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C R Edwards

Publications and source records attributed to C R Edwards.

At least 19 recordsLinked to original sources

The influence of posture on the response to loop diuretics in patients with chronic cardiac failure is reduced by angiotensin converting enzyme inhibition.

The diuretic and natriuretic response to an intravenous dose of frusemide 40 mg was assessed in the erect and supine positions in 10 patients with cardiac failure who were being treated with enalapril 10 mg twice daily in addition to diuretics (Enalapril group) and in 10 patients with cardiac failure taking diuretics alone (Control group). Total 4 h diuresis in the erect position was 728 ml and in the supine position was 824 ml in the patients taking enalapril compared to 655 ml in the erect position and 1166 ml in the supine position in those patients taking diuretics alone. Total 4 h natriuresis in the erect positions was 78 mmol and in the supine position was 85 mmol in patients taking enalapril 10 mg twice daily but in those patients taking diuretics alone total 4 h natriuresis in the erect position was 67 mmol increasing to 120 mmol in the supine position. Measurements of plasma renin activity and plasma angiotensin II concentration confirmed effective converting enzyme inhibition, in the group of patients taking enalapril, but in those patients taking diuretics alone the erect position was associated with an increase in plasma renin activity, and plasma concentrations of angiotensin II and aldosterone. We conclude that the renin angiotensin system is a major factor in mediating the effect of posture on loop diuretic drugs.

Adult

Lack of correlation between the acute haemodynamic response to intravenous captopril and plasma concentrations of angiotensin II in patients with chronic cardiac failure.

We have given a series of incremental intravenous injections of captopril to ten patients with chronic cardiac failure. Small doses of captopril produced significant changes in pulmonary artery end-diastolic pressure and right atrial pressure, up to a total cumulative dose of captopril of 2.5 mg, after which further injections had no significant effect. There were large changes in systemic vascular resistance and blood pressure up to a cumulative dose of captopril of 5.0 mg, after which the injection of larger doses caused no further significant changes. Small doses of intravenous captopril produced large increases in plasma renin activity and plasma angiotensin I concentrations up to a total cumulative dose of captopril of 1.25 mg, after which there were no significant further changes in either plasma renin activity or plasma angiotensin I concentration. However the plasma concentration of angiotensin II fell more slowly, no further change being recorded after a total cumulative dose of captopril of 10 mg. These results suggest that plasma renin activity is not the only determinant of plasma angiotensin II concentrations.

Aged

The sensitivity of human blood platelets to the aggregating agent ADP during different dietary sodium intakes in healthy men.

We have investigated the effect of varying sodium intake on the renin-angiotensin system, ADP-induced platelet aggregation in vitro, and blood 5-HT concentrations in 9 male volunteers. Systolic blood pressure was slightly reduced during a low sodium diet, whereas the diastolic pressure remained unchanged. Plasma renin activity and aldosterone concentration both fell significantly when sodium intake was increased; plasma angiotensin II concentration also fell, but not significantly. There was a significant fall in haematocrit after an increased sodium intake, but there was no change in the whole-blood platelet count after correcting for this. There were no significant changes in either total (i.e. PRP) or platelet 5-HT concentrations. The extent of platelet aggregation induced by 5 and 20 mumol.l-1 of ADP increased significantly when dietary sodium intake was increased. When compared with low or normal sodium intakes, lower concentrations of ADP were required to produce 50% of maximum aggregation after a high sodium intake. The 5-HT2 receptor antagonist ketanserin (1 mumol.l-1 in vitro) reduced the extent of aggregation induced by 5 mumol.l-1 ADP after the volunteers had taken a high sodium diet, whereas the angiotensin II receptor antagonist saralasin (1 nmol.l-1) increased the rate of aggregation after the low sodium diet. Thus, during a high sodium intake, human platelets become more sensitive to the aggregating agent ADP. It is possible that this effect is mediated via platelet 5-HT2 receptors, since ketanserin abolished the increase in salt-induced aggregation seen with 5 mumol.l-1 ADP.

Adenosine Diphosphate

Contrasting patterns of arterial and venous dilatation after intravenous captopril in patients with chronic cardiac failure and their relationship to plasma angiotensin II concentrations.

A 25 mg intravenous bolus injection of captopril caused an abrupt and rapid decrease in systemic vascular resistance (time to maximum effect 15 minutes), but a more gradual decrease in right atrial pressure (time to maximum effect 75 minutes) in 12 patients with chronic cardiac failure. Plasma angiotensin II concentrations fell significantly, reaching their lowest concentrations at 75 minutes after the injection of captopril, at which time systemic vascular resistance had begun to return toward control values. There was no correlation between the acute arteriodilator response and pretreatment plasma renin activity or plasma angiotensin II concentrations, or the decrease in plasma angiotensin II concentrations. There was a significant correlation between the decrease in plasma angiotensin II concentrations and the decrease in right atrial pressure (r = 0.67, p < 0.05). These findings suggest that in contrast to the venous response to intravenous captopril, the arterial response is not entirely dependent on a decrease in the circulating plasma angiotensin II concentration.

Aged

Serotoninergic stimulation of aldosterone secretion in vivo: role of the hypothalamo-pituitary adrenal axis.

The control of aldosterone secretion in vivo by serotonin was studied in conscious rats. Serial blood samples were taken from indwelling arterial cannulae before and after i.p. administration of 1 ml (4 g/l) 5-hydroxytryptophan (5-HTP), the precursor of serotonin (5-HT), or saline, and analysed for 5-HTP, serotonin, 5-hydroxyindoleacetic acid, plasma renin activity (PRA), corticosterone, aldosterone, sodium and potassium concentration. The relative contribution of the hypothalamo-pituitary adrenal axis was investigated in animals pretreated with the synthetic glucocorticoid dexamethasone. 5-HTP caused a significant increase in all parameters within 45 min except for plasma sodium and potassium. Saline administration showed no significant effect. Dexamethasone pretreatment significantly impaired the corticosterone and aldosterone response to 5-HTP, although the aldosterone response was merely attenuated. No other parameter was affected by dexamethasone pretreatment. The results show that administration of 5-HTP, which increases serum serotonin levels, stimulates PRA, corticosterone and aldosterone secretion. Dexamethasone pretreatment inhibits the aldosterone response, though not completely, suggesting that the stimulatory action of 5-HTP involves the release of ACTH, which stimulates corticosterone and aldosterone secretion by the adrenal cortex. The failure of dexamethasone to block the aldosterone response completely, suggests the involvement of other mechanisms such as the renin-angiotensin system or a direct action of serotonin on the adrenal zona glomerulosa.

5-Hydroxytryptophan

Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man.

1. 11 beta-Hydroxysteroid dehydrogenase converts cortisol to inactive cortisone in man. In distal renal tubules, this inactivation protects mineralocorticoid receptors from cortisol. Congenital 11 beta-hydroxysteroid dehydrogenase deficiency and inhibition of 11 beta-hydroxysteroid dehydrogenase by liquorice or carbenoxolone result in cortisol-dependent hypokalaemia and hypertension. 2. 11 beta-Hydroxysteroid dehydrogenase is expressed in vascular smooth muscle. Both glucocorticoids and mineralocorticoids potentiate vascular responses to noradrenaline. 11 beta-Hydroxysteroid dehydrogenase activity may therefore influence vascular tone. 3. Experiments were performed in healthy subjects with and without 7 days of oral administration of 11 beta-hydroxysteroid dehydrogenase inhibitors (liquorice or carbenoxolone), and in a patient with congenital 11 beta-hydroxysteroid dehydrogenase deficiency. We measured the following parameters: dermal vasoconstriction after topical application of cortisol, forearm blood flow during brachial artery infusion of cortisol or noradrenaline, and blood pressure during systemic infusion of noradrenaline. 4. Cortisol-induced dermal vasoconstriction was increased by liquorice (23 +/- 6 to 52 +/- 7 units; P < 0.04) and in congenital 11 beta-hydroxysteroid dehydrogenase deficiency (87 units). In congenital 11 beta-hydroxysteroid dehydrogenase deficiency intraarterial infusion of cortisol caused vasoconstriction (20% reduction in blood flow in the infused arm) and accentuated the response to application of lower-body negative pressure, which stimulates sympathetically mediated vasoconstriction (35% reduction). However, intra-arterial infusion of cortisol had no effect in healthy subjects either with or without administration of liquorice. 5. Carbenoxolone potentiated both noradrenaline induced forearm vasoconstriction (P < 0.01) and pressor response (P < 0.001). 6. We conclude that 11 beta-hydroxysteroid dehydrogenase modulates the access of cortisol to vascular receptors and thereby influences vascular sensitivity to noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

11-beta-Hydroxysteroid Dehydrogenases

The relationship between diuretic dose, and the haemodynamic response to captopril in patients with cardiac failure.

The effect of diuretic dose on the haemodynamic response to captopril was assessed in nine patients with chronic cardiac failure. Each patient was given an intravenous dose of captopril while maintained on (a) a low dose diuretic regime, and (b) a high dose diuretic regime. Activity of the renin angiotensin aldosterone system, as assessed by plasma concentrations of these hormones, was greater when patients were receiving the higher dose diuretic regime. The magnitude of haemodynamic response produced by intravenous captopril was greater when the patients were maintained on the high dose diuretic regime, although no significant correlation was found between resting plasma renin activity and resting plasma angiotensin II concentration and the change produced by captopril in any haemodynamic response on either diuretic regime. An increased dosage of loop diuretic potentiates the haemodynamic effects of captopril in patients with cardiac failure. Reduction of diuretic dose prior to introduction of captopril may protect against severe first dose hypotension.

Adult

Mineralocorticoid excess and inhibition of 11 beta-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome.

OBJECTIVE: 11 beta-Hydroxysteroid dehydrogenase protects renal mineralocorticoid receptors from cortisol by converting cortisol to inactive cortisone. We hypothesize that 11 beta-dehydrogenase is inhibited by ACTH, providing a mechanism whereby cortisol induces hypokalaemic alkalosis in ectopic ACTH syndrome. DESIGN/MEASUREMENTS: The principal sources of plasma cortisone were assessed by selective venous catheterization with measurement of cortisol and cortisone by radioimmunoassays. The effect of ACTH on peripheral plasma cortisol/cortisone ratio was assessed in healthy volunteers during circadian rhythm, insulin induced hypoglycaemia, and infusions with exogenous ACTH or cortisol. In patients with Cushing's syndrome plasma cortisol/cortisone ratios were related to plasma potassium, corticosterone, and 11-deoxycorticosterone concentrations. PATIENTS: Catheterization was performed in 24 patients with valvular or ischaemic heart disease. Cushing's syndrome patients included: 15 with pituitary adenoma; two with adrenal adenoma; and nine with ectopic ACTH secretion. RESULTS: Plasma cortisol/cortisone ratios were low in renal vein and high in hepatic vein. In healthy volunteers plasma cortisone increased during cortisol infusion but did not change with increases in endogenous or exogenous ACTH. Plasma cortisol/cortisone ratios were higher in ectopic ACTH syndrome than in other forms of Cushing's syndrome. However, the cortisol/cortisone ratio was no better a predictor of hypokalaemia than the levels of 11-deoxycorticosterone or corticosterone. CONCLUSIONS: Peripheral conversion of cortisol to cortisone occurs mainly in the kidney and is inhibited by ACTH. In ectopic ACTH syndrome the characteristic mineralocorticoid excess can be accounted for by a combination of increased secretion of cortisol, corticosterone and of 11-deoxycorticosterone and decreased inactivation of cortisol and corticosterone by 11 beta-dehydrogenase.

11-beta-Hydroxysteroid Dehydrogenases

Ontogeny of 11 beta-hydroxysteroid dehydrogenase in rat brain and kidney.

Close regulation of circulating corticosteroid levels during the early postnatal period is crucial for normal development and maturation of the central nervous system. In the first weeks of life cerebral glucocorticoid receptor concentrations are low and the hypothalamic-pituitary-adrenal axis is relatively unresponsive to stress, which might, in part, protect the developing brain from elevated corticosteroid levels. However, central mineralocorticoid receptors are at near adult levels and free glucocorticoid concentrations may approximate adult values as corticosteroid binding globulin is absent. Thus other mechanisms controlling cerebral exposure to corticosteroids may be of importance. 11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) determines the access of corticosterone to peripheral mineralocorticoid and glucocorticoid receptors in adults in vivo by metabolizing corticosterone to inactive 11-dehydrocorticosterone. The enzyme has recently been demonstrated in brain subregions and may modulate local corticosteroid-receptor interactions. We therefore examined 11 beta-OHSD bioactivity and messenger RNA (mRNA) expression in the brain, compared with kidney, during the neonatal period. 11 beta-OHSD bioactivity (expressed as the percentage conversion of corticosterone to 11-dehydrocorticosterone) was moderately high in hippocampus and parietal cortex at birth (46 +/- 4% and 48 +/- 5%, respectively), fell significantly to a nadir (32 +/- 1% and 30 +/- 1%, respectively) at postnatal day 10 and then gradually rose to adult values (52 +/- 3% and 58 +/- 3%). By contrast, 11 beta-OHSD activity in cerebellum was high at birth (60 +/- 3%), rose significantly to a peak at postnatal day 10 (74 +/- 3%), and then fell to adult values by postnatal day 15 (64 +/- 3%). Renal 11 beta-OHSD activity was moderately high (69 +/- 3%) at birth and reached adult values (80 +/- 2%) by postnatal day 5. Northern blots showed high and similar expression of a single species of 11 beta-OHSD mRNA from birth to adulthood in the hippocampus. Only low expression of 11 beta-OHSD (two or three separate species) was found in the kidney during the first 2 weeks of life, whereas, in adults high expression of 11 beta-OHSD mRNA was detected in kidney (four species). Using in situ hybridization high 11 beta-OHSD mRNA expression was localized to the neuronal layers of the postnatal hippocampus, neocortex, and cerebellum, and low but detectable expression was found in the neonatal renal cortex. Thus, 11 beta-OHSD is highly expressed in rat brain subregions in the early postnatal period with specific developmental patterns of activity.(ABSTRACT TRUNCATED AT 400 WORDS)

11-beta-Hydroxysteroid Dehydrogenases

Tissue-specific distribution of the NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase.

11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) converts the active glucocorticoid corticosterone to inactive 11-dehydrocorticosterone in rat (or cortisol to cortisone in man), thereby protecting renal mineralocorticoid receptors from corticosterone or cortisol and allowing preferential access for aldosterone. Recent work suggests that a nicotinamide adenine dinucleotide (NAD+)-dependent 11 beta-OHSD isoform is expressed in distal renal tubule, in contrast with the hepatic isoform which is NAD(+)-phosphate (NADP+)-dependent. To establish the distribution of the NAD(+)-dependent isoform we measured in vitro conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone in homogenized rat tissues in the presence of NADP+ or NAD+. In most tissues (liver, testis, hippocampus, heart, aorta, mesenteric artery) NADP+ increased activity and NAD+ was without effect. However, in whole renal cortex, colon, placenta, and lung both NADP+ and NAD+ increased activity. No difference in cofactor utilization was demonstrated between proximal and distal renal tubules following density gradient separation. This distribution of NAD(+)-dependent activity corresponds with: (i) the distribution of multiple mRNA and/or protein species of 11 beta-OHSD; (ii) the distribution of aldosterone-specific mineralocorticoid receptors; and (iii) the equilibrium between active and inactive glucocorticoids in each tissue. We suggest that the tissue-specific expression of isoforms of 11 beta-OHSD with different kinetic properties confers on them diverse roles in modulating corticosteroid receptor activation.

11-beta-Hydroxysteroid Dehydrogenases

Differential promoter usage by the rat 11 beta-hydroxysteroid dehydrogenase gene.

11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) catalyzes the conversion of physiological glucocorticoids to inactive products, thus protecting nonselective renal mineralocorticoid receptors from circulating glucocorticoids (ensuring aldosterone selectivity in vivo) and modulating glucocorticoid access to mineralocorticoid receptors and glucocorticoid receptors in other tissues. Detection of multiple mRNA and immunoreactive 11 beta-OHSD species in kidney, but not liver, extracts suggests the presence of tissue-specific isoforms. To determine whether differential promoter usage might explain the mRNA heterogeneity we cloned and sequenced rat 11 beta-OHSD genomic DNA. Total identity was found between the nucleotide sequence of exons 1 and 2 and the previously published rat liver cDNA. Using both primer extension and RNase protection analyses we found the predominant transcription start site in liver (+1) is 105 base pairs (bp)5' of the start of translation. In kidney two additional Cap sites were detected: 1) 264 bp 5' of exon 1; there is no in-phase open reading frame, suggesting the additional 5' sequence is not translated; and 2) 65 bp upstream of exon 2, within intron A; the predicted truncated protein lacks the first 26 hydrophobic residues. Oligonucleotide probes specific to transcripts arising from each promoter confirmed that all three are employed in kidney, whereas a single predominant species was found in liver, thus demonstrating tissue-specific differential promoter usage of the 11 beta-OHSD gene.

11-beta-Hydroxysteroid Dehydrogenases

11 beta-Hydroxysteroid dehydrogenase in the rat ovary: high expression in the oocyte.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the conversion of physiological glucocorticoids to inactive products, thus modifying the access of glucocorticoids to glucocorticoid and mineralocorticoid receptors. Glucocorticoids may affect ovarian function both indirectly and via binding to ovarian receptors. We have demonstrated 11 beta-HSD bioactivity and mRNA expression in rat ovary in vitro. The enzyme was localized to oocytes and luteal bodies immunohistochemically using two antibodies raised against purified rat liver 11 beta-HSD. These data are supported by in-situ hybridization studies, which also localized 11 beta-HSD mRNA expression to oocytes and luteal bodies. The results suggest that 11 beta-HSD may modulate the effects of glucocorticoid on ovarian function.

11-beta-Hydroxysteroid Dehydrogenases

Clonidine therapy for Shapiro's syndrome.

Shapiro's syndrome comprises agenesis of the corpus callosum in association with episodic hyperhidrosis and hypothermia. We describe a 25-year-old man who is the twentieth case to be reported. There was no evidence of epilepsy, sympathetic nervous system dysfunction or inappropriate vasopressin release. However, investigation demonstrated a central defect in temperature regulation with an abnormally low hypothalamic set-point and normal homeothermic reflexes. Therapy with clonidine, an alpha 2-adrenoceptor agonist, was associated with remission of symptoms: these recurred on four occasions when clonidine was withdrawn. Clonidine therapy was also associated with a return to normal central temperature regulation. We suggest that the efficacy of clonidine reflects an action on hypothalamic thermoregulation rather than on peripheral catecholamine release. These findings have implications for the use of clonidine in other patients with Shapiro's syndrome and in more common disorders of temperature control, including perimenopausal flushing.

Adult

Lessons from licorice.

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11-beta-Hydroxysteroid Dehydrogenases

Serotonin stimulates calcium influx in isolated rat adrenal zona glomerulosa cells.

To investigate the role of calcium as a second messenger in serotonin-stimulated aldosterone secretion, radiolabelled calcium influx studies were carried out in purified rat adrenal zona glomerulosa cells using 45CaCl2. The results show that serotonin caused calcium influx within 45 seconds of addition and this continued for up to 105 seconds. Angiotensin II also caused calcium influx; however, the effect was significantly smaller than that of serotonin. Serotonin-stimulated calcium influx could be inhibited by the calcium antagonist verapamil and by methysergide, a selective serotonin receptor type-1/2 antagonist. The data indicate that serotonin directly stimulates calcium uptake in zona glomerulosa cells via calcium channels which are coupled to specific serotonin receptors.

Angiotensin II

Liquorice.

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11-beta-Hydroxysteroid Dehydrogenases