Biomedical subjects

C J Kenyon

Publications and source records attributed to C J Kenyon.

At least 91 records · Page 5Linked to original sources

PubMed1987

Does dopamine regulate aldosterone secretion in the rat?

This study investigated the role of dopamine in the control of adrenal steroidogenesis. Adrenaline, noradrenaline and dopamine have been measured in plasma and in the adrenal zona glomerulosa and medulla of rats fed low, normal and high sodium diets and in zona glomerulosa tissue of rats with adrenal regeneration hypertension (ARH). Adrenal concentrations (means +/- SE) of adrenaline, noradrenaline and dopamine in rats fed a normal diet were 1471 +/- 335, 527 +/- 75 and 51 +/- 12 nmol/g in the medulla, and 66 +/- 17, 18 +/- 9 and 6 +/- 1 nmol/g in the zona glomerulosa. The dopamine content of the zona glomerulosa was greater than could be accounted for by simple contamination from the medullary catecholamines and is commensurate with that of tissue with dopaminergic innervation. Adrenal noradrenaline and adrenaline concentrations and plasma catecholamine and corticosterone concentrations were not affected by dietary sodium intake. Plasma aldosterone concentrations were greater than 3030.4, 339.8 +/- 41.5 and 55.2 +/- 11.0 pmol/l in rats fed low, normal and high sodium diets respectively. Five weeks after right adrenalectomy and nephrectomy and left adrenal enucleation, ARH rat systolic blood pressure had increased by 47 mmHg. In the regenerated gland, the concentrations of noradrenaline and adrenaline were negligible but dopamine was present in amounts similar to that of a normal adrenal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗

PubMed1986

Inhibition of corticosteroid 11 beta hydroxylation in bovine zona fasciculata cells by the potassium entry blocker 4-aminopyridine.

The potassium entry blocker, 4-aminopyridine has been used to evaluate the importance of this cation in several tissues including the adrenal cortex. Since it inhibited corticosteroidogenesis, an important role for potassium entry in the control of this process has been implied. In the present in vitro study, 4-aminopyridine inhibited cortisol and corticosterone production and, at high concentrations, that of 11-deoxycortisol and 11-deoxycorticosterone. However, at lower concentrations, 11-deoxycorticosteroid production increased suggesting that 4-aminopyridine acts as an inhibitor of 11 beta hydroxylation. Its slight resemblance to metyrapone may suggest that it acts, at least in part, by competing for cytochrome P450. However, its use as a potassium inhibitor in studies of the adrenal cortex may give ambiguous results.

4-Aminopyridine↗

PubMed1986

Inhibition by omeprazole of adrenocortical response to ACTH: clinical studies and experiments on bovine adrenal cortex in vitro.

Omeprazole, a substituted benzimidazole, is a potent inhibitor of gastric acid secretion which is currently being evaluated in patients with peptic ulcer and Zollinger-Ellison syndrome. Drugs which possess an imidazole nucleus have previously been shown to inhibit cortisol release from the adrenal cortex, secondary to inhibition of mitochondrial cytochrome P-450 dependent hydroxylation reactions. In a double-blind placebo-controlled crossover study in healthy male volunteers, omeprazole (60 mg daily for 7 days) did not alter basal cortisol levels. The peak cortisol response to ACTH stimulation was significantly reduced. Cortisol levels 60 min after ACTH were 824 +/- 27 nmol/l on omeprazole (mean +/- SEM), and 929 +/- 35 on placebo (P less than 0.005). In vitro, omeprazole caused a concentration-dependent inhibition of ACTH-stimulated cortisol release from isolated bovine adrenal cells (ED50 = 20 micrograms/ml). This was associated with a decrease in deoxycortisol synthesis. Therefore, unlike some other imidazole-containing drugs, the inhibitory effects of omeprazole are not entirely due to steroid 11 beta-hydroxylase inhibition. Substantial inhibition occurred at omeprazole concentrations which are higher than plasma levels normally achieved in clinical use. However, impairment of adrenocortical function may occur in patients on long-term high dose omeprazole treatment for Zollinger-Ellison syndrome.

Adrenal Cortex↗

PubMed1986

Dopamine effects on 11-deoxycorticosterone concentrations in patients with Cushing's syndrome and in vitro.

The effect of dopamine (1 micrograms/kg/min by i.v. infusion) on corticosteroid levels was studied in five patients with cortisol excess caused by increased ACTH secretion. In four of the five subjects dopamine, when compared with placebo infusion, caused plasma concentrations of 11-deoxycorticosterone to rise without affecting levels of cortisol, corticosterone or aldosterone. In a parallel in-vitro study using incubations of bovine adrenal zona glomerulosa cells, dopamine (10(-9) mol/l-10(-5) mol/l) had no effect on basal or ACTH stimulated secretion of aldosterone, cortisol or 11-deoxycorticosterone. However, dopamine (10(-5) mol/l) partially inhibited angiotensin II (10(-7) mol/l) stimulated secretion of aldosterone (4.36 ng/10(6) cells/h +/- 0.28 vs 2.90 +/- 0.20, P less than 0.05) but did not alter 11-deoxycorticosterone secretion i the same incubations. these data suggest that the effect of dopamine on 11-deoxycorticosterone secretion in vivo may not be due to its direct action on the adrenal to inhibit corticosteroidogenesis. An alternative explanation is that dopamine may alter extra-adrenal synthesis of 11-deoxycorticosterone, possibly by increasing substrate availability to tissues capable of 21-hydroxylation reactions.

Adrenal Cortex↗

PubMed1986

Dose related in vitro effects of ranitidine and cimetidine on basal and ACTH-stimulated steroidogenesis.

Isolated bovine adrenocortical cells were incubated with and without 3 ng/ml ACTH, with various concentrations (10-1000 micrograms/ml) of either cimetidine or ranitidine. Cortisol, corticosterone, and deoxycorticosterone outputs were measured. Cimetidine and ranitidine at 320 and 1000 micrograms/ml inhibited ACTH-stimulated corticosterone and cortisol synthesis and cimetidine decreased basal cortisol synthesis. The inhibitory effects of cimetidine on cortisol synthesis were approximately 10 times greater than those of ranitidine. Cimetidine (1000 micrograms/ml), but not ranitidine increased deoxycorticosterone synthesis by ACTH-stimulated cells, indicating inhibition of 11 beta-hydroxylation in the adrenal steroidogenic pathway. Although doses of cimetidine and ranitidine which produce these in vitro effects are much greater than plasma concentrations in normal clinical use, they might be important in acutely ill patients given intravenous bolus injections of cimetidine, or if either antagonist were accumulated by the adrenal to produce high intracellular concentrations.

Adrenal Cortex↗

PubMed1986

Dexamethasone-suppressible hyperaldosteronism. Adrenal transition cell hyperplasia?

Dexamethasone-suppressible hyperaldosteronism is a rare familial syndrome in which hypokalemia, suppression of plasma renin concentration, and elevated aldosterone secretion are corrected by treatment with glucocorticoids. Regulation of adrenocortical function and body electrolytes was studied in two affected brothers. Both were hypertensive (210/128 and 160/106 mm Hg) with hypokalemia (3.3 and 3.5 mM) and low plasma renin concentrations. Aldosterone was elevated intermittently with levels as high as 45 ng/dl (normal range, 4-16 ng/dl). Cortisol concentrations were normal but were correlated with aldosterone levels (r = 0.9 and 0.7). Concentrations of 11-deoxycorticosterone (19 and 21 ng/dl; normal range, 4-16 ng/dl) and 18-hydroxycortisol (1000 and 950 ng/dl; normal range, 34-150 ng/dl) were elevated, and diurnal changes in both were the same as those seen with aldosterone. Infusion of adrenocorticotropic hormone (ACTH) caused exaggerated increases of aldosterone, 11-deoxycorticosterone, and 18-hydroxycortisol; cortisol response was normal. A 4-week trial of dexamethasone normalized blood pressure and caused a natriuresis, a fall in aldosterone, and a rise in plasma renin. Administration of ACTH after dexamethasone treatment again caused exaggerated increases of aldosterone. Aldosterone did not respond to angiotensin II before dexamethasone therapy (r = 0.01), but it showed a normal response after therapy (r = 0.8, p less than 0.01). Neither administration of dopamine (1 microgram/kg/min) nor long-term therapy with bromocriptine (2.5 mg t.i.d. for 4 weeks) affected aldosterone biosynthesis. Thus, loss of dopaminergic inhibition of mineralocorticoid biosynthesis does not account for hyperaldosteronism in this condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

PubMed1986

The relative importance of glucocorticoids and mineralocorticoids in the development of adrenal regeneration hypertension in rats.

The adrenocortical tissue which regenerates after adrenal enucleation, and contralateral uninephrectomy and adrenalectomy, resembles histologically zona fasciculata tissue which normally synthesises glucocorticoids. However, increases in blood pressure after enucleation (adrenal regeneration hypertension-ARH] were preceded by a rise in exchangeable body sodium similar to that found with mineralocorticoid-induced hypertension (e.g. DOC/salt rat model). Glucocorticoid involvement in ARH rats was tested, firstly by infusing dexamethasone into control and ARH rats to see whether ACTH suppression would lower blood pressure by reducing adrenocortical activity and, secondly, by infusing dexamethasone into rats with intact adrenals to see whether conditions for ARH (i.e. uninephrectomy and/or saline consumption) pre-disposed rats to the hypertensinogenic properties of glucocorticoids. Low-dose dexamethasone infusions (10 micrograms/day for 5 days) in ARH rats did not affect blood pressure but in control animals caused a significant (P less than 0.01) increase from 128 +/- 3 to 151 +/- 5 mmHg. Corticosterone, 18-hydroxycorticosterone and deoxycorticosterone plasma concentrations were suppressed in both groups by dexamethasone treatment; plasma renin concentrations were lower in ARH rats than in controls. Uninephrectomy or 1% NaCl as drinking fluid did not affect the blood pressure rise induced by sc infusion of 10 micrograms dexamethasone/day for 14 days in rats with intact adrenals. The temporal relationship between blood pressure changes and exchangeable body sodium in ARH rats resembles that in mineralocorticoid-induced hypertension. Glucocorticoid, unlike mineralocorticoid, induced hypertension is not affected by a reduction in renal mass or increased sodium intake.

Adrenal Cortex↗

PubMed1986

Dopamine effects on adrenocorticotrophin-stimulated aldosterone, cortisol, corticosterone and 11-deoxycorticosteroid concentrations in sodium-replete and sodium-deplete man.

The effect of dopamine (1 microgram/kg per min) on corticosteroid response to ACTH (0.1, 1 and 10 ng/kg per min) was compared with that of a placebo in sodium-replete (150 mmol/day) and -deplete (10 mmol/day) normal man. Dopamine had no effect on aldosterone, cortisol or corticosterone responses in either dietary phase, but increased deoxycorticosterone (897.0 +/- 126.4 (S.E.M.) vs 590.0 +/- 84.3 pmol/l, normal Na+; 1264.2 +/- 84.3 vs 764.5 +/- 84.3 pmol/l, low Na+) and deoxycortisol (6.033 +/- 0.583 vs 5.048 +/- 0.680 nmol/l, normal Na+; 5.112 +/- 0.600 vs 4.130 +/- 0.367 nmol/l, low Na+) levels during ACTH administration (all P less than 0.01). Deoxycorticosterone and corticosterone responses to ACTH were greater during sodium depletion than repletion (both P less than 0.01). Dopamine therefore increased 11-deoxycorticosteroid concentrations during ACTH-stimulated steroidogenesis. This may reflect action of dopamine to increase extra-adrenal formation of 11-deoxycorticosteroids.

Adrenal Cortex Hormones↗

PubMed1985

Potentiation of adrenaline-induced platelet aggregation by angiotensin II.

The effects of angiotensin II (ANG II) alone and in combination with other agonists on human platelet aggregation, thromboxane B2 (TxB2) and cytosolic [Ca2+]i were investigated. ANG II (10(-11) - 10(-7) M) alone had no direct effect on aggregation, TxB2 production or [Ca2+]i after short- (less than 2 min) or long-term (30 min) incubation. In contrast, low concentrations of ANG II (10(-11) M) enhanced adrenaline-induced platelet aggregation but high concentrations (10(-7) M) had an inhibitory effect. Moreover, ANG II (10(-11) - 10(-7) M) augmented platelet responses to the TxA2 mimetic, U44069. Pretreatment of platelets with flurbiprofen abolished this facilitatory effect of ANG II on adrenaline- but not on U44069-induced platelet aggregation. These results suggest that ANG II stimulation of agonist-induced platelet activation may be due to potentiation of the effects rather than the synthesis of TxA2.

Angiotensin II↗

PubMed1985

Control of renal and adrenocortical function by the renin-angiotensin system in two euryhaline teleost fishes.

Plasma ions and cortisol levels were measured sequentially during the adaptation of European eels (Anguilla anguilla) from fresh water (FW) to sea water (SW). The importance of the renin-angiotensin system in the regulation of this adaptation was assessed using captopril (SQ14225, an inhibitor of angiotensin I-converting enzyme). The effects of captopril on renal function in FW- and SW-adapted trout were also examined. During the first 5 hr in sea water, plasma levels of cortisol in eels increased threefold, plasma sodium rose steadily from 137 to 156 mmol/l and plasma potassium fell from 2.1 to 1.6 mmol/l. In contrast, captopril-treated eels when adapted to sea water had plasma cortisol levels twice those of controls. Captopril treatment did not affect the electrolyte responses to seawater adaptation. Captopril injected into eels which were fully adapted to and wholly maintained in sea water had no effect on plasma levels of cortisol, sodium, and potassium. Plasma cortisol was 30% lower in freshwater eels 2 hr after an injection of captopril but plasma sodium and potassium levels were unchanged. In both FW- and SW-adapted trout, captopril infusions doubled the glomerular filtration and urine production rates and the tubular transport maxima for glucose without changes in plasma composition.

Adrenal Cortex↗

PubMed1985

The role of calcium ions in the mechanism of ACTH stimulation of cortisol synthesis.

Removal of free calcium ions from the incubation medium of isolated bovine adrenocortical cells with EGTA reduced basal cortisol synthesis and blocked the effects of ACTH; additional calcium restored normal steroid synthesis. Calcium channel blockers, verapamil and nitrendipine and the calmodulin antagonist, trifluoperazine inhibited ACTH-stimulated cortisol synthesis in a dose-dependent manner (IC50s of 6.2, 10 and 5.2 microM, respectively). Steroidogenic effects of dibutyryl cyclic AMP were prevented with 50 microM verapamil or trifluoperazine. Calcium ionophore A23187 at 1 microM increased cortisol synthesis 2-3 fold which was less than the normal response to ACTH. Stimulatory effects of ionophore and cyclic AMP or ACTH were not additive. ACTH-stimulation of cortisol synthesis appears to involve cyclic AMP-dependent uptake of extracellular calcium ions, possibly by a mechanism requiring calmodulin. Increases in intracellular calcium ions cannot wholly mimic ACTH actions.

Adrenal Cortex↗

PubMed1985

Comparison of the effects of etomidate, thiopentone and propofol on cortisol synthesis.

The inhibitory effects of etomidate, thiopentone and propofol on basal and ACTH-stimulated cortisol synthesis by isolated bovine adrenocortical cells have been examined. Concentrations required for 50% inhibition of ACTH-stimulated cortisol output were 1.1 X 10(-4) mol litre-1 for propofol, 3 X 10(-5) mol litre-1 for thiopentone and 4.6 X 10(-1) mol litre-1 for etomidate. At concentrations likely to be achieved during anaesthesia, etomidate would block cortisol output by isolated cells, thiopentone might slightly reduce output and propofol would be unlikely to alter cortisol synthesis significantly.

Adrenal Cortex↗

PubMed1985

Regulation of platelet receptors for angiotensin II in man.

The effects of changes in dietary intake of sodium and potassium on 125I-angiotensin II binding to platelets were studied in normal subjects. We also defined binding to platelets from patients with essential hypertension and subjects with normal blood pressure. Restriction of sodium intake in normal subjects resulted in a decrease in the number of receptor sites from 6.2 +/- 0.3 sites/cell to 4.1 +/- 0.4 sites/cell (P less than 0.01) but there were no changes in affinity as measured by the Kd. Over a range of sodium intakes from 15 to 200 mmol/day there was a negative correlation between plasma concentration of angiotensin II and receptor site concentration (rs = 0.57, P less than 0.01). Changes in dietary potassium did not affect angiotensin II binding. Angiotensin II binding was also measured in 10 patients with essential hypertension (mean blood pressure [BP] 178/107 mmHg, plasma concentrations of renin [PRC] 12 +/- 2 microU/ml and angiotensin [pANG] II 14 +/- 2 pg/ml) and 10 subjects with normal blood pressure (mean BP 112/74 mmHg, PRC 13 +/- 2 microU/ml, pANG II 13 +/- 2 pg/ml). In the hypertensive patients, binding capacity and affinity (Kd = 5.0 +/- 0.6 X 10(-10) M, 5.7 +/- 0.8 sites/cell) were similar to those in the normotensive subjects (Kd = 4.9 +/- 0.8 X 10(-10) M, 5.4 +/- 0.5 sites/cell). Changes in sensitivity to angiotensin II in essential hypertension may not be determined at receptor level. Angiotensin II receptors in platelets respond to changes in sodium intake like receptors in arterial muscle.

Adult↗

PubMed1985

Potassium fluxes in bovine adrenal cells during adrenocorticotropin stimulation.

Active (ouabain-sensitive) and passive (ouabain-insensitive) fluxes of 43K were measured in isolated bovine zona fasciculata/reticularis cells. ACTH inhibited passive influx in a dose-dependent manner and, at a concentration that maximally stimulated steroidogenesis (10(-8) M), also inhibited passive efflux. ACTH did not affect active potassium transport. Angiotensin II (10(-6) M) and cAMP (10(-2) M) inhibited passive influx to the same extent as did 10(-8) M ACTH. Angiotensin II (10(-6) M) also reduced active potassium uptake, although this did not appear to be related to changes in cortisol biosynthesis. Increases in cortisol synthesis by ouabain-treated cells in response to angiotensin II and ACTH were proportional to decreases in potassium influx. The addition of cortisol (1 microgram/ml) to cells slightly reduced passive potassium uptake, but not to the same extent as did 10(-8) M ACTH. Frusemide, an inhibitor of passive sodium/potassium cotransport, did not wholly abolish the effects of ACTH on potassium influx. These changes in flux are probably related to electrophysiological changes in membrane potential. Their significance in the regulation of ACTH actions has yet to be determined.

Adrenal Glands↗

PubMed1985

Angiotensin II effects on platelet function.

The effects of angiotensin II (ANG II) alone and in combination with other agonists on platelet aggregation, thromboxane B2 (TxB2) synthesis and cytosolic [Ca2+]i were investigated. Angiotensin II (10(-11)-10(-7) mol/l) alone had no direct effect on aggregation, TxB2 production or [Ca2+]i after short- (< 2 min) or long-term (30 min) incubation. In contrast, low concentrations of ANG II (10(-11) mol/l) enhanced adrenaline-induced platelet aggregation but high concentrations (10(-7) mol/l) had an inhibitory effect. Moreover, ANG II (10(-11)-10(-7) mol/l) augmented platelet responses to the TxA2 mimetic U44069. The facilitatory effect of ANG II on adrenaline-induced platelet aggregation was abolished by pretreatment of platelets with flurbiprofen. Thromboxane B2 synthesis by adrenaline-treated platelets was inhibited by ANG II. The results indicate that ANG II stimulation of agonist-induced platelet activation is due to potentiation of the effects rather than the synthesis of TxA2.

Angiotensin II↗

PubMed1984

Analysis of mRNA synthesis following induction of the Escherichia coli SOS system.

Escherichia coli responds to impairment of DNA synthesis by inducing a system of DNA repair known as the SOS response. Specific genes are derepressed through proteolytic cleavage of their repressor, the lexA gene product. Cleavage in vivo requires functional RecA protein in a role not yet understood. We used mRNA hybridization techniques to follow the rapid changes that occur with induction in cells with mutations in the recA operator or in the repressor cleavage site. These mutations allowed us to uncouple the induction of RecA protein synthesis from its role in inducing the other SOS functions. Following induction with ultraviolet light, we observed increased rates of mRNA synthesis from five SOS genes within five minutes, maximum expression ten to 20 minutes later and then a later decline to near the initial rates. The presence of a recA operator mutation did not significantly influence these kinetics, whereas induction was fully blocked by an additional mutation in the repressor cleavage site. These experiments are consistent with activation of RecA protein preceding repressor cleavage and derepression of SOS genes. The results also suggest that the timing and extent of induction of individual SOS genes may be different.

Bacterial Proteins↗

PubMed1984

Receptors for angiotensin II on platelets from man.

Platelets were prepared from peripheral venous blood on iso-osmotic density gradients of Percoll, resulting in a good recovery of cells (50-80%) which were relatively free of contaminating blood cells (erythrocyte less than 0.1%, leucocyte less than 1%). At 22 degrees C, specific binding of 125I-labelled angiotensin II (300 pmol/l) was time and temperature dependent, saturable, reversible and linear with cell concentration. Scatchard analysis of saturation curves revealed a single class of binding sites with Kd 1.5 +/- 0.4 X 10(-10) mol/l and total binding capacity 6.3 +/- 1.2 receptors/platelet. Similar values (Kd 2.4 +/- 0.7 X 10(-10) mol/l and binding capacity 6.5 +/- 1.0 receptors/cell) were obtained by displacement analysis. From kinetic studies the forward and reverse rate constants were 3.1 X 10(8) mol min-1 l-1 and 3.6 X 10(-2)/min giving a Kd of 1.2 X 10(-10) mol/l. The relative binding potencies for angiotensin II and analogues were: [Sar1, Thr8]ANG II greater than ANG II greater than ANG III greater than [Sar1, Ala8]ANG II greater than ANG I. Incubation with an extracellular marker (51Cr-labelled EDTA) demonstrated that binding of angiotensin II to platelets was not due to free fluid endocytosis.

Adult↗

PubMed1984

Glucocorticoid inhibition of mineralocorticoid action in the rat.

The mineralocorticoid activity of corticosterone based on acute changes in urinary Na+/K+ ratios in adrenalectomized rats was 1000 times less than that of aldosterone. However, corticosterone had only kaliuretic actions whereas aldosterone had both antinatriuretic and kaliuretic properties. Corticosterone inhibited the antinatriuretic actions of aldosterone. Adrenalectomized rats infused continuously with a physiological dose of corticosterone (1 mg/day) were 5 time less sensitive to the antinatriuretic and 25 times less sensitive to the kaliuretic actions of aldosterone when administered acutely than were control adrenalectomized rats. The long term effects of infusions of physiological doses of aldosterone and corticosterone were assessed in adrenalectomized rats maintained in metabolic cages. Aldosterone lowered plasma renin activity and reduced fluid (0.3% NaCl) intake; these effects were diminished when aldosterone and corticosterone were infused simultaneously. Plasma renin activity and fluid intake were correlated in long term infusion experiments. Both hormones had hypokalaemic effects but these were not additive. Corticosterone, but not aldosterone, increased systolic blood pressure and plasma sodium levels. We conclude that glucocorticoid effects on water and electrolyte metabolism are different from those of mineralocorticoids, that glucocorticoids may antagonize mineralocorticoid effects and that interactions between mineralocorticoids and glucocorticoids may be important in long term blood pressure regulation.

Adrenalectomy↗