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Biomedical subjects

C R Edwards

Publications and source records attributed to C R Edwards.

At least 145 records · Page 8Linked to original sources
PubMed1987

Adrenal synthesis of corticosterone in response to ACTH in rats is influenced by leukotriene A4 and by lipoxygenase intermediates.

The possible involvement of the lipoxygenase pathway of arachidonic acid metabolism in the events which take place during ACTH-induced stimulation of corticosterone secretion has been studied using an isolated rat adrenal cell system. Incubation with arachidonic acid resulted in an inhibition of ACTH-stimulated corticosterone production. The lipoxygenase pathway inhibitors nordihydroguaretic acid (NDGA), eicosatetraynoic acid (ETYA) and compound BW755C also produced inhibition of ACTH-stimulated corticosterone synthesis. The concentrations of the inhibitors at which 50% inhibition occurred were 15, 34 and 37 mumol/l respectively. The inhibitions produced by NDGA and ETYA were independent of cyclic AMP output. NDGA also inhibited corticosterone production induced by dibutyryl cyclic AMP but had no effect on corticosterone synthesis induced by pregnenolone. Preincubation of adrenal cells with the lipoxygenase products 5, 12 and 15 hydroxyeicosatetraenoic acid (HETE) and with leukotrienes A4, B4, C4, D4 and E4 resulted in significant inhibitions of corticosterone production in response to ACTH with leukotriene A4 (LTA4) and with 15HETE and 5HETE. Conversely, incubation with glutathione (GSH), which is known to reduce intracellular LTA4 levels, produced stimulation (at 5 mmol GSH/l) and inhibition (at 50 mmol GSH/l) of corticosterone output. These studies suggest that the lipoxygenase pathway may be involved in ACTH-stimulated corticosterone synthesis.

Adrenal Glands↗
PubMed1987

High sodium intake increases platelet aggregation in normal females.

Platelet activation and aggregation appear to play an important part in the development of vascular disease. We studied the effect of varying sodium intake on total plasma serotonin and in vitro aggregation of blood platelets. A total of 12 normal female volunteers were studied after 5 days on a 10 or 200 mmol/day sodium diet. Aggregation studies were performed by incubating stirred platelet-rich plasma (PRP) with adenosine diphosphate (ADP) at final concentrations of 1 and 4 mumol/l; we also studied the effect of pre-incubating PRP with ketanserin or saralasin (1 mumol/l and 1 nmol/l final concentration, respectively). Salt-loading produced a significant increase in platelet aggregation induced by both 1 and 4 mumol/l ADP, and also a significant fall in PRP in serotonin concentration; since there was also a significant drop in the yield of platelets in PRP during salt-loading, the difference in serotonin concentration was not significant when expressed as pmol serotonin/10(8) platelets. There was a significant negative correlation between log serotonin levels (nmol/l) and % aggregation induced by 4 mumol/l ADP. Ketanserin decreased aggregation (induced by 4 mumol/l ADP) in PRP obtained during high salt intake; saralasin had no effect on aggregation, but did cause a decrease in light transmission. These results indicate that in normal females: (1) in vitro platelet aggregation is increased with high sodium intake, and this effect was reduced by addition of ketanserin; (2) PRP platelet count and total plasma serotonin levels are both significantly altered by changes in sodium status; (3) aggregation (%) is inversely proportional to log serotonin concentration (nmol/l).

Adult↗
PubMed1986

cDNA sequence of human beta-preprotachykinin, the common precursor to substance P and neurokinin A.

The nucleotide sequence of cDNA encoding the human substance P precursor, beta-preprotachykinin (beta-PPT), has been determined. The source of mRNA was a human laryngeal carcinoid tumour that contained a high concentration of immunoreactive substance P. The human beta-PPT polypeptide is 129 amino acids long and contains regions encoding substance P and neurokinin A, each flanked by basic amino acid residues. Residues 72-107 of the human beta-PPT polypeptide encode the sequence of neuropeptide K, an N-terminally extended form of neurokinin A recently isolated from porcine brain.

Animals↗
PubMed1986

Changes in total body calcium following surgery for primary hyperparathyroidism.

The aims of this study were to measure the deficit in total body calcium in patients with primary hyperparathyroidism and to observe whether this deficit was reversed by parathyroidectomy. Total body calcium was measured in five women and three men preoperatively, and the mean was found to be 11% below that of age-and sex-matched controls after normalization for postmenopausal age and body size (P less than 0.01). Following parathyroidectomy, repeat total body calcium measurements showed an increase of 7.1% over an average period of 14 months (P less than 0.03). In patients with primary hyperparathyroidism, total body calcium returns toward normal following surgical removal of the adenoma.

Adenoma↗
PubMed1986

Development and application of a superfusion technique for the study of renin secretion in rat renal cortical cells.

A dynamic column superfusion system has been developed for the study of renin secretion in rat renal cortical cells. Cells were isolated by collagenase digestion and mechanical dispersion, before suspension with polyacrylamide beads and superfusion with oxygenated physiological medium. Renin was detected in the superfusate by incubation of fractions with excess nephrectomized sheep substrate in the presence of angiotensinase inhibitors followed by radioimmunoassay of the angiotensin I generated. Optimized methodology included a purpose-built polytetrafluorethylene flow cell, a 1 h equilibration to achieve a steady state, 5 min eluate collections, a 15 min stimulatory and a 30 min recovery period, and duration of perfusion of up to 270 min. Significant increments above baseline renin release were seen with the stimuli of adrenaline, noradrenaline and isoprenaline. These could be demonstrated with concentrations of 10(-9) mol/l (adrenaline), 5 X 10(-10) mol/l (noradrenaline) and 10(-9) mol/l (isoprenaline). This technique has significant advantages over previous methods for the study of renin secretion in vitro at the cellular level. It is reproducible and sensitive, and avoids many of the limitations of static cell suspension and kidney slice methods.

Animals↗
PubMed1986

Aldosterone in cystic fibrosis: measurement in saliva and correlation with disease severity.

Aldosterone was measured in the saliva of 20 patients with cystic fibrosis and a group of 20 normal children matched for age and sex. Mean levels were higher in the patient group but overall differences were small and statistically not significant. For the first time a link between aldosterone level and disease severity in patients with cystic fibrosis was established using a simple scoring system to assess disease activity. Urinary and salivary electrolytes were similar in the two groups. The results do not support the proposed hypothesis that the salivary glands of patients with cystic fibrosis are insensitive to aldosterone.

Adolescent↗
PubMed1986

Intravenous captopril treatment in patients with severe cardiac failure.

The effect of intravenous captopril was studied in 26 patients with severe chronic heart failure. Fourteen patients received a 25 mg intravenous bolus dose and 12 patients were given a series of incremental intravenous doses over the range 0.3125-45 mg. After the 25 mg bolus dose there was a rapid reduction in systemic vascular resistance and systemic blood pressure. The effect was greatest five minutes after the dose when cardiac output was increased by 20%. Mean right atrial pressure and pulmonary end diastolic pressure fell more slowly and reached their nadir 60 minutes after administration. Plasma free captopril concentration was significantly correlated with percentage reduction in systemic vascular resistance 15 minutes after the bolus injection, but was not correlated with either changes in right atrial or pulmonary artery pressures. With the series of incremental doses there was a progressive fall in systemic vascular resistance until a cumulative dose of 5.0 mg was reached; beyond this there was no further significant change. The rapid response to intravenous captopril indicates that it may be useful in the treatment of patients with severe heart failure who require intensive treatment. After intravenous injection of captopril haemodynamic responses in patients with heart failure were greatest at plasma concentrations of 100 g/ml to 150 ng/ml. This is considerably higher than the plasma free captopril concentrations found after conventional oral doses of captopril.

Adult↗
PubMed1985

The adrenal secretion of progesterone stimulates testicular steroidogenesis in the rat in vitro.

We have used a multicolumn isolated cell superfusion system to investigate the interaction between isolated rat adrenal and testicular cells in the secretion of sex steroids. The steroid responses of a mixed population of adrenal and testicular cells to the administration of ACTH 100 pg/ml was compared with the responses of the separate cell types. Steroid responses from 5 separate experiments were analysed. We have demonstrated increased secretion of 17 alpha-hydroxyprogesterone (P less than 0.0005), androstenedione (P less than 0.05) and testosterone (P less than 0.0005) by a mixture of cells when compared with the responses of either cell type alone. In contrast, the secretion of progesterone (P less than 0.0005) and corticosterone (P less than 0.005) was reduced in the mixed cell population, suggesting that progesterone is preferentially converted by testicular cells to 17 alpha-hydroxyprogesterone, androstenedione and testosterone. This is confirmed by increased secretion of 17 alpha-hydroxyprogesterone, androstenedione and testosterone but not corticosterone by a mixed population following the administration of progesterone 10 ng/ml. These results suggest that the adrenal secretion of progesterone can stimulate testicular steroidogenesis in the male rat in vitro.

Adrenal Glands↗
PubMed1985

The production and assessment of monoclonal antibodies to cortisol.

In an extensive series of experiments, Balb/C mice and Lou rats were immunised with 3-O-(carboxymethyl)oximinocortisol conjugated to bovine serum albumin. The spleen cells from selected animals were fused with cells from mouse or rat plasmacytoma lines. Out of many hundreds of hybridomas screened, more than seventy produced antibody that bound 125I-labeled cortisol. These cultures were investigated further for stability of antibody production, affinity for cortisol and cross-reactivity with other steroids. An unexpected but consistent finding was that immunised rats produced antibody which cross-reacted with 11-deoxycortisol to a level greater than 100% and this characteristic was reproduced by rat-rat hybridomas. Strategies designed to improve the chances of generating non-cross-reactive anti-cortisol monoclonal antibodies did not appear to be successful. Nevertheless, several monoclonals were identified with properties that suggest they may be useful for the development of sensitive and specific cortisol assays.

Animals↗
PubMed1985

Male sex hormone status in dermatitis herpetiformis.

In twenty-eight men with dermatitis herpetiformis (DH) the mean serum testosterone levels were within normal limits, but high levels were found in three patients with partial villous atrophy and two who had normal jejunal biopsies. The introduction of a gluten-free diet in patients with villous atrophy produced a statistically significant fall in the testosterone level in those able to discontinue their drug treatment but not in those noticing no change or only a reduction in drug requirements. The serum levels of luteinizing hormone or follicle-stimulating hormone were increased in nine patients; only one of these had a raised testosterone level and six were over 60 years of age. Four out of twenty married males with DH had no children, a figure higher than expected. Three of these men had elevated gonadotrophin levels although none had an increased serum testosterone. Thus, raised levels of testosterone and gonadotrophin were found in only a minority of men with DH, in contrast to the more marked changes previously reported in males with coeliac disease.

Adult↗
PubMed1985

Factors affecting the secretion of 18-hydroxycortisol, a novel steroid of relevance to Conn's syndrome.

A recently developed radioimmunoassay for direct measurement of 18-hydroxycortisol (18-OH-F) in plasma and urine has been used to study the physiology of this newly described steroid in normal subjects. Plasma levels of 18-OH-F show a circadian variation similar to that of cortisol and are increased and suppressed by administration of ACTH and dexamethasone respectively. A clear increase was observed in response to sodium restriction but despite this, angiotensin II infusion failed to cause a rise in 18-OH-F levels and a possible explanation is discussed. The results are interpreted in terms of a proposed biosynthetic pathway involving 18-hydroxylation of cortisol during a second passage through the adrenal gland.

Adrenal Glands↗
PubMed1985

Plasma free captopril concentrations during short and long term treatment with oral captopril for heart failure.

Plasma free captopril concentrations and haemodynamic response to captopril were studied in 20 patients with severe chronic heart failure. A 25 mg oral dose of captopril produced a 36% reduction in systemic vascular resistance, with individual responses varying from 13% to 64%. Mean systemic pressure fell by 20% and cardiac output rose 28%. The absorption of captopril was rapid. Peak plasma free captopril concentration occurred at 45 minutes after the dose and was followed by a smaller second peak. Peak plasma free captopril concentrations varied more than 20-fold but did not correlate with the maximal reduction in systemic vascular resistance. Elimination half life was seven hours. Fourteen patients were restudied after 1-2 months of captopril treatment and 12 showed symptomatic benefit. There was a sustained improvement in haemodynamic state and in non-invasive indices of myocardial function. During long term treatment the predose plasma free captopril concentration correlated well with dosage, but steady state captopril concentrations did not show a significant relation with haemodynamic response. On a dosage regimen of 25-50 mg three times daily the morning predose plasma free captopril concentration and plasma renin activity were relatively low and suggested that maximal inhibition of the renin-angiotensin system was not maintained throughout the dosage interval.

Aged↗
PubMed1985

The effect of sodium intake on the renin response to dopamine in superfused rat renal cortical cells.

In addition to its natriuretic effect in the kidney, dopamine can also stimulate renin release. This study employs an in vitro system to examine the relationship between sodium intake and dopamine-induced renin release. Enzymically dispersed renal cortical cells obtained from rats on low, normal and high sodium diets were superfused at 37 degrees C with Krebs buffer [0.2% glucose, 0.2% bovine serum albumin (BSA)]. Dopamine was given as 10-min infusions and renin activity was measured in the superfusate as angiotensin I generated following incubation of samples with excess nephrectomized sheep renin substrate. Rats on a low sodium diet showed a higher basal cellular renin release and an enhanced renin response to dopamine (10(-7), 10(-6) mol/l) compared with the normal sodium diet group. Rats on a high sodium diet, in contrast, showed a lower cellular renin release and a decreased sensitivity to dopamine (10(-7), 10(-6) mol/l) compared with the normal sodium diet group. These results demonstrate that the renin response to dopamine is dependent upon sodium intake.

Angiotensin I↗
PubMed1985

Inhibition of the renin-angiotensin-aldosterone axis by low dose intravenous captopril as a treatment for accelerated phase hypertension.

A parenteral preparation of captopril has been used to produce a smooth reduction of blood pressure in patients presenting with accelerated phase hypertension. In five out of six patients studied, an intravenous infusion of captopril at dose rates ranging from 250-2000 micrograms/h lowered blood pressure from 199 +/- 13/115 +/- 5 to 143 +/- 14/86 +/- 5 mmHg over several hours without adverse effects. Partial inhibition of the angiotensin converting enzyme was demonstrated by a rise in plasma renin activity (PRA) and a fall (although not to normal) in elevated levels of angiotensin II and aldosterone. The plasma level of free captopril at the point of blood pressure control was 15 +/- 4 ng/ml and its short effective half-life was demonstrated by a rise in blood pressure within 15 minutes of stopping the infusion. These data demonstrate that very small amounts of captopril can produce a dose-dependent inhibition of angiotensin converting enzyme without abrupt changes in blood pressure.

Adult↗
PubMed1985

A radioimmunoassay for 18-hydroxycortisol in plasma and urine.

Increased excretion of 18-hydroxycortisol has been proposed as a specific biochemical marker for differential diagnosis of primary aldosteronism. We describe the development of a direct RIA with an 125I label that permits measurement of the steroid in less than or equal to 0.5 microL of urine or less than or equal to 25 microL of plasma. For control subjects, the mean concentrations of 18-hydroxycortisol in urine and plasma were 310 (SD 178) nmol/24 h (n = 32) and 2.27 (SD 0.80) nmol/L (n = 37), respectively; patients with Conn's adenoma or glucocorticoid-remediable aldosteronism had values for urine in the range 1084 to 6534 nmol/24 h and concentrations in plasma ranging from 6.49 to 31.20 nmol/L. Patients with idiopathic zona glomerulosa hyperplasia had values for urine and plasma ranging from 353 to 734 nmol/24 h and from 0.26 to 6.60 nmol/L, respectively. Concentrations of 18-hydroxycortisol in urine clearly discriminate patients with idiopathic hyperplasia from those with other forms of primary aldosteronism, but further work is required to assess the diagnostic accuracy of determinations in plasma.

Animals↗
PubMed1984

Production of high affinity monoclonal antibodies to deoxycorticosterone.

Monoclonal antibodies to deoxycorticosterone were produced. Mice were immunised with deoxycorticosterone-3-mono-oxime-BSA conjugate and spleen cells were then hybridised with NS1/1Ag4-1 mouse myeloma cells using 1500 mol. wt polyethylene glycol. The hybrids were grown in RPMI 1640 medium containing HAT to facilitate selection of positive clones. The clones and subclones were screened by using deoxycorticosterone-3-mono-oxime-[125I]iodohistamine. Dextran-coated charcoal was used for separation of antibody bound and free fractions. Two independent clones producing antibody which specifically binds labelled deoxycorticosterone were obtained. Cells from the two best sub-clones were used to raise ascites fluid. Comparison of these antibodies with one of the best conventional antisera previously raised in rabbits showed that the affinity constants were almost comparable (0.49-1.4 X 10(10) l/mol). Cross-reactivity of monoclonal antibodies with cortisol, corticosterone, testosterone and pregnenolone was lower than for polyclonal antisera, but for progesterone the cross-reactivity was similar in both cases. The assay sensitivity obtained with ascites fluid was comparable to that of conventional antibody (2.5 pg/ml). The dilution of ascites fluid which produced 50% binding of the label was 1:4,000,000. These results confirm that it is possible to produce monoclonal antibodies to corticosteroids.

Animals↗
PubMed1984

Autonomic neural control mechanisms and the release of adrenal steroids after hypoglycaemia in man.

The changes in blood glucose, plasma potassium, plasma renin activity, aldosterone, cortisol, corticosterone and ACTH were measured in 11 normal subjects, 6 tetraplegic subjects (pre-ganglionic sympathectomy) and 6 tetraplegic subjects given atropine (sympathectomy with cholinergic blockade), in response to acute insulin-induced hypoglycaemia. After hypoglycaemia, blood glucose recovery was impaired only in the tetraplegic group given atropine in whom ACTH secretion was delayed and the peak cortisol and corticosterone concentrations were lower compared with the other groups. Plasma renin activity rose both in the normal and the tetraplegic subjects; the aldosterone rise and the fall in potassium were similar in all three groups. Aldosterone release after hypoglycaemia appears to occur independently of stimulation of the sympatho-adrenal system and cholinergic blockade, and may result from activation of the renin-angiotensin system, rather than from ACTH stimulation. Activation of ACTH secretion in response to hypoglycaemia may involve a cholinergic mechanism at the hypothalamic level, with a consequent reduction in the increments of plasma cortisol and corticosterone after atropine administration.

Adrenal Cortex Hormones↗