Vasoactive effects of 8-epi-prostaglandin F(2alpha)in isolated human placental conduit and resistance blood vessels in vitro.

The effects of 8-epi-prostaglandin F(2alpha)(8-epi-PGF(2alpha)) and the thromboxane A(2)-mimetic U46619 were examined on isolated human fetal placental arteries obtained from normal pregnancies and from those complicated by pre-eclampsia. The effects of these agents were examined on both conduit and resistance arteries. 8-epi-PGF(2alpha)was found to be markedly less potent than U46619 in constricting both size vessels. Vasoconstrictor EC(50)s for 8-epi PGF(2alpha)were 4.10x10(-7) m (2.02-8.35x10(-7) m) (mean, 95 per cent CI and 2.05x10(-6) m (0.43-9.89 x10(-6) m) in conduit and resistance arteries, respectively. The maximum vasoconstriction produced by 8-epi-PGF(2alpha)(112+/-17 per cent), (relative to maximum KCl induced vasoconstriction) in conduit vessels was significantly less than that caused by U46619 (152+/-20 per cent). In resistance vessels the maximum vasoconstrictor effects to 8-epi-PGF(2alpha)(208+/-10 per cent) and U46619 (201+/-19 per cent) were similar, and in both cases significantly greater than the maximal effects seen in conduit vessels. U46619 displayed a similar vasoconstrictor potency in both conduit (EC(50)=1.21x10(-9) m, 0.58-2.51x10(-9) m) and resistance arteries [EC(50)=5.95x10(-9) m, (0.81-43.60x10(-9) m] as was found for 8-epi PGF(2alpha). 8-epi-PGF(2alpha)was equipotent in resistance arteries obtained from women with severely pre-eclamptic pregnancies (EC(50)=1.25x10(-6) m, 0.25-6.17x10(-6) m) compared with normotensive controls. However, the maximum vasoconstrictor effect induced by 8-epi-PGF(2alpha)in placental resistance arteries was significantly reduced (99+/-20 per cent) in vessels obtained from severely pre-eclamptic compared with normal pregnancies. These results indicate that 8-epi-PGF(2alpha)displays differential vasoconstrictor activity in the fetal-placental vasculature. Furthermore the vasoconstrictor effects of 8-epi-PGF(2alpha)are reduced in pre-eclampsia, the effect being selective to placental resistance vessels. This reduction may occur as a result of more serious disturbances in the placental microcirculation with the disease process in pre-eclampsia.

Effects of nitrovasodilators on the human fetal-placental circulation in vitro.

This study examines the vasorelaxation of isolated human placental chorionic plate arteries and the perfused fetal-placental vasculature, in vitro, to a variety of nitrovasodilator compounds including glyceryl trinitrate (GTN) sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-N-glutathione (SNG) and NaNO(2). The effects of these compounds were also examined under conditions of high (>450 mmHg) and low oxygen (<50 mmHg) tension. In a separate series of experiments the effects of GTN and NaNO(2)were further investigated with addition of the antioxidants cysteine (100 microm), glutathione (100 microm) or superoxide dismutase (SOD) (30 I.U./ml). The order of nitrovasodilator potency, when added directly to isolated fetal vessels was GTN=SNP>SNAP=SNG>NaNO(2). The order under low oxygen tension was similar, GTN=SNP>SNG= SNAP>or=NaNO(2). SNG ( approximately fourfold) and NaNO(2)( approximately 50-fold) were significantly more potent under low oxygen conditions. Cysteine, glutathione and SOD were without effect on GTN induced vasodilatation. However, all three agents significantly enhanced (six- to ninefold) the effects of NaNO(2)under similar conditions. When infused directly into the fetal-placental circulation during in vitro perfusion experiments the order of potency was GTN>SNP>or=SNG>or=SNAP>or=NaNO(2). When the nitrovasodilators were infused indirectly via the maternal intervillous space the order of potency was GTN>or=SNP>or=NaNO(2)>or=SNAP=SNG. Our observations suggest that there are important differences in the action of different classes of nitrovasodilator compounds on the fetal-placental circulation. The changes observed with SNG and NaNO(2)may be influenced by levels of tissue oxygenation.

Fetal placental vascular responses to corticotropin-releasing hormone in vitro. Effects of variation in oxygen tension.

In this study, using the human placenta perfused in vitro with Krebs' bicarbonate solution, we have examined the effects of changes in oxygen tension on the vasoreactivity of fetal placental blood vessels to corticotropin releasing hormone (CRH). Vasodilatory responses to human synthetic CRH were measured during sub-maximal vasoconstriction of the fetal placental circulation with prostaglandin F(2alpha)(PGF(2alpha)) (1-100 micrometer). Decreases in fetal placental arterial perfusion pressure (FAP) were obtained with CRH under conditions of high oxygen or low oxygen tension, >/=450 mmHg and

Analysis of mid-trimester corticotrophin-releasing hormone and alpha-fetoprotein concentrations for predicting pre-eclampsia.

The aims of this study were firstly to examine if corticotrophin-releasing hormone (CRH) concentrations in maternal plasma were significantly elevated in Chinese pregnancies complicated by pre-eclampsia, secondly to assess if this elevation could be detected in the mid-trimester before onset of clinical signs of the disease, and thirdly to evaluate the performance of using maternal CRH and/or alpha-fetoprotein (AFP) concentrations in the mid-trimester for prediction of pre-eclampsia. The first part of this study was tested in a cohort of 39 subjects. The CRH concentrations were significantly elevated in pregnant women complicated by pre-eclampsia. The second and third parts of the study involved a different cohort of 1021 subjects. Both CRH and AFP concentrations in the mid-trimester were significantly elevated in those who subsequently developed pre-eclampsia. However, when used for prediction of pre-eclampsia, neither the CRH nor AFP concentrations alone in the mid-trimester had strong predictive value. Although the combination of both tests improved the detection rate compared to the use of CRH alone, the small increase in the likelihood ratio from 1.9 to 2.6 did not suggest that the combination would be of great clinical value.

Can preclinical medical students be integrated into the continuing medical education process by instructing prehospital care providers?

OBJECTIVE: To develop a model introducing medical students (MS) to the continuing medical education (CME) process while simultaneously developing a curriculum to enhance the relevant surgical anatomy knowledge base of the advanced prehospital care provider. METHODS: A CME curriculum for teaching human anatomy was developed and approved by the governing state agencies for prehospital education. The curriculum focused on structures relevant to the prehospital care of the trauma patient in a case based format using common scenarios presented by surgery and emergency medicine faculty. Five year-one medical students who completed gross anatomy served as teaching staff and were given a structures list one week prior to the CME course. Human cadavers were prosected by the medical students prior to the CME program under the guidance of the surgical faculty. Course attendees and medical student staff were anonymously surveyed at the end of the program (rating scale 1 = low to 5 = high). Prehospital providers were given a multiple-choice posttest and surveyed at 3 months after the course with regard to applicability to their current practice. Data are means +/- SD. RESULTS: Nineteen licensed practicing paramedics attended the course. All of the paramedics scored above the 85% passing cutoff on the posttest (95. 6% +/- 6.2%). Instructor qualities were rated highly (4.62 +/- 0.49) with no instructor rating less than a 3. MS believed themselves well prepared to teach (5 +/- 0), and spent 2 +/- 0.81 hours in preparation. They were only infrequently faced with questions they were not well prepared to answer (1.25 +/- 0.5) and would uniformly participate in CME offerings in the future (5 +/- 0). The CME program improved the MS view of CME (3 +/- 0), prehospital education (3 +/- 1.4), and the surgeon as educator (3.25 +/- 1.5). At 3 months, the paramedics felt that the CME program significantly impacted the care they rendered (4.37 +/- 0.76), and improved their understanding of injury complexes (4.53 +/- 0.61), and resuscitation (4.26 +/- 0. 73). The cadaver course was uniformly recommended to coworkers (5 +/- 0). CONCLUSIONS: This model provided prehospital care providers direct contact with clinically relevant human anatomy, enhanced their understanding of pertinent anatomy, and positively impacted their patient care. MS were introduced to the CME process and found it to be one with which they would become reinvolved. Furthermore, the MS felt prepared to present human anatomy, met the expectations of the course attendees, improved their understanding of prehospital education, and positively altered their perception of the surgeon as an educator. This process holds promise as both a model for prehospital education and as a tool for integrating MS into the role of allied health educator early in their career.

U46619-mediated vasoconstriction of the fetal placental vasculature in vitro in normal and hypertensive pregnancies.

OBJECTIVES: To measure in-vitro responses to the thromboxane A2 (TxA2) mimetic U46619 in the fetal placental vasculature of human placentae from normotensive women and those with pre-eclampsia. Furthermore, to compare fetal vascular responses to endothelin-1,5-hydroxytryptamine, potassium chloride (KCl) and prostacyclin (PGI2) in placentae from normal or pre-eclamptic pregnancies. METHODS: Single placental lobules of intact placentae were bilaterally perfused in situ (fetal and maternal) with constant flows of Krebs' solution. Changes in fetal arterial perfusion pressure during intra-arterial infusion of vasoactive agents were recorded. Fetal placental vasoconstrictor concentration response curves were obtained to U46619 (0.01-300 nmol/l), endothelin-1 (0.4-160 nmol/l), KCl (3-300 mmol/l) and 5-hydroxytryptamine (0.03-30 mumol/l). In addition, vasodilator concentration response curves were obtained for PGI2 (1.2-350 nmol/l) in the fetal placental circulation during submaximal increases in perfusion pressure with prostaglandin F2 alpha (PGF2 alpha; 0.7-2.0 mumol/l). RESULTS: The maximum increase in perfusion pressure caused by U46619 in placentae from normotensive women was 194 +/- 25 mmHg. The maximum response to U46619 was significantly reduced in the placentae from women with pre-eclampsia (104 +/- 21 mmHg). In contrast, there were no differences in constrictor responses to endothelin-1,5-hydroxytryptamine and KCl, or in dilator responses to PGI2 in placentae obtained from either normotensive women or those with pre-eclampsia. CONCLUSION: TxA2 receptor-mediated vasoconstriction is reduced in the fetal vasculature of placentae from women with pre-eclampsia, possibly to compensate for the increased levels of TxA2 seen in these conditions.

Thyrotoxic periodic paralysis in a Jamaican male.

Thyrotoxic periodic paralysis is a rare endocrine disorder most prevalent among individuals of Asian descent that presents as proximal muscle weakness, hypokalemia, and signs of hyperthyroidism. We present the case report of a patient with previously undiagnosed hyperthyroidism, protracted muscle weakness with transient exacerbations, and nocturnal onset of periodic paralysis affecting the upper and lower limbs.

Thyrotoxic periodic paralysis in a Jamaican male

Thyrotoxic periodic paralysis is a rare endocrine disorder most prevalent among individuals of Asian descent that presents as proximal muscle weakness, hypokalemia, and signs of hyperthyroidism. We present the case report of a patient with previously undiagnosed hyperthyroidism, protracted muscle weakness with transient exacerbations, and nocturnal onset of periodic paralysis affecting the upper and lower limbs (AU)

Symptoms during normal pregnancy: a prospective controlled study.

Symptoms of normal pregnancy have received scant attention in the literature and what is reported is largely unsubstantiated. Yet this is an important aspect of antenatal counselling and care which deserves further investigation if symptoms are to be interpreted correctly. Accordingly, we conducted a prospective controlled study of symptoms during normal pregnancy in both primigravidas and multigravidas. A total of 38 symptoms occurred with a significantly different frequency (mainly increased) in the pregnant subjects in the third trimester compared with the controls. Of these a mean of 24.2 symptoms was experienced by each pregnant woman, double that (mean, 11.2) experienced by healthy nonpregnant controls. The 5 symptoms reported most frequently by the pregnant subjects were frequency of micturition, fatigue, pelvic pressure, insomnia and lower backache. However, a wide range of symptoms involving most body systems were reported. This study has established that symptoms of pregnancy are more numerous than mentioned in current obstetric texts and that they can be attributed to the effects of pregnancy. The third trimester is associated with the greatest number of symptoms and there is a marked decline in their number after delivery.

Vasodilator actions of urocortin and related peptides in the human perfused placenta in vitro.

Urocortin, is a recently isolated peptide belonging to the CRH family that binds with high affinity to the CRH2 receptor. Like CRH, urocortin causes hypotension in the rat, but its vasoactive actions have not yet been studied in the human. We have compared the vasoactive properties of urocortin, CRH, and urotensin-1 in the human fetal placental vasculature in vitro. 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 perfusion pressure were recorded. Submaximal vasoconstriction was induced by PGF2alpha (4+/-0.7 micromol/L), which increased perfusion pressure from 19.6+/-1.4 to 100.7+/-3.1 mm Hg (n=38; P < 0.001). Subsequent fetal arterial infusion of urocortin (0.001-1 nmol/L) caused concentration-dependent vasodilatation. Urocortin was equipotent with urotensin-1 and 25 times more potent than CRH in causing vasodilatation. Nevertheless, the maximum vasodilator responses to each of the peptides were similar (P > 0.05). The CRH receptor antagonist, alpha-helical CRH-(9-41) (0.2 nmol/L) significantly attenuated the vasodilatation produced by urocortin, urotensin-1, and CRH (P < 0.05). These results indicate a possible physiological role for urocortin in the modulation of human fetal placental vascular tone by activation of CRH2-like receptors.

Arterial reactivity is enhanced in genetic males taking high dose estrogens.

OBJECTIVES: We sought to assess whether high dose estrogen treatment is associated with enhanced arterial reactivity in genetic males. BACKGROUND: Although estrogens have been shown to enhance arterial reactivity in women, and are thereby thought to confer cardiovascular benefit, the vascular effects of long-term estrogen therapy in genetic males is unknown. METHODS: We studied the arterial physiology of 30 genetic males--15 male to female transsexuals receiving long-term high dose estrogen therapy and 15 healthy male control subjects matched for age, smoking history and vessel size. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation [EDD]) and after nitroglycerin (GTN), an endothelium-independent dilator. Blood pressure, cholesterol and testosterone levels were also measured in each subject. RESULTS: Total testosterone and free testosterone index levels were lower in the transsexuals compared with the control subjects (p < 0.001). In contrast, EDD was significantly higher in the transsexuals than in the control males (mean [+/-SD] 7.1 +/- 3.1% vs. 3.2 +/- 2.8%, p = 0.001), as was the GTN response (21.2 +/- 6.7% vs. 14.6 +/- 3.3%, p = 0.002). Total and high density lipoprotein cholesterol, blood pressure levels and baseline vessel size were similar in the two groups. On multivariate analysis, enhanced EDD was associated independently with estrogen therapy (p = 0.02) and with low total cholesterol (p = 0.04). An enhanced GTN response was also significantly associated with estrogen therapy (p = 0.03). CONCLUSIONS: Long-term treatment with high dose estrogens is associated with enhanced arterial reactivity in genetic males, which may be due to the effects of estrogen excess or androgen deprivation, or both.

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 Kreb's 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 effects of chronic high dose androgen or estrogen treatment on the human prostate [corrected].

Prostate development and disease are androgen dependent. However, the nature of hormonal effects on the prostate of healthy young men is not clear. We, therefore, measured prostate size in males chronically exposed to high doses of androgens (AS; habitual anabolic steroid abusers; n = 15) or estrogens (E; male to female transsexuals; n = 11) and compared the results with those in age-matched healthy eugonadal men without known prostate disorders. Prostate size was measured by planimetric ultrasound as cross-sectional areas and maximal dimensions in three orthogonal dimensions with a 7.5-megahertz B-mode sector scanner biplane in a transrectal transducer at 2.5 mm steps from the base to the apex of prostate. Total prostate volume (TPV) was reconstructed from planimetric sections, central prostate volume (CPV) was calculated by the ellipsoidal formula from the appropriate three maximum dimensions, and peripheral prostate volume was determined by the difference between TPV and CPV. Compared with age-matched controls, TPV was normal (-2%) in AS (P = 0.752) and reduced by 31% in E (P = 0.002), whereas CPV was increased by 20% in AS (P = 0.002) and reduced by 46% in E (P = 0.002), and the ratio of CPV/peripheral prostate volume was increased by 77% in AS (P < 0.001) and decreased by 33% in E (P = 0.047). Blood sex hormone-binding globulin was elevated by nearly 500% in E (P < 0.001), but was reduced by 47% in AS (P = 0.003). Prostate-specific antigen was normal (-6%) in AS (P = 0.799) and decreased by 86% in E (P = 0.002). Prostatic acid phosphatase was increased by 26% in AS (P = 0.007), but was unchanged (-28%) in E (P = 0.106). Total and free testosterone levels were reduced to castrate levels in E, whereas LH, FSH, and total testosterone levels were significantly reduced in AS. We conclude that in the human prostate of young men, CPV is more hormonally sensitive than TPV, and during high dose treatment, CPV is preferentially increased by chronic androgen treatment and decreased by chronic estrogen treatment. The reduction of TPV by estrogens was less than expected if solely attributable to inhibition of endogenous gonadotropin and testosterone secretion, suggesting that estrogens also have a positive effect on the normal human prostate. The reversibility and long term significance of androgen-induced stimulation of CPV and, in particular, its relationship to the onset and severity of benign prostatic hyperplasia remain to be clarified.

Actions of magnesium, nifedipine and clonidine on the fetal vasculature of the human placenta.

The anticonvulsant magnesium and the antihypertensives clonidine and nifedipine are extensively used for the clinical treatment of preeclampsia and eclampsia. Little, however, is known about the possible effects of these agents on human fetal-placental vascular resistance. We therefore examined the actions of these agents on the human fetal placental vascular bed in vitro relating the concentrations causing any vasoactive effects to the maternal blood levels attained during treatment. Placentas (n = 24) were obtained within 20 minutes of delivery from women (aged 30.2 +/- 0.9 years). In each a placental lobule was bilaterally perfused with Krebs' solution (5 mL/minute, 37 degrees C, 95% O2, 5% CO2) and fetal arterial inflow pressure (FAP) monitored. Submaximal vasoconstriction of the fetal vascular bed was induced by continuous infusion of prostaglandin F2 alpha (4.2 +/- 0.5 microM) which increased FAP from 25.9 +/- 3.9 to 95.1 +/- 6.2 mm Hg. Using a group of placentas for each drug, the effects of MgCl2, nifedipine and clonidine, were examined. Magnesium (0.3-100 mM) (n = 4) dilated the placental fetal circulation with an IC50 of 8.1 mM and a maximal response of 89.7 +/- 3.6% (n = 4). This effect of Mg2+ was not changed during concomitant infusion of the cyclo-oxygenase inhibitor, indomethacin (3 microM). Nifedipine (3-10,000 nM) also produced vasodilatation (maximum response 42 +/- 9%, n = 5). Clonidine (3-1,000 nM) caused no significant change (p < 0.05 n = 5) in vascular resistance (maximum response 11.2-5.7%) relaxation), when compared to controls. Thus in concentrations likely to be therapeutically present in maternal blood, magnesium causes a greater degree of placental fetal vasodilatation than does nifedipine, whereas clonidine is unlikely to have any effect on fetal placental vascular resistance.

Effects of variation in oxygen tension on responses of the human fetoplacental vasculature to vasoactive agents in vitro.

The human placenta perfused in vitro with Krebs' solution has been used to examine the effects of low oxygen tension on the vasoreactivity of the fetal placental vessels to several vasodilator and vasocontrictor autacoids. Increases in fetal arterial perfusion pressure (FAP) produced by endothelin-1 (ET-1, human), the thromboxane A2-mimetic U46619, 5-hydroxytryptamine (5-HT), angiotensin II (A II) and bradykinin (BK) were examined under conditions of high ( >or= 450 mmHg) and low

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 A2 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-PGF1 alpha 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. DESIGN: Prospective, longitudinal cohort study. SETTING: John Hunter Hospital clinic, Newcastle, Australia. SUBJECTS: One hundred and sixty primiparous women, recruited when presenting for their first routine antenatal visit, were investigated at, or close to, 19, 28 and 37 weeks of gestation; a subgroup was also studied in the postnatal period. The measurements of the patients who developed pregnancy induced hypertension or pre-eclampsia were compared with those of controls selected from the cohort. MAIN OUTCOME MEASURES: Serial measurements of the circulating concentrations of the stable metabolites of thromboxane A2 and prostacyclin (TXB2 and 6-keto-PGF1 alpha, respectively), venous distensibility and immediate (no rest) and resting (for at least 30 min) blood pressures. RESULTS: There was no significant difference between the subject and control groups at any time during or after the pregnancy in the concentrations of prostaglandin metabolites, their ratio or venous distensibility. In contrast, there was a significant difference between the groups at 19 weeks for immediate and resting readings of diastolic pressure (6 mmHg (95% CI 1.5 to 10.5) and 4 mmHg (95% CI 0.1 to 7.9), respectively). These differences increased through the pregnancy but mean postnatal readings for the groups were almost identical suggesting that the subjects were not intrinsically hypertensive compared with controls. Blood pressures for the subject group, both immediate and resting, were significantly different from the 19 week readings at 28 weeks (diastolic) and at 37 weeks (systolic and diastolic). The only significant change from first readings among controls was in postnatal systolic pressure which was significantly higher than 19 week values, probably reflecting the vasodilatation, with accompanying hypotension, of early, normal pregnancy. This difference was not observed in those who subsequently developed pregnancy induced hypertension or pre-eclampsia. CONCLUSIONS: Our study was unable to demonstrate differences in circulating metabolites or venous distensibility between normotensive women and those with pregnancy induced hypertension or pre-eclampsia. If pregnancy induced hypertension or pre-eclampsia in humans represents not so much the presence of abnormal constrictor influences as a process initiated by failure of normal vasodilatation in early pregnancy, studies carried out later may detect mainly adaptive and secondary changes.

Vascular responses to sodium nitroprusside in the human fetal-placental circulation.

This study examined the activity of sodium nitroprusside (SNP) in the human fetal-placental circulation in vitro in pathological and experimental conditions in which vascular function may be impaired. SNP (13-3400 nM) caused a concentration-dependent reduction in fetal arterial perfusion pressure (FAP) in Krebs' perfused placental cotyledons, at basal tone and following pre-constriction with prostaglandin F2 alpha (PGF2 alpha). SNP-induced reduction in FAP in the PGF2 alpha pre-constricted fetal-placental circulation was enhanced approximately six-fold (5.85) in those placentae pre-treated with the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (100 microM). Reductions in FAP in the preconstricted fetal-placental vasculature caused by SNP were not altered by prior infusion of ouabain (100 nM) into the fetal circulation or during low oxygen perfusion (O2 tension < 50 mmHg). No differences were observed in the responses obtained to SNP in placentae obtained from women with normotensive pregnancies or those associated with (i) pregnancy-induced hypertension, (ii) intra-uterine growth retardation, or (iii) an elevated umbilical-artery Doppler-ultrasound systolic/diastolic ratio, in either preconstricted placentae or those at basal tone. These findings are consistent with an up-regulation of guanylate cyclase/cGMP-mediated vasodilatation in the fetal-placental vasculature following complete blockade of endogenous NO production.

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. 2. The low placental vascular resistance is due to a lack of nervous influences together with pregnancy-induced changes promoting vasodilatation. Increases occur in output of the vasodilators prostacyclin and nitric oxide and also in membrane sodium pump activity. 3. Many autacoids are present in umbilical blood. Fetal vessels of the placenta develop intense vasoconstriction in the presence of some autacoids, such as thromboxane A2 and prostaglandins F2 alpha and E2, and respond weakly to others, such as angiotensin II and 5-hydroxytryptamine. Nevertheless, vasodilator influences predominate. 4. The diseases of pre-eclampsia and fetal growth retardation are associated with reduced output of nitric oxide and prostacyclin and with increased production of thromboxane A2 and endothelin-1. These changes promote vasoconstriction, increased vascular sensitivity to vasoconstrictor stimuli, platelet aggregation and intravascular coagulation, retarding blood flow and feto-placental growth. 5. Aspirin and glyceryl trinitrate have been investigated for possible therapeutic use in pre-eclampsia and fetal growth retardation. Improved drug therapy is likely as knowledge increases of the importance of autacoids in normal placental function and in the changes that occur during disease.