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R. A. Fraser, D. Attardo, and S. Harvey


Central GH receptors (GHR) have been identified in hypothalamic and extra-hypothalamic tissues of rabbit and chicken brains. Plasma membranes of the rabbit brain demonstrated specific saturable high-affinity, low-capacity binding sites for 125I-labelled GH. RNA extracted from hypothalamic and extra-hypothalamic tissues of rabbit and chicken brains contained mRNA that hybridized with a cDNA probe for the rabbit liver GHR. This transcript was of a similar size to the major GHR mRNA moiety in rabbit liver. The expression of these moieties was age related, and higher in adult than in neonatal animals.

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R. M. Shepherd, R. Fraser, and C. J. Kenyon


Stimulation of aldosterone synthesis by angiotensin II (AII) is associated with depolarization of the cell membrane. Since the potential difference of adrenocortical cells is dependent on membrane permeability to potassium ions, the effects of agents which hyperpolarize the cell (by increasing permeability to K+) on the control of aldosterone synthesis were investigated further. Basal and AII-stimulated aldosterone synthesis was increased by 20–70% in cells incubated with 1 or 10 nm of the potassium ionophore valinomycin; higher concentrations markedly inhibited AII-stimulated synthesis. Cromakalim, a potential antihypertensive drug which facilitates the opening of K+ channels in smooth muscle cells, stimulated basal aldosterone synthesis at 2 μm but had no effect at 40 μm. AII-stimulated aldosterone synthesis was not affected by cromakalim except at 40 μm, which was inhibitory. The inhibitory effects of cromakalim, unlike those of valinomycin, were not reversible. Aldosterone synthesis from added hydroxycholesterol and pregnenolone (but not from deoxycorticosterone and corticosterone) was significantly inhibited by 40 μm cromakalim.

Potassium efflux from cells preloaded with 43K was unaffected by low concentrations of valinomycin, but was markedly increased by concentrations which inhibited AII-stimulated aldosterone production. Small decreases and increases in 43K efflux, caused by 1 and 40 μm cromakalim respectively, corresponded with increases and decreases in basal aldosterone production; cromakalim did not affect 43K efflux from AII-stimulated cells.

We suggest that increasing adrenocortical cell membrane permeability to K+ reduces steroidogenesis, but that valinomycin and cromakalim have other actions which complicate the relationship between 43K efflux and aldosterone production. Cromakalim appears to inhibit 21-hydroxylase activity in the biosynthetic pathway and may also affect 3β-hydroxysteroid dehydrogenase activity.

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A Jamieson, J M C Connell, and R Fraser

Glucocorticoid-suppressible hyperaldosteronism (GSH), first described in 1966 (Sutherland et al. 1966), is a rare cause of familial hypertension. It presents in young adults with hypertension, hypokalaemia and suppressed plasma renin activity (features caused by the excess activity of aldosterone secretion), and is distinguished from other forms of primary hyperaldosteronism by its autosomal dominant mode of inheritance and the reversal of all its clinical and biochemical abnormalities by the administration of small doses of the synthetic glucocorticoid dexamethasone (Connell et al. 1986). GSH is also characterized by abnormally elevated levels of 18-hydroxycortisol and 18-oxocortisol, the excretion of which also falls to normal following dexamethasone administration (Chu & Ulick, 1982; Ulick et al. 1983; Gomez-Sanchez et al. 1984). The study of the production of these unusual 18-hydroxylated steroids has led to a reappraisal of the late reactions in aldosterone and cortisol synthesis by the adrenal cortex,

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SM MacKenzie, M Lai, CJ Clark, R Fraser, CE Gomez-Sanchez, Seckl JR, JM Connell, and E Davies

The central nervous system produces many of the enzymes responsible for corticosteroid synthesis. A model system to study the regulation of this local system would be valuable. Previously, we have shown that primary cultures of hippocampal neurons isolated from the fetal rat can perform the biochemical reactions associated with the enzymes 11beta-hydroxylase and aldosterone synthase. Here, we demonstrate directly that these enzymes are present within primary cultures of fetal rat hippocampal neurons.

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SM MacKenzie, CJ Clark, R Fraser, CE Gomez-Sanchez, JM Connell, and E Davies

The terminal stages of cortisol and aldosterone production in the human adrenal gland are catalysed by the enzymes 11beta-hydroxylase and aldosterone synthase, which are encoded by the CYP11B1 and CYP11B2 genes respectively. Recent studies have suggested that aldosterone and cortisol are also made in other tissues such as the brain, heart and vascular system and may play a role in cardiovascular homeostasis. The aim of this study was to confirm the presence of these enzymes and localise them precisely in the rat brain. Reverse transcription-polymerase chain reaction (RT-PCR)/Southern blotting confirmed transcription of CYP11B1 and CYP11B2 in whole brain and hypothalamus minces from Wistar-Kyoto rats. 11beta-Hydroxylase and aldosterone synthase were immunolocalised in paraffin-embedded rat adrenal and brain sections using mouse monoclonal antibodies. Negative controls utilised a mouse monoclonal antibody raised against a non-mammalian epitope. In the brain, 11beta-hydroxylase and aldosterone synthase were detected in the cerebellum, especially the Purkinje cells, as well as the hippocampus. The specificities of the 11beta-hydroxylase and aldosterone synthase antibodies were confirmed by positive immunostaining of the relevant regions of the adrenal cortex. This is the first direct evidence that steroid hydroxylases involved in the final stages of corticosteroid biosynthesis are present in specific regions of the central nervous system.

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CJ Kenyon, M Panarelli, L Zagato, L Torielli, RP Heeley, CD Holloway, R Fraser, G Casari, RG Sutcliffe, and G Bianchi

The Milan hypertensive strain of rat (MHS) displays abnormalities in both renal function and adrenocortical activity. While the pressor role of the former has been studied in detail, the role of the latter has not yet been clearly evaluated. In the present study, glucocorticoid receptor (GR) binding characteristics in liver cytosol from adult MHS and Milan normotensive controls (MNS) have been investigated. Dexamethasone, aldosterone and corticosterone were bound with lower affinity to cytosol of MHS rats compared with that of MNS rats. This pattern of binding could explain the raised plasma corticosterone concentrations and adrenocortical hypertrophy previously noted in MHS. The coding sequence of MHS and MNS GR genes have been determined. The MHS gene differed in four respects from that of MNS: three silent point mutations and a polymorphic microsatellite region in exon 2. The latter polymorphism has been used in cosegregation studies of F2 hybrids of MHS x MNS. The MHS GR genotype was associated with hypercalciuria and lower blood pressure in female rats and lower body weight in male rats. Although the effect on blood pressure is small, it is consistent with the affinity data. MHS GR genotype cosegregated with lower blood pressure in F2 rats and displayed a lower affinity in binding studies. In conclusion, GR polymorphism may be responsible for differences of adrenocortical function between MHS and MNS. This may lead to a reduction in the blood pressure difference between the two strains.