G. C. Inglis

An influence of variation in the aldosterone synthase gene (CYP11B2) on corticosteroid responses to ACTH in normal human subjects.

OBJECTIVE Previous evidence suggests that the efficiency of 11β‐hydroxylase is at least partly heritable and also that it may be mildly impaired in essential hypertension. In both cases, assessment of activity was based on the response of 11‐deoxycorticosterone (DOC) and 11‐deoxycortisol to ACTH. The gene (CYP11B1) coding for this enzyme is highly homologous with and lies a relatively short distance downstream from the gene coding for aldosterone synthase (CYP11B2) on chromosome 8. Two polymorphisms of CYP11B2 have been described. The first involves a change of −344C to T in a putative steroidogenic factor‐1 (SF‐1) binding site and the other, the intron conversion, an exchange of intron 2 for that of CYP11B1. These polymorphisms are in linkage dysequilibrium. Their effects on 11β‐hydroxylation were studied.

The role of plasma osmolality, angiotensin II and dopamine in vasopressin release in man

A sensitive and specific radioimmunoassay for arginine vasopressin was used to compare the relative importance of changes in plasma osmolality, angiotensin II and dopamine in the regulation of vasopressin secretion in man. One hour after water loading plasma vasopressin fell from 0·40 to 0·06 pmol/1, while 8 h and 24 h fluid restriction resulted in a rise of vasopressin from 0·29 to 0·54 and 1·37 pmol/1 respectively. In contrast neither dietary sodium deprivation, when plasma angiotensin II increased 5‐fold, nor dopamine infusion, at a rate which increased circulating dopamine levels up to 244‐fold, had any effect on basal plasma vasopressin values. These results confirm that, under physiological conditions, osmoregulation is the major mechanism controlling vasopressin release and suggests that circulating angiotensin II and dopamine have no significant part to play.

Polymorphic differences from normal in the aldosterone synthase gene (CYP11B2) in patients with primary hyperaldosteronism and adrenal tumour (Conn's syndrome)

OBJECTIVE The hypertension of Conns syndrome is due to autonomous aldosterone production by a unilateral adrenocortical adenoma. The source of tumour initiation and the reasons for excess aldosterone production as opposed to cortisol are not known, although variations in the promoter region of the gene coding for aldosterone synthase (CYP11B2) might account for the altered rate of aldosterone secretion.

Abnormal Epinephrine Release in Young Adults With High Personal and High Parental Blood Pressures

BACKGROUND Increased activity of the sympathetic nervous system has been proposed as a cause of high blood pressure (BP) and may be related to diet and body weight. To determine the role of these factors in predisposition to high BP, we studied 100 young adults with high or low BP from families in which both parents had either high or low BP. METHODS AND RESULTS Plasma catecholamine, glucose, and insulin levels were measured before and after an oral glucose load. There was a significant correlation between fasting plasma norepinephrine and mean arterial pressure (P=.001). Subjects with high BP, irrespective of parental BP, were heavier (P=.003) and fatter (P=.002) and had a greater rise in plasma insulin (P=.003) following glucose than those with low BP. Offspring with high BP whose parents also had high BP showed an unexpected rise in plasma epinephrine (P=.004) following glucose. This adrenal medullary response was not the result of high parental or high personal BP alone as it was not seen in offspring with low BP whose parents had high BP or in offspring with high BP whose parents had low BP. CONCLUSIONS Irrespective of family history, high BP is associated with increased body weight and hyperinsulinemia and reflects personal environment and behavior. However, abnormal epinephrine release is characteristic of the combination of genetic, environmental, and behavioral factors that is associated with high personal BP and a familial predisposition to high BP.

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.

Clinical, biochemical and genetic features of five extended kindred's with glucocorticoid-suppressible hyperaldosteronism.

Glucocorticoid-suppressible hyperaldosteronism (GSH) is an uncommon form of dominantly inherited hypertension caused by the inheritence of a chimaeric 11 beta-hydroxylase/aldosterone synthase gene. Affected individuals appear to have an increased risk of premature morbidity and mortality from stroke, but treatment with low doses of dexamethasone can completely reverse the biochemical and clinical features. We assessed the clinical and genetic features of 5 British kindreds with GSH, the largest collection outwith the United States, and determined the location of the crossover regions in the chimaeric gene of all 5 kindreds. All of the kindreds were of celtic origin, another feature peculiar to GSH. In total 19 out of 60 individuals screened by genotyping were found to possess the chimaeric gene and sequencing of the chimaeric gene revealed that all the crossover regions were within the exon 3- exon 4 region of, in keeping with previous studies, and three kindreds possessed indistinguishable chimaeric genes.

Serotonin and Platelet Aggregation in Patients with Essential Hypertension Compared with a Normotensive Control Group

Serotonin is a naturally occurring amine with vasoactive and platelet aggregating properties. It may be involved in the pathogenesis of hypertension. Almost all the serotonin circulating in blood is stored in platelets. Serotonin and other platelet contents are released from platelets during platelet aggregation, which occurs in a stepwise manner. Initially there is a reversible change in platelet shape from a disc to a spiny sphere, and then platelet clumping, and finally a release of platelet contents (Holm sen 1977). The contents of the dense granules, including serotonin, adenosine diphosphate, adenosine triphosphate, calcium and inorganic pyrophosphate, are released before the contents of the a granules, which include ~-thromboglobulin, platelet factor 4, acid hydro lases and fibrinogen (DeClerck 1986; Holmsen et al. 1977). Serotonin released during platelet aggregation could cause vasoconstriction, increased blood pressure and further platelet aggregation. The object of this study was to compare serotonin-induced and spontaneous platelet aggregation in whole blood, platelet serotonin content and plasma ~-thromboglobulin in patients with untreated essential hypertension and in a normotensive control group.