A.L.A. Boura

AUTACOIDS AND CONTROL OF HUMAN PLACENTAL BLOOD FLOW

1. Humans have a haemochorial, villous placenta. Uterine blood passes through maternal sinuses, bathing placental villi through which fetal blood circulates. Blood flow through each circulation is high and vascular resistance low. This haemodynamic situation is essential for efficient placental function.

Vascular actions of purines in the foetal circulation of the human placenta

1 The vasoactive effects of adenosine triphosphate (ATP), adenosine and other purines in the foetal circulation of the human placenta were examined. Single lobules of the placenta were bilaterally perfused in vitro with Krebs buffer (maternal and foetal sides 5 ml min−1 each, 95% O2:5% CO2, 37°C). Changes in foetal vascular tone were assessed by recording perfusion pressure during constant infusion of each purine. To allow recording of the vasodilator effects, submaximal vasoconstriction was induced by concomitant infusion of prostaglandin F2α (0.7–2.0 μmol 1−1). 2 ATP (1.0–100 μmol 1−1) usually caused concentration‐dependent reductions in perfusion pressure. However, biphasic with initial transient increases, or only increases in pressure were sometimes observed. Falls in pressure caused by ATP were significantly reduced by addition to the perfusate of NG‐nitro‐l‐arginine (l‐NOARG) (100 μmol 1−1) but not NG‐nitro‐d‐arginine (d‐NOARG) (100 μmol 1−1). They were not influenced by addition of indomethacin (10 μmol 1−1) or l‐arginine (100 μmol 1−1). 3 Adenosine (0.01–1.0 mmol 1−1) consistently caused concentration‐dependent reductions in perfusion pressure, this effect not being influenced by indomethacin. l‐NOARG, but not d‐NOARG, reduced the potency of adenosine approximately three fold. l‐Arginine, but not d‐arginine enhanced its potency by a similar amount. 4 2‐Methylthio‐ATP, a selective P2y agonist was approximately 50 times more potent than ATP as a vasodilator agent, always causing decreases in perfusion pressure. 5 β‐γ‐Methylene ATP, a selective P2x agonist, was approximately 100 times more potent than ATP as a vasoconstrictor, but only caused transient increases in perfusion pressure. 6 The rank order of vasodilator potencies of a selection of adenosine receptor agonists was, 2‐chloroadenosine >> 5‐(N‐cyclopropyl)‐carboxamidoadenosine, >5‐N‐ethylcarboxamidoadenosine, >2‐chloro‐N6‐cyclopentyladenosine, >CGS‐21680 > N6‐cyclohexyladenosine = adenosine. Vasodilatation due to adenosine was inhibited by the P1‐A2 receptor antagonist 3,7‐dimethyl‐1‐propargylxanthine (DMPX). 7 These results suggest that ATP may cause an endothelium‐dependent vasodilatation in the foetal vessels of the human placenta via activation of a P2y receptor linked to the formation of nitric oxide (NO). Vasodilatation caused by ATP may mask an accompanying vasoconstrictor effect mediated, via a P2x receptor, in the villous vascular smooth muscle. Adenosine acting on P1‐A2 receptors, which are also present in the foetal vasculature, may require synergistic interaction with NO to achieve a maximal vasodilator response.

Autacoids and the control of vascular tone in the human umbilical-placental circulation

Increased knowledge of the factors influencing vascular tone in the uteroplacental circulations will not only throw further light on the control of normal blood flow but also suggest directions to be taken towards possible improvements in therapy of some diseases of pregnancy. Changes in maternal and/or fetal placental blood flow are known to occur in such conditions as pre-eclampsia, hypertension and fetal growth retardation (Fox, 1966; 1978; Chesley, 1978; Las Heras et al, 198.5) and can be modified both beneficially and adversely by administration of drugs (Lindheimer and Katz, 198.5). This review focuses predominantly on the role of autacoids in control of vascular tone in the human fetal extracorporeal circulation. Autacoids are a group of chemically heterogeneous mediators synthesized by various tissues. Many of them are highly potent and have varied biological activities. They can modifjr intracellular mechanisms in the cells of their origin or affect functions of adjacent or more distant cells by acting as local or circulating hormones. Some are powerful stimulants or depressants of the contractile activity of smooth muscle, while others affect vascular permeability or interact with blood constituents, particularly white cells and platelets, thereby influencing the inflammatory and coagulation processes. Throughout the review emphasis is placed on results obtained from work on human tissues although when conclusions derived from such work can be supported by knowledge acquired from animal experimentation brief mention will be made of this. Both the umbilical cord and placenta are devoid of nerves (Spivack, 1943; 1946; Walker and MacLean, 1971; Roach, 1976; Sastry and Sadavongvivad, 1979; Fox and Khong, 1990), so that only non-nervous mechanisms can be capable of influencing vascular tone in these tissues. The influences on fetal placental and umbilical vascular tone to be considered are autacoids of fetal, umbilical cord, placental, or maternal origin; intrinsic myogenic mechanisms; blood rheology; and extrinsic physical factors, including changes in maternal uterine

Evidence for inhibition by endotheliumderived relaxing factor of thromboxane A2 receptor-mediated vasoconstriction in the fetal vessels of the human perfused placenta

Three inhibitors of the release or effects of endothelium-derived relaxing factor (EDRF), N-nitro-L-arginine, methylene blue and oxyhemoglobin, caused further increases in perfusion pressure during vascular constriction with submaximal concentrations of the thromboxane A2-mimetic, U46619 in fetal vessels of human placental lobules perfused in vitro. The results suggest the EDRF, released during constriction of fetal placental vessels in response to thromboxane A2 receptor stimulation, attenuates the vasoconstrictor response. Hence, impairment of EDRF release or function could contribute to the reduced placental blood flow observed in various disease states associated with increased thromboxane A2 production such as pre-eclampsia.

Effect of inhibition of nitric oxide synthase and guanylate cyclase on hydralazine-induced vasodilatation of the human fetal placental circulation.

1. The vasodilator effects of hydralazine in vitro, using the Krebs’ perfused human placental lobule was studied. Single placental lobules were bilaterally perfused (maternal and fetal sides 5 mL/min each, 95% O2, 5% CO2, 37°C) and changes in fetal arterial pressure (FAP) and venous outflow (VO) were recorded.

RELEASE OF A SUBSTANCE FROM THE HUMAN PLACENTA HAVING DIGOXIN‐LIKE IMMUNOREACTIVITY

1. The human placental lobule, perfused with a constant flow (5 mL/min) of Krebs’ solution after delivery at term, released into the fetal perfusate a digoxin‐like substance, as measured by a fluorescence polarization immunoassay.

Effects of eicosanoid and endothelial cell derived relaxing factor inhibition on fetal vascular tone and responsiveness in the human perfused placenta

Summary Local output of endothelial cell-derived relaxing factor (EDRF) appeared tomake a greater contribution to the low resistance of the fetal circulation of the human placenta perfused in vitro than did prostaglandins, such as prostacyclin. Whereas blockade of the effects of EDRF, using three drugs inhibiting EDRF by differing mechanisms, caused increased fetal vascular resistance, reduction of prostaglandin output using three drugs inhibiting various stages of prostaglandin biosynthesis did not. Concomitant EDRF release also appeared to be important for modulation of vasoconstrictor responses to 5-hydroxytryptamine, endothelin-1, bradykinin, and angiotensin II and was more important than prostaglandin release for mediating the vasodilator effects of adenosine triphosphate. Reduced EDRF release, consequent to endothelial cell damage, could make an important contribution to the increased fetal placental vascular resistance associated with pre-eclampsia and fetal growth retardation.

CHARACTERIZATION OF THROMBOXANE A2 RECEPTORS IN THE HUMAN FETAL PLACENTAL VESSELS AND UMBILICAL VEIN

1. An in vitro examination has been made of the thromboxane A2 receptors in human fetal placental villous vessels and umbilical veins utilizing the TxA2 agonist U46619 and its competitive antagonist AH22921.

Effects of Bufo marinus skin toxins on human fetal extracorporeal blood vesseLS

The effects of extracts of Bufo marinus toad skin toxin on human isolated umbilical arterial rings and the fetal vessels of perfused placentae were examined and compared with those of ouabain, an inhibitor of Na+/K(+)-ATPase. Umbilical artery rings and fetal vessels of the perfused placenta responded to extracts, or ouabain, with constriction which persisted after the removal of each agent. Extraction of the skin, using various solvents, revealed that the umbilical artery constriction was due mainly to the effects of water-soluble, polar compounds. Fractionation of a water extract and bioassay on the rat isolated aorta revealed maximum vasoconstrictor activity in a low mol. wt fraction. During Na+/K(+)-ATPase inactivation in the fetal circulation of the human placenta, by perfusion with K(+)-free Krebs solution, reactivation of the enzyme by K+ infusion caused vasodilatation. This effect was inhibited both by water extracts of load skin and by ouabain. Thus, properties of some of the endogenous compounds in B. marinus skin resemble those of ouabain, by causing persistent constriction of human fetal blood vessels. A component of the vasoconstrictor response probably results from inhibition of vascular smooth muscle Na+/K(+)-ATPase, but it is likely that a contribution is also made by additional vasoconstrictor substances contained in B. marinus toxin.

The control of fetal vascular resistance in the human placenta

Summary The human placenta, perfused after delivery at term, has revealed useful information about the control of placental fetal vascular resistance. The placenta is not innervated, resistance in the fetal circulation being controlled by myogenic mechanisms interacting with effects of autacoids. The fetal vasculature in vitro responds readily to some vasoconstrictor autacoids, particularly thromboxane A 2 and endothelin-1. However the vasoconstrictor concentrations needed are well in excess of those normally present in umbilical blood. Efficient mechanisms exist in the fetal circulation to maintain its normal low resistance to blood flow. Amongst these is the fetal endothelium (and possibly the trophoblast), which in response to endogenous peptides such as corticotropin-releasing hormone, and shear forces caused by passage of blood releases the dilator autacoid nitric oxide. This interacts with prostacyclin to cause cell membrane stabilization and activation of intracellular vasodilator mechanisms in vascular smooth muscle. Hypoxia in the perfused healthy placenta causes fetal vascular sensitivity changes to autacoids similar to those found in placentae from some pre-eclamptic women. In particular fetal placental release of NO appears to be impaired by hypoxia. We also conclude that hypoxia in the fetal circulation which may occur during preeclampsia (with or without restricted fetal growth) and in pregnancies uncomplicated with pre-eclampsia when fetal growth restriction is present, could possibly contribute to placental fetal vasoconstriction and reduced blood flow.