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Prostaglandins E1, E2, F2α and A2 are enzymically inactivated to different extents during passage through the pulmonary circulation. The enzyme responsible is probably 15-hydroxyprostaglandin dehydrogenase.

WE report here the synthesis of substances, structurally related to the prostaglandins, capable of selectively antagonizing the smooth muscle effects of both prostaglandins E1 and F1α. The availability of specific antagonists of prostaglaiidin may help solve problems about the physiological roles of the prostaglandins1.

This article traces the background and implications of the recent finding that aspirin and indomethacin block the production of prostaglandins E2 and F2α.

Noradrenaline releases prostaglandins in the kidney, and in rats these augment rather than reduce vasoconstriction produced by the amine. Homogenates of kidneys of New Zealand rats inbred for hypertension exhibit lower prostaglandin inactivation by 15-hydroxydehydrogenase than controls. At the same time, augmentation of noradrenaline vasoconstriction by the released prostaglandin is exaggerated. This biochemical defect could be the inherited abnormality primarily responsible for the development of hypertension in these animals.

In homogenate of rat brain, morphine, at concentrations obtainable in vivo, inhibited the stimulation by prostaglandin E1 or E2 of cyclic AMP formation, without inhibiting the basal production of cyclic AMP. Heroin was more atnd methadone less active than morphine, whereas dextrorphan was inactive and naloxone antagonised the effect of morphine. This inhibition may represent a mechanism whereby morphine-like drugs exert their analgesic or other effects.

WORK on cell lines derived from tumours of the nervous system has been carried out to establish models for neurones and glial cells. Clonal cell lines derived from mouse neuroblastoma C 1300 possess many properties characteristic of neurones1–11. While the neuroblastoma cells increase in their intracellular levels of adenosine 3′,5′-cyclic monophosphate (cyclic AMP) in the presence of prostaglandin E1 (PGE1) (refs 12 and 13), acetylcholine14 and adenosine15, rat glioma cells16 do so when exposed to noradrenaline17,18 or PGE1 (ref. 19).

GROWTH and differentiation of mammalian cells is considered to be controlled in part by the interaction of various hormones and other growth promoting factors1. Corticosteroids are hormones with a wide range of tissue specificity, intracellular receptor proteins having been described in various tissues2 and cultured cells3,4. Glucocorticoids exert paradoxical effects on cell proliferation. Thus they promote cell growth of the mammary gland epithelium in mice and rats5,6 and in mouse and rat organ7–9 and rat tissue culture systems10, and DNA synthesis in cultured parenchymal rat liver cells11. But they inhibit all stages of the inflammatory response, including the reparative growth of fibroblasts, loss of immune competence due to damage to lymphocytes, lipolysis and other anabolic (contra-insulin) effects in adipose tissue12. In cultured fibroblasts hydrocortisone can, in different conditions, either stimulate13 or inhibit14–16 DNA synthesis and cell devision. The growth promoting effects of the corticosteroids in fibroblasts and mammary epithelial cells may be related to their ability to synergise with the fibroblast growth factor (FGF) (refs 17 and 18) and prolactin10 respectively. Growth inhibitory effects may be due to the predominantly catabolic action of the glucocorticoids12. Here we report that hydrocortisone can inhibit specifically the stimulation of DNA synthesis and cell division induced by prostaglandin F2α (ref. 19) in Swiss mouse 3T3 and 3T6 cells. We suggest that the cell-growth-regulating properties of the corticosteroids are in part dependent on the identity of the co-inducing growth controlling factors, and that glucocorticoid inhibition of prostaglandin-stimulated cell growth may have a role in the anti-inflammatory response.

This article has the same title as one published in Nature about fourteen months ago1. Its purpose is to reexamine a thesis put forward then, and to mention some of the recent developments.

IN the isolated, perfused heart, increased activity induced by catecholamines and/or calcium ions is followed by enhanced coronary flow, attributable to some metabolic process in the myocardium. This metabolically induced coronary baso-dilatation (MCD) is inhibited by prostaglandin E1 (ref. 1). The increased MCD response correlates with 3′5′-cyclic AMP levels. Furthermore, when prostaglandins (PGs) are infused, inhibition of MCD correlates with diminished cyclic AMP production2,3. The inhibition of MCD by exogenous administration of PGs suggests that these autacoids may play a role as modulators of the coronary reaction to increased cardiac activity4. If it were possible to demonstrate the participation of PGs produced endogenously, their relevance in this modu-latory mechanism of adaptation of coronary flow would become evident.

PROSTAGLANDINS (PGs) are being used increasingly as abortifacients although their precise mechanism of action is uncertain. One of the compounds frequently used is PGF2α, which has been shown to stimulate the myometrium in vitro1 and in vivo2. Whether or not the direct action of this agent on the uterine muscle alone is responsible for the interruption of pregnancy is not clear, but the long interval between infusion and abortion3 suggests that other mechanisms might be involved; for example, a luteolytic effect4–6. The prompt increase in uterine activity after treatment with prostaglandin, however, argues that the direct effect plays some part in the abortifacient action. Little is known of the influence of other myometrial regulatory agents such as the ovarian steroids on the uterine response to PGs. Accordingly we examined the influence of progesterone on myometrial responses to prostaglandin F2α in the rabbit, a species in which progesterone is known to have a blocking action on the uterine muscle7.

ANTIBODIES directed against prostaglandin–albumin conjugates have been used previously as prostaglandin antagonists. Horton and Poyser1 have demonstrated that the oestrus cycle in the guinea pig is prolonged in animals immunised against prostaglandin F2α (PGF2α). Ferreira et al.2 demonstrated that rats containing antibodies to E-type prostaglandins develop a significantly reduced inflammatory oedema in response to carageenin compared with control animals. We report here that antibodies can be used to antagonise the effects of prostacyclin both in vitro and in vivo.