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F Broughton Pipkin

Publications and source records attributed to F Broughton Pipkin.

At least 37 records · Page 2Linked to original sources
PubMed1998

Distortion of maternal-fetal angiotensin II type 1 receptor allele transmission in pre-eclampsia.

OBJECTIVE: To investigate the fetal angiotensin II type 1 receptor genotype in pre-eclampsia. DESIGN: Case-control study. POPULATION: Forty-one maternal-fetal pairs from pre-eclamptic pregnancies and 80 maternal-fetal pairs from normotensive pregnancies. METHODS: Maternal and fetal DNA was genotyped at three diallelic polymorphisms, at nucleotides 573, 1062, and 1166, in the coding exon of the angiotensin II type 1 receptor gene, and at a dinucleotide repeat polymorphism in its 3' flanking region. RESULTS: Allele and genotype frequencies at the four polymorphic regions investigated did not differ between pre-eclamptic and normotensive groups, in either fetal or maternal samples. Mothers heterozygous for the dinucleotide repeat allele designated A4 transmitted this allele to the fetus in 15 of 18 informative pre-eclamptic pregnancies and in eight of 26 normotensive pregnancies. This was greater than the expected probability in pre-eclamptic pregnancies (p=0.04) and less than expected in normotensive pregnancies (p<0.005). The 573T variant, which is in partial linkage disequilibrium with the A4 allele, showed a similar distortion of maternal-fetal transmission. CONCLUSION: Angiotensin II type 1 receptor gene expression in the fetus may contribute to the aetiology of pre-eclampsia. It is unclear whether susceptibility is conferred by the fetal genotype acting alone, or by allele sharing by mother and fetus. Possible mechanisms for the effect of the angiotensin II type 1 receptor gene are suggested by the association of the 573T variant with low levels of surface receptor expression on platelets. If receptor expression is similarly genetically determined in the placenta, responsiveness to angiotensin II may be affected, with the potential to influence placentation or placental prostaglandin secretion.

Alleles↗
PubMed1997

Functional and genetic studies of the angiotensin II type 1 receptor in pre-eclamptic and normotensive pregnant women.

OBJECTIVE: To examine and compare angiotensin II type 1 receptor genotype and its relationship to platelet angiotensin II binding for pre-eclamptic and normotensive pregnant women. DESIGN: In a case-control study, 43 pre-eclamptic women and 83 normotensive women were genotyped at the angiotensin II type 1 receptor gene locus. Platelet angiotensin II binding was measured for a subset of 11 pre-eclamptic and 57 normotensive pregnant women. We genotyped 162 healthy blood donors also, to examine the allelic background and patterns of linkage disequilibrium in the Nottingham population. METHODS: Patients were recruited during pregnancy using a rigorous definition of pre-eclampsia. DNA was extracted from peripheral venous blood and genotyped at six previously described diallelic polymorphisms in the angiotensin II type 1 receptor gene, using competitive allele-specific oligonucleotide hybridization, and at a dinucleotide repeat polymorphism in the 3' flanking region of the gene. Platelet angiotensin II binding and plasma angiotensin II concentrations were determined for peripheral venous blood. RESULTS: Normotensive pregnant women homozygous for cytosine at nucleotide 573 had significantly higher levels of platelet angiotensin II binding than did heterozygous women and women homozygous for thymidine at this site. Pre-eclamptic women had significantly higher levels of platelet angiotensin II binding than did normotensive pregnant women. The frequencies of allelic variants did not differ significantly between normotensive and pre-eclamptic women. CONCLUSION: The physiological regulation of platelet angiotensin II type 1 receptor expression in normal pregnancy is determined in part by angiotensin II type 1 receptor genotype. There was no evidence that the polymorphisms in the angiotensin II type 1 receptor gene were associated with pre-eclampsia.

Adult↗
PubMed1997

Changes in the maternal and fetal renin-angiotensin systems in response to angiotensin II type 1 receptor blockade and angiotensin-converting enzyme inhibition in pregnant sheep during late gestation.

The effects of maternal administration of either an angiotensin II type 1 (AT1) receptor antagonist (GR138950) or an angiotensin-converting enzyme (ACE) inhibitor (captopril) on the renin-angiotensin system (RAS) were investigated in chronically catheterized ewes and their fetuses during late gestation. From 127 +/- 1 days of gestation until parturition at 145 +/- 2 days, each ewe received daily i.v. injections of GR138950 (3 mg kg-1, n = 10 animals) or captopril (3 mg kg-1, n = 6) or an equivalent volume of vehicle solution (0.9% NaCl, n = 10). On the first day of treatment, plasma renin concentrations in the pregnant ewe increased within 2 h of administration of either GR138950 (median change followed by lower and upper quartiles (25%, 75%): +38.3 ng ml-1 h-1 (15.6, 80.7); P < 0.05) or captopril (+22.1 ng ml-1 h-1 (19.2, 28.8); P < 0.05). Maternal plasma concentrations of angiotensin II (AII) also increased by 871 pg ml-1 (555, 1340; P < 0.05) in the GR138950-treated ewes. In the fetuses of both groups of drug-treated animals, an increase in plasma renin concentration was observed within 2 h of maternal treatment with either GR138950 (+11.6 ng ml-1 h-1 (1.2, 18.6); P < 0.05) or captopril (+59.3 ng ml-1 h-1 (41.7, 74.6); P < 0.05). These short-term changes in circulating renin and AII concentrations observed in the pregnant ewe were sustained after 1 week of GR138950 administration. In addition, 1 week of GR138950 treatment decreased plasma angiotensinogen (Ao) concentrations in both the ewe (-0.36 microgram ml-1 (-0.58, -0.16); P < 0.05) and the fetus (-0.43 microgram ml-1 (-0.59, -0.09); P < 0.05). A long-term reduction in maternal plasma AII, and an increase in fetal plasma renin concentration, were associated with 1 week of captopril administration. Neither drug had any consistent effect on plasma ACTH or cortisol concentrations in the pregnant ewe or fetus. These findings show that, during ovine pregnancy, antagonism of maternal AII activity, either by blockade of the AT1 receptor or by inhibition of AII synthesis, induces changes in the circulating components of the RAS in the mother and fetus. In both the pregnant ewe and fetus, the RAS is shown to be activated by suppression of AII activity.

Angiotensin II↗
PubMed1997

Does angiotensin play a role in human fetal erythropoiesis?

Angiotensin affects the growth of many cell types and there have been suggestions that it could influence cells which respond to erythropoietin. During first trimester, human fetal haematopoietic cells are exquisitely responsive to erythropoietin and we have assessed the potential for angiotensin to also influence the growth of these cell types in a standard culture system. The data obtained from these studies indicate that angiotensin does not influence fetal haematopoiesis over a range of concentrations.

Angiotensin II↗
PubMed1997

Angiotensin II has depressor effects in pregnant and nonpregnant women.

Studies in anesthetized animals suggest that angiotensin II evokes a depressor as well as a pressor effect, which becomes evident on cessation of infusion. We have studied 18 nonpregnant and 8, 23, and 22 women in the first, second, and third trimesters of pregnancy to determine whether such an effect is present in conscious women, whether it is dose dependent, and whether it is influenced by pregnancy. Angiotensin II was infused intravenously in doubling concentrations at 10-minute intervals until a pressor effect of approximately 20 mm Hg was observed. The infusion was stopped, and blood pressure was monitored at 2-minute intervals for 30 minutes. There was a significant diastolic depressor effect after stopping angiotensin II in the nonpregnant women and those in the second and third trimesters of pregnancy. Individual women required differing doses of angiotensin II to evoke the standardized pressor response. It was thus possible to examine the depressor response in each group in relation to infused doses of angiotensin II. In nonpregnant women and in those in the second and third trimesters of pregnancy, the depressor response was dose dependent (P<.001). At any given dose, the depressor response deepened as pregnancy progressed (P<.001). Basal plasma prostacyclin concentrations rise in pregnancy, and angiotensin II can stimulate prostacyclin synthesis. This might mediate the depressor effect. In conclusion, the diminished pressor response to angiotensin II in normal pregnancy may be partly due to an increasing depressor effect of the hormone.

Adult↗
PubMed1996

DNA polymorphisms and linkage disequilibrium in the angiotensinogen gene.

A number of recent studies have implicated the angiotensinogen gene in the aetiology of essential hypertension in Caucasian, Japanese and African Caribbean subjects. We have genotyped 153 healthy white Caucasian subjects at a dinucleotide repeat polymorphism and seven diallelic sites in the coding or flanking regions of the angiotensinogen gene, including one polymorphism not previously studied. We have also documented patterns of linkage disequilibrium between polymorphisms. There is evidence of variation in the frequency of several mutations when compared with published results from other Caucasian control populations, possibly due to cryptic ethnic differences between these groups. This should be considered in the design and interpretation of studies of the angiotensinogen gene.

Adult↗
PubMed1996

Angiotensinogen: molecular biology, biochemistry and physiology.

Angiotensinogen is the only known substrate for the enzyme renin. Angiotensin II, the end product of the reaction, is an extremely potent vasoconstrictor and a major determinant of salt and water homeostasis. It is also a growth factor. Angiotensinogen has been identified as a non-inhibitory member of the serine proteinase inhibitor family. Although the most abundant source of plasma angiotensinogen is the liver, the use of Northern blotting and reverse transcriptase PCR techniques has confirmed angiotensinogen mRNA expression in a wide range of tissues, including the kidney, brain, vascular tissue, adrenal gland, placenta and leucocytes. The sequencing of the rat and human angiotensinogen genes has increased our understanding of this protein and its role in physiology and the pathogenesis of human disease. Early observations on the regulation of angiotensinogen are now explicable at the molecular level, with the identification of the core promoter, hormone and acute phase responsive elements and tissue-specific enhancers. The role of angiotensinogen in the aetiology of hypertensive disorders has been tested in transgenic animals, and in case-controlled genetic association and linkage studies. This review examines our current understanding of angiotensinogen, in the light of recent advances.

Angiotensinogen↗
PubMed1996

Angiotensin receptors in myometrium and myometrial vessels from uteri of women during the follicular and luteal phases of the menstrual cycle and in late pregnancy.

1. Receptors for angiotensin II were identified and characterized in membrane fractions from myometrial samples obtained at non-pregnant hysterectomy in women of reproductive age. Specific binding was also measured in paired samples of vascular and "vessel-free' myometrium. 2. A single class of high-affinity receptor sites was identified in the total myometrial preparations (n = 10), with a median equilibrium dissociation constant (Kd) of 0.122 nmol/l (range 0.065-0.465 nmol/l) and concentration of receptor sites (Bmax) of 149 fmol/mg protein (range 105-435 fmol/mg). Receptor characterization studies using losartan (an angiotensin type 1 receptor antagonist) and PD123177 (an angiotensin type 2 receptor antagonist) showed the myometrium to contain almost entirely type 2 receptors. 3. The median Kd and Bmax for specific angiotensin II binding in isolated myometrial vessel homogenates were 0.086 nmol/l (range 0.060-0.433) and 260 fmol/mg protein (range 197-737 fmol/mg) respectively. Vascular specific binding density was always higher in dissected out myometrial vessels than in paired vessel-free myometrium (median 372 compared with 120 fmol/mg protein; n = 20; P < 0.001). The specific binding in the paired samples was strongly correlated (r = 0.8904, P < 0.0001). 4. The specific binding of 125I-labelled angiotensin II in "vessel-free' myometrium was higher in samples from the follicular phase than in samples from the luteal phase (median 144 compared with 37 fmol/mg; P < 0.02). A similar trend was found in the vessels themselves, but this failed to reach statistical significance (459 compared with 225 fmol/mg; P = 0.051). 5. It is suggested that the down-regulation of the angiotensin type 2 receptors in the luteal (secretory) phase is a preparation for pregnancy, removing an inhibitory factor to uterine growth and vascularization and allowing greater prostacyclin synthesis.

Adult↗
PubMed1996

Comparison of angiotensin II type 1 receptor blockade and angiotensin-converting enzyme inhibition in pregnant sheep during late gestation.

1. The effects of antagonism of the maternal renin-angiotensin system (RAS) with either an angiotensin II type 1-(AT1) specific receptor blocker (GR138950) or an angiotensin-converting enzyme (ACE) inhibitor (captopril) were compared in chronically-catheterised ewes and their foetuses during late gestation. 2. Daily from 127 +/- 1 days of gestation until parturition at 145 +/- 2 days, each ewe received i.v. either GR138950 (3 mg kg-1; n = 10), captopril (3 mg kg-1; n = 6) or an equivalent volume of vehicle solution (0.9% w/v saline; n = 10). 3. Within 2 h of drug administration, GR138950 abolished the maternal, but not the foetal, pressor responses to angiotensin II (AII; 100-188 ng kg-1, i.v.; P < 0.05), whereas captopril abolished both the maternal and foetal pressor responses to angiotensin I (AI; 400-750 ng kg-1, i.v.; P < 0.05). 4. On the first day of treatment, maternal blood pressure decreased in all GR138950-treated (-21 +/- 4 mmHg; P < 0.05) and captopril-treated (-13 +/- 5 mmHg; P > 0.05) ewes at 2 h after drug administration. Captopril also significantly decreased foetal blood pressure by 5 +/- 1 mmHg (P < 0.05). However, foetal blood pressure in the GR138950-treated animals remained unchanged. Maternal and foetal heart rates were unaffected by any treatment. Uterine blood flow was significantly reduced within 2 h of both GR138950 (-130 +/- 20 ml min-1; P < 0.05) and captopril (-72 +/- 16 ml min-1; P < 0.05) administration. 5. On the first day of treatment, maternal arterial haemoglobin (Hb) concentration and oxygen (O2) content increased at 2 h in all GR138950-treated and captopril-treated ewes. Foetal arterial pH and oxygenation (O2 content, O2 saturation and Pao2) were reduced by a similar extent in both groups of drug-treated ewes. 6. After one week of daily GR138950 administration, maternal blood pressure decreased from a pretreatment value of 96 +/- 5 mmHg on day 1 to 79 +/- 2 mmHg by day 7 (P < 0.05). Captopril treatment had no long-term effect on maternal blood pressure. Although foetal blood pressure increased by 3 +/- 1 mmHg over a week of vehicle treatment (P < 0.05), no significant differences were observed between the long-term changes in foetal blood pressure in all three groups of animals. 7. There were no long-term effects of drug administration on maternal Hb concentration or oxygenation, or on the foetal haematological parameters. However, changes in maternal PaCo2 observed in the GR138950-treated (+1.4 +/- 0.5 mmHg; P < 0.05) and captopril-treated (+3.3 +/- 1.1 mmHg; P > 0.05) ewes were significantly different from those seen in the vehicle-treated animals (P < 0.05). 8. There were no apparent adverse effects of maternal GR138950 or captopril treatment on foetal viability. 9. The present study demonstrated that administration of either GR138950 or captopril to pregnant ewes effectively blocked the maternal RAS, and caused hypotension and a decrease in uterine blood flow. However, only captopril appeared to cross the placenta to influence directly the RAS of the sheep foetus. This suggests that the fall in foetal oxygenation observed after AT1-specific receptor blockade and ACE inhibition originates primarily from changes in the maternal and/or placental vasculature. Despite these changes, neither GR138950 nor captopril were detrimental to the outcome of pregnancy when foetal blood loss was kept to a minimum.

Angiotensin Receptor Antagonists↗
PubMed1994

Waveform shape analysis: extraction of physiologically relevant information from Doppler recordings.

1. Doppler recordings were made from the brachial artery of healthy female subjects during a series of manoeuvres which altered the pressure-flow characteristics of the vessel. 2. Changes were induced in the peripheral circulation of the forearm by the application of heat or ice-packs. A sphygmomanometer cuff was used to create graded occlusion of the vessel above and below the point of measurement. Recordings were also made whilst the subjects performed a standardized Valsalva manoeuvre. 3. The Doppler recordings were analysed both with the standard waveform indices (systolic/diastolic ratio, pulsatility index and resistance index) and by the method of Laplace transform analysis. 4. The waveform parameters obtained by Laplace transform analysis distinguished the different changes in flow conditions; they thus had direct physiological relevance, unlike the standard waveform indices.

Adult↗
PubMed1994

Pre-eclampsia--the 'disease of theories'.

Hypertension in pregnancy remains a major cause of maternal and fetal morbidity and mortality. It is a late manifestation of a multifactorial, multisystem disease, initiated very early in pregnancy, the features of which suggest an inadequate maternal response to pregnancy. There is a genetic susceptibility to pre-eclampsia. Endothelial cell dysfunction in response to an unknown factor(s) may evoke some of the hormonal anomalies. In established severe disease there is volume contraction, reduced cardiac output, enhanced vascular reactivity, platelet exhaustion and disseminated intravascular coagulation in addition to the hypertension. Delivery is associated with resolution of the hypertension. Pharmacological treatment is most suitable for early-onset, severe disease when an attempt to delay delivery is indicated. Methyldopa or beta-blockers and/or vasodilators may be used. ACE inhibitors are contra-indicated. Low-dose aspirin may be useful in prophylaxis.

Adrenergic beta-Antagonists↗
PubMed1994

Neonatal platelet reactivity and serum thromboxane B2 production in whole blood: the effect of maternal low dose aspirin.

OBJECTIVES: Concern has been expressed about possible neonatal side effects after the use of maternal anti-platelet agents in pregnancy, particularly low dose aspirin treatment. We have studied neonatal platelet behaviour using whole blood techniques, and assessed the neonatal effect of the maternal ingestion of 60 mg aspirin daily. DESIGN: Cross sectional and randomised, double-blind, placebo-controlled. SETTING: University hospital. SUBJECTS: 1. Eight normal women, studied before conception, and their infants. 2. Twenty-four infants whose mothers had been randomised to receive either 60 mg aspirin daily, or placebo, in double-blind fashion. METHODS: The Clay Adams Ultra Flo 100 whole blood single platelet counter was employed to measure platelet aggregation in response to various agonists. The platelet release reaction was also measured in whole blood, and serum thromboxane B2 (TxB2) production was measured by radio-immunoassay. Umbilical cord blood samples were obtained at delivery. RESULTS: 1. Neonatal platelet aggregation induced by adrenaline, ADP and platelet activating factor was reduced in comparison with their mothers (P < 0.01), whereas the neonatal platelet release reaction was reduced when stimulated by collagen and U46619 (a thromboxane mimetic) (P < 0.01). Serum TxB2 production was similar in mothers and babies. 2. Neonatal platelet aggregation, release reaction and serum TxB2 production were not significantly reduced in infants exposed to maternal aspirin in comparison with those neonates exposed to maternal placebo. This is in contrast to the effect on maternal platelets. CONCLUSIONS: Although only a small number of patients were studied, we interpret this as a relative sparing of neonatal platelet reactivity due to the presystemic action of low dose aspirin.

Adult↗
PubMed1994

Neonatal and maternal platelet cytosolic calcium in normotensive and hypertensive pregnancies.

A prospective study investigated platelet cytosolic calcium in non-pregnant volunteers (n = 30) and samples from the umbilical veins of babies from both normotensive (n = 18) and hypertensive (n = 15) primigravidae, and their mothers. There was no significant difference between the neonatal umbilical venous platelet cytosolic calcium concentration (p[Ca2+]i) in babies born to normotensive primigravidae or to those whose pregnancies were complicated by gestational hypertension (88 x 9 (SE) 2 x 5) in normotensive primagravidae, 80 x 6 (2 x 8) in pregnancy induced hypertension without proteinuria, and 89 x 3 (3 x 2) nmol/l in pre-eclampsia. There was also no significant difference in the p[Ca2+]i from the umbilical veins of the pregnancies studied and those of non-pregnant female volunteers in the follicular phase of their menstrual cycle. This was despite a gradual and significant rise in p[Ca2+]i with increasing severity of disease in the mothers of the babies studied (119 x 9 (4 x 1) in normotensive primagravidae, 130 x 8 (7 x 3) in pregnancy induced hypertension without proteinuria, and 148 x 2 (4 x 5 ) nmol/l in pre-eclampsia). The mean maternal p[Ca2+]i in the three samples returned to concentrations comparable with those in non-pregnant subjects by 12 weeks after birth. These data demonstrate no significant difference between the mean p[Ca2+]i in non-pregnant women and those obtained from the umbilical venous blood of normotensive or hypertensive primigravidae. They suggest that the functional hypoactivity of neonatal platelets is probably not secondary to a decrease in basal p[Ca2+]i. They also suggest that the progressively raised p[Ca2+]i in normal and hypertensive pregnancies might be due to a pregnancy specific factor that does not cross the placenta,

Adult↗