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ABSTRACT

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.

ABSTRACT

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.

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,