Biomedical subjects
Publications and source records attributed to V Glover.
We have shown that a baby's stress (saliva cortisol) and crying response to inoculation at 8 weeks was related to mode of delivery, with the greatest response shown in those born by assisted delivery and the least response in those born by elective caesarean section.
Invasive diagnostic and therapeutic techniques are increasingly applied to the fetus. It is not known if the fetus feels pain during such procedures, but the fetus does mount significant stress hormonal and circulatory changes in response to these from 18-20 weeks. Perinatal stress may have long-term neurodevelopmental implications. During open fetal surgery, maternal general anaesthesia provides fetal anaesthesia. However, in closed procedures, fetal analgesia presents difficulties. The optimal drug, dose, and route of administration remain to be determined.
Isatin is an endogenous indole which has been shown to counteract some of the effects of atrial natriuretic peptide (ANP) both in vitro and in vivo. The present study was designed to determine whether it could antagonise in vivo effects of the related peptides brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). The model used was consolidation of memory in a one-trial step-through passive-avoidance paradigm in the rat. Previous studies have shown that all three peptides (1 microg intracerebroventricular) can consolidate such learning and increase latency to entry a dark box. Isatin was given intraperitoneally at doses of 5, 10 and 50 mg/kg before the peptide, or a saline control. Both BNP and CNP significantly increased the latency of entry. Isatin alone had no effect. Isatin reduced the effect of both BNP and CNP; this was significant for its effect on BNP at 50 mg/kg and on CNP at both 10 and 50 mg/kg. These results show that isatin can inhibit behavioural effects of BNP and CNP as well as ANP.
The influence of indole-2,3 dione (isatin) on particulate guanylyl cyclase (GC) from rat heart membranes was investigated in the presence of adenylylimidodiphosphate (AMP-PNP). The latter activated GC in a concentration-dependent manner and 100 microM isatin abolished this effect. The IC(50) value, 2 microM, for the inhibition of stimulation of GC induced by 50 microM AMP-PNP, was close to the upper physiological level of isatin. These results indicate that isatin may interact with GC independently of its regulation by natriuretic peptides.
Isatin is an endogenous indole and an inhibitor of atrial natriuretic peptide (ANP) receptors coupled with particulate guanylyl cyclase (GC). In this study, several isatin analogues were tested as inhibitors of ANP-stimulated GC in rat brain and heart membranes. None of these analogues affected activity in the absence of ANP, or stimulated ANP-induced activity. In both tissues, some 5-substituted isatins (5-hydroxyisatin, 5-methylisatin, and 5-aminoisatin) exhibited more effective inhibitory activity than isatin itself, with IC50 values in the range 1.3-20 microM. The efficacy of other analogues varied and was not consistent between the two tissues, raising the possibility of receptor heterogeneity and relative selectivity of inhibition. Some substituted isatins may have a role as pharmacological tools for investigating the physiological roles of natriuretic peptides and their receptors.
OBJECTIVE: To investigate whether maternal anxiety in the third trimester is associated with an increased uterine artery resistance index. DESIGN: Cohort based study. SUBJECTS: 100 pregnant women, with a mean gestation of 32 weeks. OUTCOME MEASURES: Self rating Spielberger questionnaire for state anxiety and trait anxiety, and uterine blood flow waveform patterns as assessed by colour Doppler ultrasound. RESULTS: A significant association was found between uterine artery resistance index and scores for both Spielberger state anxiety and trait anxiety (rs=0.31, P<0.002 and 0.28 P<0.005 respectively). Women with state anxiety scores >40 (n=15) had a higher mean uterine resistance index than those with scores </= 40 (mean difference with mean resistance index 24%, 95% confidence interval 12% to 38%; P<0.0001). Similarly, women with trait anxiety scores >40 (n=32) had a higher mean resistance index than those with scores </= 40, although to a lesser extent. The presence of notches in the waveform pattern produced by uterine artery blood flow was found in 4/15 (27%) women with high state anxiety scores compared with 4/85 (5%) with low anxiety scores (P<0.02). CONCLUSIONS: This study shows an association between maternal anxiety in pregnancy and increased uterine artery resistance index. It suggests a mechanism by which the psychological state of the mother may affect fetal development, and may explain epidemiological associations between maternal anxiety and low birth weight. The influence of maternal anxiety may be one mechanism by which the intrauterine environment contributes to later disease in offspring.
OBJECTIVES: We sought to investigate the fetal hemodynamic response to the acute stress of invasive procedures. STUDY DESIGN: The middle cerebral artery pulsatility index was measured by Doppler ultrasonography before and after 136 invasive procedures (fetal blood sampling, transfusion, shunt insertion, tissue biopsy, and ovarian cyst aspiration). The response of fetuses submitted to invasive procedures involving transgression of the fetal body, such as intrahepatic vein blood sampling, was compared with that of control procedures at the placental cord insertion. RESULTS: The middle cerebral artery pulsatility index value fell with fetal blood sampling performed at the intrahepatic vein (median, -0.26; 95% confidence interval, -0.35 to -0.15) but not at the placental cord insertion (median, 0.05; 95% confidence interval, -0.04 to 0.19). With transfusions, the middle cerebral artery pulsatility index also fell with procedures at the intrahepatic vein (mean, -0.51; 95% confidence interval, -0.66 to -0.35) but not at the placental cord insertion (mean, -0.04; 95% confidence interval, -0.23 to 0.14). The magnitude of the response was greater with transfusions than with blood sampling alone. The middle cerebral artery pulsatility index value also fell with non-fetal blood sampling procedures involving transgression of the fetal body (mean, -0.32; 95% confidence interval, -0.56 to -0.09) but not with control non-fetal blood sampling procedures. The change in the middle cerebral artery pulsatility index was not related to gestational age, with the youngest fetus showing a fall in the middle cerebral artery pulsatility index value being at 16 weeks' gestation. Although the degree of response was weakly correlated with the duration of needling (y = -0.21 - 0.00014x; R (2) = 0.08; P =.02), multiple logistic regression demonstrated that this was instead a function of the type of the procedure. A response was seen within 70 seconds of fetal puncture. The fetal heart rate did not change significantly with procedures in any of the above-mentioned groups. CONCLUSIONS: The human fetus mounts a cerebral hemodynamic response to invasive procedures involving transgression of the fetal body, which is consistent with the brain-sparing effect.
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Fetal and maternal plasma noradrenaline responses to invasive procedures were determined in pregnancies of 18 to 37 wk gestation. Fetal umbilical venous blood sampling was performed either from the placental cord insertion, which is not innervated, or the intrahepatic vein, which is innervated, and thus may be more stressful for the fetus. Samples from diagnostic procedures, as well as from transfusion procedures, were compared between the two sites. Fetal plasma levels were significantly elevated in blood samples obtained from the intrahepatic vein compared with those from the placental cord insertion during diagnostic procedures [p < 0.05, geometric means and 95% confidence intervals (CI) were 0.67 nmol/L (0.43-1.04) and 0.36 nmol/L (0.25-0.54), respectively]. Plasma levels in samples taken before transfusion from the intrahepatic vein were also significantly higher than those from the placental cord insertion. After transfusion, there was a significant rise in fetal plasma noradrenaline levels at both sites; however, after transfusion through the intrahepatic vein, the rise was substantially greater than after transfusion through the placental cord insertion (p < 0.05, change, mean deltaNA, and 95% CI were 0.67 (0.37-1.22), and 0.20 (0.12-0.33), respectively). The deltaNA was significantly associated with the duration of the stimulus (the time the needle remained in situ) (p = 0.05, adjusted R2 = 0.48) and with gestational age. Maternal levels rose substantially and equally after transfusions at either site (mean deltaNA and 95% CI, 6.46 nmol/L, 1.74 to 11.18 and 9.49 nmol/L, 6.24 to 12.75 for the intrahepatic vein and placental cord insertion groups, respectively). There was no significant correlation between baseline fetal and maternal levels (r = 0.08, n = 41) or between deltaNA pre- and posttransfusion maternal and fetal values in either group. These results indicate that the fetus is capable of mounting an independent noradrenaline stress response to a needle transgressing its trunk from 18 wk gestation. The effect was observable in samples taken at a mean of 5.6 min after needling. The lack of correlation between maternal and fetal levels suggests that virtually no noradrenaline crosses the placenta directly, and that the observed fetal responses are not due to direct transport from the mother.
We have recently carried out a study of 100 mothers at Queen Charlotte's Hospital, at 32 weeks' gestation, and shown that those who were most anxious had impaired blood flow through the uterine arteries. This may help to explain why the babies of very anxious mothers tend to be smaller or born earlier. We have also shown that there is a strong correlation between plasma levels of the stress hormone cortisol in the mother and in the fetus. If the pregnant mother has raised cortisol, this may have a direct effect on the development of the fetal brain, and affect the child's later responses to stress.
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Recent research on tribulin [low molecular weight endogenous inhibitory activity of monoamine oxidase (MAO)] has confirmed that its level is increased in both human urine and rat tissues by stress or anxiety, and by anxiogenic drugs. However tribulin is now known to contain several different molecules. The raised inhibitory activity in rat tissues is selective for MAO-A. There is a parallel decrease in MAO-A activity ex vivo, suggesting a possible functional effect. Increase in endogenous MAO I may competitively inhibit the binding of irreversible MAO I drugs, and may also help to mediate some mood altering effects of other drugs, or procedures such as ECT. In human urine both MAO-A I and MAO-B I have been found to be increased in mild stress. Similar findings have been made with human saliva. Selective inhibitors of MAO-A have been identified from human urine, and pig brain, but it is not yet clear to what extent they account for the MAO-A I activity increased in stress. Isatin is an endogenous selective inhibitor of MAO-B (K1 approximately 3 microM). It has a distinct distribution in rat brain, with highest concentration in the hippocampus of 0.1 microgram/g. Its level is increased by pentylene tetrazole, and isatin is itself anxiogenic in rodent models. Its administration also increases monoamine levels in the brain. It is a potent antagonist of the ANP receptor, and it may act to link the control of monoamine function and natriuresis.
Long-term administration of the monoamine oxidase inhibitor (-)-deprenyl (0.5 mg/Kg) for up to 20 months significantly increased mortality in the male Wistar rat, whereas the dopamine agonist pergolide (0.4 mg/Kg) and the antioxidant diethyldithiocarbamate (400 mg/Kg) had no significant effect on mortality. The increased mortality was not related to dietary intake or body weight of the rats. This is of interest in the light of recent evidence that (-)-deprenyl increases mortality in humans.
The effect of isatin on rat brain particulate guanylate cyclase (GC) was investigated. The enzyme was stimulated by atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and urodilatin, but not by C-type natriuretic peptide (CNP). Their effects were not additive, pointing to action via the GC-A receptor. Isatin, in dose-dependent manner, abolished this stimulation. The non-hydrolysable ATP analogue, adenylylimidodiphosphate, potentiated the effects of submaximal doses of ANP, BNP and urodilatin on this particulate GC-A, and attenuated or abolished sensitivity to isatin. These results suggest that isatin antagonises the generation of second messenger by GC-A; this sensitivity might be regulated at an ATP binding site, possibly a protein kinase-like domain.
Rhazya stricta leaves, which have both antidepressant and sedative properties in animal models, are widely used in folk medicine in the Arabian peninsula. In this study, the effects of oral administration of leaf extracts on rat brain tribulin levels [endogenous monoamine oxidase (MAO) A and B inhibitory activity], were determined. In an acute study, low doses brought about an increase in MAO A inhibitory activity, while intermediate doses caused a significant reduction. The highest doses had no significant effects on activity. There were no significant effects on MAO B inhibitory activity at any dose. Subchronic administration (21 days) caused a significant decrease in MAO A inhibitory activity, most prominent at low dosage, and an increase in MAO B inhibitory activity. Acute intramuscular administration also resulted in a similar pattern. Such paradoxical effects were at least partially explained when different extracts of the leaves were used; a weakly basic chloroform fraction caused an increase in MAO A inhibitory activity, whereas butanol extracts brought about a decrease. These fractions had no significant effects on MAO B inhibitory activity. The findings show that Rhazya stricta leaves contain at least two different components that affect MAO inhibitory activity in opposite directions. It may be that the antidepressant and sedative actions of the plant are explicable in terms of these different components.
Stress is often associated with water retention and its resolution with diuresis. The biological systems for the control of stress and water balance are very closely related. Corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) are co-localised in the hypothalamus and often act synergistically. Atrial natriuretic peptide (ANP) can exert a feedback control on the hypothalamic/pituitary/adrenal axis. ANP has been shown to be anxiolytic, whereas AVP may be anxiogenic. AVP and ANP levels have been found to be abnormal in a range of stress disorders and psychiatric illnesses. Isatin is an endogenous anxiogenic factor which is also a potent inhibitor of the ANP receptor. It may provide a link between the function of monoamines during stress, and the control of water balance by ANP.
A sensitive, capture enzyme-linked immunosorbent assay (CELISA) has been applied to the accurate and reproducible measurement of brain-derived neurotrophic factor (BDNF) protein in normal human blood platelets, a mean concentration of 1.03 +/- 0.04 ng (SEM)/mg of platelet protein being observed. The method, which requires only 10 ml blood, is now suitable for the investigation of a variety of clinical disorders.
Red wine, like the drugs reserpine and fenfluramine, causes the release of 5-hydroxytryptamine (5-HT) from storage sites in vitro. This study used a neuroendocrine challenge test design to determine whether the parallel between red wine and these drugs can be extended to central actions in healthy volunteers. Vodka diluted to an equal alcohol content was used as a control. No significant differences were observed between the groups in plasma cortisol, plasma prolactin or in temperature levels. Thus no evidence was obtained for a central 5-HT releasing action by red wine. Self-rating stress and arousal questionnaires were also given. No differences were found in arousal. However whereas vodka had a clear effect in reducing stress, red wine did not. This suggests that red wine does have psychoactive properties independent of its alcohol effects.