William A. W. Walters

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

Symptoms during normal pregnancy: a prospective controlled study.

EDITORIAL COMMENT: This is an important study which attempts to evaluate the effect of pregnancy on numerous symptoms. The point of this comment is to direct readers to table 3 because it contains much information of interest and importance that has not been dealt with in the text because of space considerations. For example, there is confirmation of the wide‐held belief that epistaxis is much more common in pregnancy and the same can be said for fainting, flushing and shortness of breath. The increased incidence of nausea, heartburn and bleeding gums also fits with traditional teaching and beliefs, at least of the editor, but the finding that headache is less common in pregnant women was a surprise. There is confirmation that leg cramps and abdominal pain are common in pregnancy. The increased frequency of nail changes was news to the editor, although the urogenital symptoms preponderance in the pregnant group was expected. The huge increase in dyspnoea during at rest and exertion in the pregnancy group also warrants emphasis. N.B.

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.

Endothelial cell function enhancement in a late normal human pregnancy.

Objective: To assess endothelial cell function throughout normal human pregnancy.

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.

Hypertensive and normal pregnancy: a longitudinal study of blood pressure, distensibility of dorsal hand veins and the ratio of the stable metabolites of thromboxane A2 and prostacyclin in plasma

Objective By combining serial measurements of the circulating concentrations of thromboxane A, and prostacyclin with measurements of venous distensibility (taken during the pregnancies of both normal women and those with pregnancy induced hypertension or pre‐eclampsia), to test the following hypotheses: 1. that changes in the venous plasma ratio of thromboxane (TXB2) and 6‐keto‐PGF1α would correlate with changes in the blood pressure of women developing and recovering from pregnancy induced hypertension or pre‐eclampsia and 2. that changes in venous distensibility would correlate with changes in arterial blood pressure in pregnancy induced hypertension or pre‐eclampsia.