Dexamethasone suppressible hyperaldosteronism: insights into adrenal physiology.
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Adolescent↗
Biomedical subjects
R Fraser
Publications and source records attributed to R Fraser.
Studies on the pathogenesis of hypertension in Cushing's disease and acromegaly.
The pathogenesis of the hypertension associated with Cushing's syndrome and with acromegaly is poorly understood. We have investigated the possible roles of sodium retention, activation of the renin-angiotensin system and increased sympathetic nervous system activity in untreated patients. In 11 patients with Cushing's disease, seven of whom were hypertensive, total exchangeable sodium was normal despite increased levels of the mineralocorticoid hormones, 11-deoxy-corticosterone and corticosterone. The renin-angiotensin system was also normal. Cardiac sensitivity to the beta-receptor agonist isoprenaline was increased, but this was not due to an increase in beta-adrenoceptor density. Hypertension in Cushing's disease is neither sodium-dependent nor angiotensin II-mediated, but increased cardiac sensitivity to catecholamines, by increasing cardiac output, may contribute to the pathogenesis of hypertension. In nine patients with acromegaly (three of whom were hypertensive) total exchangeable sodium was elevated. Although no correlation between blood pressure and exchangeable sodium was found, hypertension in acromegaly is probably sodium dependent. No evidence was found for a pathogenetic role for either the renin-angiotensin-aldosterone or the sympathetic nervous system.
Acromegaly↗
[18-Hydroxycorticosterone, 18-hydroxydesoxycorticosterone. Why, when, how to determine plasma levels in some adrenal pathologies].
The authors review some current ideas concerning the role of 18-hydroxylated corticosteroids as mineralocorticoids themselves and as possible precursors of the principal mineralocorticoid, aldosterone. In particular, the physiological and pharmacological agents affecting their secretion are discussed together with a description of the methods used for their analysis in plasma in the department of Clinical Biochemistry Pitié-Salpétrière. Finally, the value of these assays in the differential diagnosis of mineralocorticoid hypertension and inborn errors of corticosteroid biosynthesis is assessed and the constraints on sampling technique listed.
18-Hydroxycorticosterone↗
Effect of a teleost GnRH analog on steroidogenesis by the follicle-enclosed goldfish oocytes, in vitro.
The influence of an agonist analog of teleost GnRH [(D-Arg6, Trp7, Leu8, Pro9-NEt)-GnRH; tGnRH-A] on steroidogenesis was studied in prophase-I arrested, follicle-enclosed, goldfish oocytes in vitro. Incubation of the follicles with carp gonadotropin (GtH) significantly increased production of 17 alpha-hydroxyprogesterone (HP) and testosterone following 24 hr of incubation in vitro. Concomitant incubation with tGnRH-A (10(-7) M) significantly attenuated the dose-related increase in GtH-induced testosterone production, but was without effect on the GtH-induced HP level. Time course studies indicated that tGnRH-A exerted its maximum inhibitory action on the GtH-induced testosterone production during the initial 8 hr of incubation in vitro. The inhibition of GtH-induced testosterone production by tGnRH-A was dose dependent with an ED50 of 1.39 +/- 2.88 nM. A significantly higher testosterone level was obtained in the incubation media containing HP as substrate; concomitant treatment with tGnRH-A reduced the conversion of HP to testosterone. The incubation media also contained low, but measurable levels of 17 alpha-hydroxy-20 beta-dihydroprogesterone (DHP), which increased in the presence of 3-isobutyl-methyl-xanthine; lower levels of DHP were obtained in the groups incubated with tGnRH-A. In view of our present findings and previous observations concerning inhibitory effects of tGnRH-A on the progestogen and GtH-induced reinitiation of meiosis in the follicle-enclosed goldfish oocytes (H. R. Habibi, G. Van Der Kraak, E. Bulanski, and R. E. Peter, Amer. J. Physiol. 255, R268-R273 (1988] the influence of testosterone on the GtH- and DHP-induced meiosis in vitro was also studied. Testosterone (1 micrograms/ml) enhanced both GtH- and DHP-induced oocyte meiosis in the goldfish oocytes. Testosterone alone was also found to significantly increase oocyte meiosis in the goldfish oocytes in a dose-related fashion. The present findings demonstrate an inhibitory effect of a GnRH agonist on GtH-induced testosterone production in goldfish oocytes and suggest that tGnRH-A might influence oocyte meiosis in part by influencing steroidogenesis.
Animals↗
The role of dopamine in the control of corticosteroid secretion and metabolism.
The relation between aldosterone and its trophins is altered by electrolyte status and in some hypertensive conditions in man by a mechanism or mechanisms not understood. Dopamine has been suggested as the agent for the altered sensitivity of plasma aldosterone to angiotensin II based on the results of studies with dopamine itself, both in vivo and in vitro, and with pharmacological agonists and antagonists. The evidence derived from these studies is presented and discussed. Questionable specificity of the agents used makes interpretation difficult. Similarly, dopamine infusion rates used in man and animals have resulted in plasma concentrations far in excess of those found normally and these pharmacological concentrations have been shown to alter both the clearance rate of exogenous angiotensin II, and the pattern of steroid response to ACTH. Direct study of adrenal tissue has provided more promising results. The adrenal cortex possesses specific dopamine receptors and dopamine has been shown to modify aldosterone biosynthesis in vitro. Moreover, dopamine is present in adrenocortical tissue in concentrations in the range calculated to operate the receptors. However, there is, as yet, no evidence that dopamine concentrations change in a physiological meaningful way, for example, during changes in sodium status.
Adrenal Cortex↗
Effect of the benzodiazepines diazepam, des-N-methyldiazepam and midazolam on corticosteroid biosynthesis in bovine adrenocortical cells in vitro; location of site of action.
Diazepam and midazolam inhibited cortisol and aldosterone synthesis in bovine adrenal cells in vitro. The biologically active metabolite des-N-methyldiazepam did not. Midazolam was a more potent inhibitor (IC50: 6 micrograms/ml) than diazepam (IC50: 13 micrograms/ml) in ACTH-stimulated cells. Both compounds inhibited steroidogenesis at several points in the biosynthetic chain; the greatest effects were on 17 alpha hydroxylation and 21 hydroxylation. Diazepam had a relatively greater effect on 17 alpha hydroxylation; midazolam on 21 hydroxylation. Both were less potent inhibitors of 11 beta hydroxylation and had little apparent effect on side chain cleavage. Thus microsomal hydroxylation is more vulnerable to benzodiazepines than mitochondrial hydroxylation. It is suggested that the drugs act by competing with steroid mixed function oxidases for cytochrome P-450. The plasma concentrations required for these effects are high in relation to therapeutic levels but may be achieved, for example, during acute infusions or when they are used in combination with imidazole drugs such as cimetidine.
Adrenal Cortex↗
Dexamethasone therapy selectively increases the sensitivity to noradrenaline of the rat mesenteric circulation.
We studied the effects of dexamethasone on the vascular responsiveness of the isolated perfused mesenteric vascular bed of the rats. Dexamethasone was infused at a low dose (2 micrograms/day) to avoid steroid-induced catabolic effects. The mesenteric arteries were perfused with increasing concentrations of noradrenaline, vasopressin and potassium chloride. Vascular responses to vasopressin and potassium chloride were similar in both dexamethasone-treated and control arteries. However, the dexamethasone treatment increased the sensitivity, but not the maximal pressor response, to noradrenaline. These results show that dexamethasone selectively increases the vascular sensitivity to noradrenaline in rats before the development of systemic hypertension.
Animals↗
Histology of port wine stains after copper vapour laser treatment.
We report histological changes in four patients with port wine stains treated with 578 nm yellow light from a high power copper vapour laser. Histology showed that selective damage occurred to the ectatic blood-vessels in the dermis, without haemorrhage and damage to non-vascular structures, and without scarring. The initial damage to the overlying epidermis was not permanent, and the damaged ectatic vessels returned to normal size or were completely necrosed and replaced by collagen.
Adolescent↗
Cervical spine injuries in road traffic crashes in South Australia, 1981-86.
The records of all cases of injury to the cervical spine sustained in road crashes for the 6 year period (1 January 1981 to 31 December 1986) which were admitted to the Spinal Injuries Unit of the Royal Adelaide Hospital, to the Adelaide Children's Hospital, or were identified at post-mortem examination were examined, and the relevant data extracted. There were 291 cases in the non-fatal group, and 161 in the fatal group. These represent a complete enumeration of all such patients in the state of South Australia over the 6 year period, given that up to 50% of cervical injuries in fatal cases can be missed. Comparison of the two groups showed that the fatal group had a much higher proportion of pedestrians, and persons over 50 years of age. About one-half of the fatal group had injuries at the level of C1 or the atlanto-occipital articulation. The most frequent level of injury in the non-fatal group was C2 (29.2%). About 30% of the non-fatal cases had some spinal cord damage. Case fatality rates were calculated, and ranged from 100% for injury at the atlanto-occipital articulation to 8% at C2. The fatality rate of pedestrians was about 4 times higher than that of vehicle occupants. About three-quarters of all cervical spine injuries occurred in vehicle occupants. There was an increase in the number of cases occurring in each year of the period studied. This rise was noted in non-fatal cases, in males, in vehicle occupants, and in crashes in the country.
Accidents, Traffic↗
A multicentre randomized trial comparing delivery with a silicone rubber cup and rigid metal vacuum extractor cups.
A total of 258 women requiring assisted delivery where vacuum extraction was thought to be suitable were randomly allocated to delivery with a new silicone rubber cup or metal vacuum extractor cups. There was a tendency for the silicone rubber cup to effect delivery more quickly and to cause less scalp trauma, but to fail to effect delivery on more occasions than metal cups. However, none of these differences was statistically significant. There were no statistically significant differences in the rates of birth canal trauma, maternal blood loss, or neonatal jaundice. The silicone rubber cup produced a cosmetically more acceptable chignon than the metal cups. The introduction of vacuum extractors with silicone rubber cups into obstetric units should be encouraged.
Double-Blind Method↗
Clapping or percussion causes atelectasis in dogs and influences gas exchange.
We examined the effects of 10 min of lower lateral chest wall percussion with a mechanical percussor or hand clapping in groups of anesthetized, paralyzed, and ventilated supine dogs. Mechanical percussion was applied at 10-16 Hz and caused an esophageal pressure swing (delta Pes) of 10-17 cmH2O. Hand clapping was applied at 4-7 Hz and caused a delta Pes of 6-17 cmH2O. At necropsy there were large reddened areas on the lateral surface of the underlying lung as well as smaller reddened areas on the hilar surfaces of both lungs and on the lateral surface of the opposite lung. These reddened regions were demonstrated to be atelectatic by postmortem lung inflation (which caused the reddened areas to disappear) and by microscopic examination. Despite the atelectasis, gas exchange improved toward the end of the percussion or clapping period. In four dogs that were ventilated for an additional 20 min after percussion, there was a tendency for gas exchange initially to worsen and then to gradually improve.
Animals↗
Low-dose infusion of atrial natriuretic factor in mild essential hypertension.
Intra-arterial blood pressure, cardiac output, heart rate, right heart indexes, urinary electrolytes, and urinary volume were monitored in eight patients with untreated (WHO Class I) essential hypertension. The patients were given synthetic atrial natriuretic factor (ANF) (99-126 alpha-hANP) at 1 and 2 pmol/kg/min in series (phases 1 and 2, 2 hours each dose) or vehicle (hemaccel) in random order on two separate occasions while on their usual diet. Arterial plasma ANF levels increased significantly from basal and time-matched placebo values from 25 +/- 2 and 28 +/- 3 pmol/l to 50 +/- 4 and 83 +/- 9 pmol/l at the end of phases 1 and 2, respectively (p less than 0.001). After 30 minutes during phase 2, systolic blood pressure decreased significantly by 20 +/- 4 mm Hg (p less than 0.001) from basal and time-matched placebo values and remained significantly reduced (-17 +/- 4 mm Hg, p less than 0.001) by the end of the recovery period (2 hours after infusions were completed). Pulmonary systolic blood pressure decreased by 5 +/- 1 mm Hg (phase 2, p less than 0.05). Cardiac output decreased by 0.5 +/- 0.1 l/min below baseline at the end of phase 2 of ANF infusion, whereas it increased significantly (p less than 0.02) by 0.6 +/- 0.1 l/min during vehicle infusion. Systemic diastolic, pulmonary diastolic, right atrial, and wedge pressures were not significantly changed during ANF or vehicle infusions, nor were pulmonary vascular resistance or heart rate altered. Systemic vascular resistance did not change significantly during both infusions, whereas during recovery, systemic vascular resistance decreased significantly after ANF infusion was discontinued (p less than 0.05). Microhematocrit levels increased dose dependently during ANF. The maximum increase was observed at the end of phase 2 (+4.7 +/- 1.7%), whereas the microhematocrit level decreased to -2.4 +/- 0.6% with vehicle (p less than 0.001) at the end of phase 2. Urinary sodium excretion increased significantly (p less than 0.02) by the end of phase 2 under ANF infusion (+38 +/- 15%), whereas it decreased (-10 +/- 6%) under placebo infusion by the end of phase 2. Urinary magnesium excretion was significantly increased during ANF infusion from phase 1 (p less than 0.02), whereas urinary potassium levels, calcium levels, creatinine levels, volume, and glomerular filtration rate did not differ significantly between the two infusions. Plasma renin, angiotensin II, aldosterone, and catecholamine concentrations did not change significantly during ANF or vehicle infusions.(ABSTRACT TRUNCATED AT 400 WORDS)
Atrial Natriuretic Factor↗
Hypokalaemia in alcoholics.
Hyponatraemia has been described in beer drinkers and hypokalaemia resulting from increased levels of aldosterone is well recognised in patients with cirrhosis and ascites. We have encountered episodes of hypokalaemia in alcoholics accompanied by normal or increased serum concentrations of sodium. Despite a resemblance to syndromes of mineralocorticoid excess, increased levels of aldosterone and other mineralocorticoids were not found.
Adrenal Cortex Hormones↗
Effects of cholesterol and lipoproteins on aldosterone secretion by bovine zona glomerulosa cells.
Freshly isolated bovine adrenocortical cells were pretreated with various concentrations of cholesterol and of high- (HDL) and low-density lipoprotein (LDL) fractions of known cholesterol content and then incubated in medium alone with and without angiotensin II. Preincubation with cholesterol (323 mumol/l) caused basal aldosterone synthesis to increase from 0.89 +/- 0.08 to 2.77 +/- 0.22 pmol/10(6) cells per hour (+/- S.E.M.) but did not significantly affect angiotensin-stimulated synthesis. Human HDL containing cholesterol at a final concentration of 129-647 mumol/l increased both basal and angiotensin-stimulated aldosterone synthesis. In HDL-treated cells, both the threshold response and responses to increasing concentrations of angiotensin were raised. Human LDL had no effect on basal or stimulated aldosterone synthesis nor did LDL alter the effects of HDL when cells were incubated with HDL and LDL in combination. Qualitatively similar results were obtained with bovine lipoproteins. These studies show that, in short-term incubations of fresh tissue, the supply of cholesterol may be a limiting factor in aldosterone synthesis and that HDL rather than LDL is the preferred source. These observations are discussed in relation first to the mechanisms by which cholesterol/HDL might augment steroid responses and secondly to other studies with cultured cells which have demonstrated a role for LDL.
Aldosterone↗
Volunteers and patient support.
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Canada↗
Defenestration of hepatic sinusoids as a cause of hyperlipoproteinaemia in alcoholics.
The hepatic sinusoidal endothelium separates sinusoidal blood from hepatocytes; changes in the porosity of this endothelium may affect the passage of chylomicrons into hepatocytes and influence lipid metabolism. Chronic exposure to ethanol reduces the porosity of the endothelium; this mechanism may underlie the hyperlipoproteinaemia observed in some people who drink heavily.
Adult↗
In vivo and in vitro studies of the site of inhibitory action of omeprazole on adrenocortical steroidogenesis.
The site of omeprazole inhibition of adrenal steroidogenesis has been sought in vivo by analyzing the patterns of urinary steroid metabolite excretion after 6 days of treatment with placebo/omeprazole. Excretion rates of androsterone, aetiocholanolone, dehydroepiandrosterone, 11 beta hydroxyandrosterone, tetrahydrocortisone, tetrahydrocortisol and alpha cortolone were reduced, indicating a block at an early step in steroidogenesis, possibly cholesterol side-chain cleavage. In vitro studies have confirmed this finding by measuring conversion of added precursors to cortisol in isolated bovine adrenocortical cells. Cortisol synthesis from added 20 alpha hydroxycholesterol was inhibited by 83% in the presence of 100 micrograms omeprazole/ml. Conversion from pregnenolone and progesterone and their 17 alpha hydroxylated derivatives was inhibited by 20-40% whereas cortisol production from added 11 deoxycortisol was not affected. These data suggest that omeprazole primarily inhibits cholesterol cleavage and does not inhibit 3 beta hydroxysteroid dehydrogenase, 17 alpha hydroxylase or 11 beta hydroxylation; 21 hydroxylase activity may be marginally attenuated.
Adrenal Cortex↗