV, this contraction was opposed by a relaxation induced by LTD4, dependent on the release of nitric oxide, which was mediated, at least in part, via a non-LT, receptor. In addition, LTD4 relaxation on contracted HPA was not mediated by LT, receptors. 5 The mechanical effects of LTD4 on human pulmonary vasculature are complex and involve both direct and indirect mechanisms mediated via at least two types of cysteinyl-leukotriene receptors.