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Biomedical subjects

F Broughton Pipkin

Publications and source records attributed to F Broughton Pipkin.

At least 91 records · Page 5Linked to original sources
PubMed1989

Hypertension in pregnancy: a physiological response to a pathological problem?

In pregnancy-induced hypertension the secondary wave of trophoblast invasion fails, there is a progressive increase in pressor responsiveness to angiotensin II and an imbalance develops in the prostacyclin:thromboxane ratio towards thromboxane. As pregnancy progresses one can imagine that fetal demands gradually outstrip the ability of the relatively narrowed spiral arteries to perfuse the placenta. By analogy with renal artery stenosis, a defence mechanism would be stimulated (synthesis both of renin and vasodilator prostanoids) with systemic hypertension but improved perfusion. Where vasodilator synthesis is impaired, hypertension alone, with worsening perfusion, would ensue.

Adult↗
PubMed1988

The effects of intravenous angiotensin II upon blood pressure and sodium and urate excretion in human pregnancy.

Twelve women in their first 3 months of pregnancy received an i.v. saline load (3 mmol sodium/kg) and a graded infusion of angiotensin II (Ang II; i.e. 4, 8 and 16 ng/kg per min). As controls, twelve comparable pregnant subjects received the saline infusion alone. Eight non-pregnant women underwent both protocols, with doses of 2, 4 and 8 ng/kg per min Ang II, and thus acted as their own controls. Saline loading evoked proportionately similar falls in basal plasma renin (PRC) and plasma aldosterone (PAC) concentrations in pregnant and non-pregnant women. Angiotensin II evoked a dose-dependent pressor response, a graded increase in PAC and a reduction in sodium and urate excretion in both pregnant and non-pregnant women. The administration of Ang II had a proportionately greater effect on sodium and urate excretion in non-pregnant than in pregnant women; the pressor response to Ang II was also decreased in the pregnant women. The stimulation of PAC by Ang II, however, did not differ between the two groups. These results show that refractoriness to the renal and vascular effects of Ang II is present as early as the eleventh week of gestation. They also support the hypothesis that there is a degree of dissociation between the renin-angiotensin system and PAC in normal pregnancy.

Adult↗
PubMed1988

The effect of nitrendipine (NIT) on maternal and fetal blood pressure, uterine blood flow, and blood gas status in pregnant sheep.

Ewes of between 126-134 days of gestation (term 147 days) were anesthetized and underwent vascular cannula placement in the maternal and fetal jugular vein and carotid artery. A flow probe was placed around the uterine artery supplying the pregnant horn. A median of 7 days after surgery, the effect of nitrendipine (NIT) (2-8 micrograms/kg/min in stepwise increments of 30 min each followed by a 2-h recovery period) on maternal and fetal systemic arterial blood pressure (BP), heart rate (HR), the uterine blood flow (UBF), and blood gas tensions was determined (n = 5 experiments). Control experiments (n = 4) in which vehicle only was infused were also performed. The infusion of NIT was associated with a small fall in maternal systolic BP and a progressive fall in maternal diastolic BP (p less than 0.01, less than 0.001; two-way ANOVA); UBF did not change. Fetal systolic BP actually rose during the NIT infusion (p less than 0.02) but there was no difference in fetal diastolic BP. Both maternal and fetal HR rose in the NIT group. Fetal pH remained very stable throughout as did PaCO2. Fetal PaO2 fell somewhat during the recovery stages in both NIT and control groups. There is considerable interest in the possible use of calcium channel blockers in treating pregnancy-induced hypertension. These preliminary experiments provide no evidence in conflict with such a use.

Animals↗
PubMed1988

Studies on the effects of nitrendipine on oxytocin-, angiotensin II- and ergometrine-induced contraction of pregnant human myometrium in vitro.

Calcium channel blockers inhibit myometrial contractility by preventing the increase in intracellular free calcium which follows stimulation. They could thus be useful in treating premature labour. The effect of nitrendipine, a dihydropyridine calcium channel antagonist, on the contractile response of strips of pregnant human myometrium to oxytocin, angiotensin II (AII) and ergometrine has been examined. A total of 68 tissue strips were studied, with random allocation to treatment group. Initial concentration: response curves to one of the three agonists were determined; the concentration:response determinations were repeated in the presence or absence of nitrendipine at 10(-9)M. The initial EC50S for tissues exposed to oxytocin and AII were 8.2 X 10(-10)M and 3.4 X 10(-8)M respectively. The contractile response to both agonists was significantly blunted in the presence of nitrendipine (ANOVA; P less than 0.001 for both agents). This effect was greatest at high agonist concentrations. The initial EC50S for tissues exposed to ergometrine was 3.9 X 10(-8)M. Exposure to nitrendipine blunted the response (ANOVA; P less than 0.001), an effect most marked at low concentrations of ergometrine. The effect of nitrendipine on myometrial responses to the naturally occurring hormones oxytocin and AII supports suggestions of a role for it in inhibiting premature labour.

Angiotensin II↗
PubMed1987

The effect of prostaglandin E1 upon the pressor and hormonal response to exogenous angiotensin II in human pregnancy.

The effect of prostaglandin E1 (PGE1) on the pressor and hormonal response to angiotensin (ANG) II has been studied in 22 women in second trimester pregnancy. Three-point dose-response curves were initially determined for all women. Eleven then received an infusion of PGE1 while the remainder received an infusion of normal saline as controls. The dose-response curves to ANG II were re-studied after a period of stabilization. Although assignation to treatment group was random, differences were found in age and basal blood pressure between the control group and those given PGE1. The pressor data from the PGE1 group were thus split by age for analysis. The administration of ANG II alone was associated with significant (P less than 0.001 at all doses) pressor effects without accompanying bradycardia. Plasma renin concentration (PRC) was suppressed (P less than 0.001). Plasma aldosterone concentration rose (P less than 0.001), the magnitude of the rise being directly associated with the plasma ANG II concentrations achieved (P less than 0.05). The infusion of PGE1 had no significant effect on basal blood pressure, but evoked a sustained tachycardia in both age groups (P less than 0.001). Basal hormone concentrations were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Some observations on the effects of a calcium channel blocker, nitrendipine, in early human pregnancy.

The effects of a dihydropyridine calcium channel antagonist, nitrendipine 20 mg orally, have been investigated in 24 women in the first trimester human pregnancy in a double-blind, placebo controlled study. The effects on systemic arterial pressure, pulse rate (PR), blood loss at termination of pregnancy (TOP), plasma renin, renin substrate and aldosterone concentrations and platelet aggregation to adenosine diphosphate 0.5 microM, adrenaline bitartrate 0.1-1.0 microM, thrombin 0.05 u ml-1 and sodium arachidonate 0.1-0.2 mM were studied. Administration of nitrendipine was associated with a statistically-significant fall in diastolic pressure (BPD) the magnitude of which was directly related to the individual peak concentrations of the drug (P less than 0.02). No significant effects were observed on systolic pressure (BPS);PR rose slightly. Baseline variability of all three parameters fell in the nitrendipine-treated group over the first 2 h but then increased significantly (BPS, P less than 0.05; BPD, P less than 0.025; PR, P less than 0.005). There was a positive association in both placebo and treated groups between the rates of change of BPD and PR (P less than 0.005 for both); nitrendipine exerted a highly significant (P less than 0.001) effect on this association compatible with its effect as a vasodilator. Blood loss consequent on TOP did not differ in the two groups (nitrendipine 104 +/- 16 ml; placebo 114 +/- 20 ml). There were no significant differences in basal or stimulated hormone concentrations in the two groups. The ex vivo platelet aggregatory response in whole blood to 0.1 mM sodium arachidonate was inhibited by nitrendipine (P less than 0.05); responsiveness to the other aggregatory agents studied was not changed. There was a wide individual variation in both time to peak concentration of nitrendipine and the size of the peak, making classical pharmacokinetic analysis impossible. The median time after ingestion to peak concentration was 105 min; the median concentration was 7.8 ng ml-1. These data suggest that, in the context of the severe vasoconstriction and platelet aggregability of pregnancy-induced hypertension, further studies of this drug in pregnancy are warranted.

Blood Pressure↗
PubMed1987

Studies on the effects of angiotensin II on human chorionic plate arteries and their modification by a calcium antagonist, nitrendipine.

1 Six-point concentration-response curves were initially established for the contractile effect of angiotensin II (AII), at final concentrations of 10(-11) to 10(-6) M, on helically-cut strips of human chorionic plate arteries. The strips were then randomly allocated to one of four treatment groups: a control group and three treatment groups (n = 10 in each group) which were exposed to carrier or nitrendipine 10(-11), 10(-10) or 10(-9) M final concentration respectively, before the establishment of second concentration-response curves. 2 The initial responses of the tissues to AII were very similar in the four treatment groups with median EC50s ranging between 2.51 X 10(-10) and 4.04 X 10(-10) M (P greater than 0.8). The addition of nitrendipine was associated with significant (P less than 0.005) dose-related inhibition of AII-induced contractions. The median EC50 of the control group during the second half of the experiment was 1.77 X 10(-7) M, while that of the 10(-11) M nitrendipine treatment group was 2.16 X 10(-7) M. The EC50 for the other treatment groups could not be calculated from the curves due to the markedly blunted responses. 3 It is thus suggested that nitrendipine might be effective in vivo in the relief of vasospasm of the placental vascular system in pregnancy-induced hypertension.

Angiotensin II↗
PubMed1987

Post-exercise hypotension: the effects of epanolol or atenolol on some hormonal and cardiovascular variables in hypertensive men.

1 Eight men with primary hypertension were treated for 3 weeks with placebo, epanolol (200 mg or 400 mg), or atenolol 100 mg in a randomised cross-over study. Each active treatment period was preceded by a 3 week placebo treatment period and both investigators and subjects were blind to the active drug sequence. 2 At the end of each period, measurements were made of resting cardiovascular (heart rate, blood pressure, forearm blood flow) and biochemical variables (plasma renin, angiotensin II, aldosterone, adrenaline, noradrenaline, vasopressin, sodium and potassium concentrations and osmolality). Responses to exercise (including gas exchange, sweat rate, and ratings of perceived exertion) and the reflex cardiovascular adjustments to distal body subatmospheric pressure were also assessed. 3 The reduction of exercise-induced tachycardia by epanolol 400 mg was comparable to that of atenolol. There was very little difference in the effects of atenolol or epanolol 400 mg on resting blood pressure, but in both cases blood pressures were usually significantly lower than with epanolol 200 mg. 4 Although each active treatment influenced the renin-angiotensin system and circulating levels of catecholamines, the exercise-induced reduction in blood pressure was unaffected. Thus, the hypotensive effects of pharmacological and non-pharmacological interventions were additive.

Adrenergic alpha-Antagonists↗
PubMed1986

The effect of maternal labetalol on the newborn infant.

The possibility that placentally-transferred labetalol might cause sympathetic blockade in the newborn infant was examined by measuring systolic blood pressure, heart and respiratory rates, palmar sweating, blood glucose and the metabolic and vasomotor responses to cold stress. Measurements were made serially over the first 72 h of life in 22 term infants, 11 born to mothers treated with labetalol and 11 carefully matched controls. Infants of mothers treated with labetalol showed a mild transient hypotension which had disappeared within 24 h [mean systolic blood pressure at 2 h, 58.8 (SEM 2.4) mmHg compared with 63.3 (SEM 3.0) mmHg for controls, P less than 0.05]. There were no other significant differences between the two groups. It is concluded that labetalol does not cause clinically important sympathetic blockade in the mature newborn infant.

Blood Pressure↗
PubMed1986

The effect of enalapril (MK421), an angiotensin converting enzyme inhibitor, on the conscious pregnant ewe and her foetus.

The effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, on maternal and foetal blood pressure, heart rate and components of the renin-angiotensin-aldosterone system were studied in 9 chronically-cannulated pregnant ewes and their foetuses. Six ewes received 1 mg kg-1 enalapril i.v. while 3 were given 2 mg kg-1. Although the initial fall in blood pressure was slightly greater in the higher dose group, there was substantial overlap of data. The pressor response to angiotensin I, assessing ACE activity, was abolished within 10 min of administration, and did not recover during 3 h of observation. Maternal systolic and diastolic pressures reached a nadir 90 min after administration (P less than 0.001, P less than 0.002 respectively). The maximum tachycardia was seen at 60 min (P less than 0.05). The foetuses of the ewes given 1 mg kg-1 enalapril showed no change in systolic or diastolic blood pressure or heart rate. Those of the ewes given the higher dose showed late-onset hypotension, coincident with the lowest maternal blood pressures. Maternal plasma renin concentration (PRC) had risen significantly by 30 min (P less than 0.02), reaching a maximum at approximately 90 min. Maternal plasma angiotensin II and aldosterone concentrations both fell initially (P less than 0.05) but were almost at basal levels by the end of the experiment. Foetal plasma renin, angiotensin II and aldosterone concentrations were unchanged throughout the experiment. Peak values of enaprilic acid, the active principle, were recorded in maternal plasma 65-90 min after administration of 1 mg kg-1, and 25-30 min after the administration of 2 mg kg-1. A trace amount of the active principle was recorded in the foetal plasma of one lamb, whose mother had been given the higher dose. None was recorded in the plasma from three other lambs. Maternal plasma ACE concentrations fell by an average of 84%; in 4 of the 6 ewes in which concentrations were measured they were undetectable after treatment. Foetal plasma ACE concentrations were unchanged throughout. Enalapril at 1 mg kg-1 thus exerts a depressor effect on the pregnant ewe which is probably related to its blockade of the renin-angiotensin system. Both direct measurement of the drug and foetal observation suggest that it does not cross the sheep placenta at this dose. This is consistent with its failure to cross the blood-brain barrier. Foetal effects were noted at 2 mg kg-1, and there was an unexpected foetal death in this group.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

Changing basal and stimulated activity of the renin-angiotensin system during the second half of gestation in the anaesthetized piglet.

Concentrations of components of the renin-angiotensin system were studied in eighty anaesthetized pig fetuses aged between 57 and 112 d of gestation (term = 114 +/- 1 d). Plasma renin concentration rose from a mean value of 3.2 +/- 0.4 ng X ml-1 X h-1 (mean +/- S.E.M.) at 57 d to 17.5 +/- 2.7 ng X ml-1 X h-1 at 93 d of gestation and thereafter declined to 5.0 +/- 1.6 ng X ml-1 X h-1 just prior to term. There was no distinct pattern of change in plasma renin substrate concentrations during gestation; the concentration near term (0.33 +/- 0.10 micrograms X ml-1) was not different from that at 57 d (0.50 +/- 0.18 micrograms X ml-1) or that at 93 d (0.31 +/- 0.08 micrograms X ml-1) of gestation. Plasma angiotensin II concentrations increased from 33 (log10 (mean +/- S.E.M.) = 1.554 +/- 0.050) pg X ml-1 at 60 d to 232 (2.365 +/- 0.225) pg X ml-1 at 105 d of gestation, after which it decreased to 50 (1.699 +/- 0.100) pg X ml-1 in 20-d-old neonatal piglets. Haemorrhage of 10-20% estimated blood volume produced no consistent changes in plasma renin substrate concentrations, and inconsistent changes in renin and angiotensin II concentrations at 85-90 d of gestation, but a consistent increase in both renin and angiotensin II concentrations thereafter. These results indicate that the components of the renin-angiotensin system are present in the circulation of the pig fetus, and that their responses to stimuli develop during the second half of gestation.

Anesthesia↗
PubMed1986

Changing renin substrates in human pregnancy.

Renin substrate of high molecular weight was identified in plasma from pregnant women, non-pregnant subjects and in samples of umbilical arterial and venous plasma, using gel filtration chromatography. The proportion existing in the high molecular weight form in pregnant women was significantly increased above that of non-pregnant subjects by 11 weeks after the last menstrual period and continued to rise to term. In contrast, the proportion in fetal plasma was significantly lower than that of the non-pregnant group. High molecular weight renin substrate was itself heterogeneous and appeared to consist of four sub-groups. In non-pregnant adults the first peak, eluting near the void volume of the column, was the largest. In the fetus this profile was reversed. The elution profile in maternal plasma had changed markedly by as early as 8 weeks of gestation. Thereafter, it was possible to see increasing dominance of the minor 'intermediate' peaks visible in the non-pregnant adult until, in the third trimester, the high molecular weight form was eluted as a large broad band with little evidence of the individual peaks. Oestrogens are the most likely stimulus for the increased production of the high molecular weight renin substrate in pregnant women. In the fetus, although the same form of renin substrate is stimulated, the actual amount in the high molecular weight range is very small. This may be because oestrogens are sulphated in the fetus or because the fetal liver is not very responsive to the stimulation. The similarity between the profiles of mother and fetus may indicate a common source of production of renin substrate in the feto-placental unit.

Angiotensinogen↗
PubMed1985

Blood platelet behaviour in mothers and neonates.

Blood platelet behaviour was compared in mothers at birth and their babies, and in non-pregnant, female controls. Platelet responses to arachidonic acid (AA) and to adrenaline were measured in platelet-rich plasma and the inhibitory effects of prostacyclin (PGI2) were determined. Platelets from the mothers differed from those from the neonates and controls in that lower concentrations of AA were needed to induce platelet aggregation and a release reaction. In addition, more PGI2 was needed to inhibit AA-induced platelet aggregation. Platelets from the neonates differed from the mothers and controls in that they were almost completely insensitive to adrenaline. They did not differ from the controls in their sensitivity to AA or PGI2 but the extent of the release reaction induced by AA was significantly reduced.

Arachidonic Acid↗
PubMed1985

The effect of dietary supplementation with linoleic and gammalinolenic acids on the pressor response to angiotensin II--a possible role in pregnancy-induced hypertension?

Dietary supplementation with 3 g/day linoleic acid, 32 mg/day gammalinolenic acid and co-factors for prostaglandin synthesis was given to 10 pregnant and 10 non-pregnant subjects for a week. Their pressor response to the infusion of three doses of angiotensin II (AII) (pregnant: 4, 8, 16 ng kg-1 min-1: non-pregnant: 1, 2, 4 ng kg-1 min-1) was then compared with that of 40 pregnant and 24 non-pregnant controls who had not been given such supplementation. Dietary supplementation was not associated with changes in basal systolic or diastolic blood pressure or heart rate during the week of treatment in pregnant or non-pregnant subjects. Basal systolic blood pressure, diastolic blood pressure and heart rate values did not differ between the treated and untreated subjects in each group. The diastolic pressor response to AII was significantly less after treatment at all doses; the effect was more marked in the pregnant subjects. The systolic response to AII, normally less than the diastolic, was somewhat blunted in the treated pregnant patients at the two higher infusion doses. No significant effect was found in the non-pregnant group. Evidence from other studies suggests that increasing plasma linoleic acid concentrations leads to increased plasma concentrations of epoprostenol (prostacyclin, PGI2) while increased availability of gammalinolenic acid is associated with a rise in prostaglandin E1 and E2 production. Pregnancy-induced hypertension is associated with a diminished tissue production of both epoprostenol and E series prostaglandins, and with an enhanced pressor response to AII.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

The effect of a calcium antagonist, nitrendipine, on the responses of isolated strips of human, chorionic plate artery to prostaglandins E2 and E1.

Six point concentration-response curves were established for the contractile effect of prostaglandin E2 (PGE2) on helically-cut strips of human chorionic plate arteries. Tissues were then allocated to one of four treatment groups: a control group and 3 groups exposed to the calcium channel blocker nitrendipine at 10(-9), 10(-7) or 10(-5) M. The concentration-response curves were then repeated. The addition of nitrendipine was associated with a significant depression of the induced contraction. The contractile response to the lower doses of PGE2 was replaced by a small relaxation in 63% of the treated tissues. It is suggested that in these tissues PGE2 exerts its constrictor effect via the receptor-operated channels and that nitrendipine is blocking this effect. Similar experiments performed with PGE1 showed great variability in the initial response. Nitrendipine 10(-5) M failed to exert any detectable effect on this response. Pregnancy-induced hypertension is associated with vasoconstriction in both the maternal and placental circulations. There also appears to be a relative excess of vasoconstrictor eicosanoid production. Nitrendipine may be of use in the treatment of this condition.

Alprostadil↗