David L. Davies

Effects of ACTH and Cortisol Administration on Blood Pressure, Electrolyte Metabolism, Atrial Natriuretic Peptide and Renal Function in Normal Man

Both Adrenocorticotrophin (ACTH) and glucocorticoids raise blood pressure in man and animals, but the relationship of this and altered renal function to other cardiovascular variables, and the differences and similarities of the effects of the two agonists have not been fully explained. The present study compares the effects of ACTH (0.5 mg i.m; every 12 h) and cortisol (50 mg orally, every 6 h) in six normal men over a period of 5 days, preceded and followed by control periods of 3 and 2 days, respectively. Plasma cortisol levels were higher during ACTH treatment than during cortisol treatment. Both treatments raised blood pressure significantly and caused a marked antinatriuresis and expansion of extracellular fluid and plasma volume. ACTH also enhanced potassium excretion but this was less obvious for cortisol. Plasma concentrations of atrial natriuretic peptide rose to more than twice the basal level with both treatments. Both treatments markedly altered renal function. They raised glomerular filtration rate (GFR), i.e. inulin clearance (141% with ACTH; 113% with cortisol) although creatinine clearance was not changed, showing this to be an unreliable index during steroid administration. Filtration fraction (FF) also increased during both treatments, and renal blood flow (RBF) fell, although this achieved statistical significance only during cortisol treatment. Effective renal plasma flow [para-amino hippurate (PAH) clearance] remained unchanged while calculated renal vascular resistance increased. Fractional sodium reabsorption also rose but achieved statistical significance only during ACTH treatment. The similarity of response to treatment suggests that cortisol is largely responsible for the effects of ACTH. The respective roles of the marked increases in sodium retention, changes in fluid volume and vascular reactivity in the increases in blood pressure remain to be defined.

Human α-Adducin Gene, Blood Pressure, and Sodium Metabolism

Abstract —The adducin genes contribute significantly to population variation in rat blood pressure and cell membrane sodium transport. The 460Trp mutation of the human α-adducin gene has been associated with hypertension, in particular hypertension sensitive to sodium restriction. We studied the relationship between the 460Trp mutation and population variation in blood pressure and sodium metabolism. From 603 Scottish families, we selected 151 offspring and 224 parents with blood pressures in either the upper (high) or bottom (low) 30% of the population distribution and measured the 460Trp mutation using allele-specific hybridization. In offspring, we also measured exchangeable sodium, plasma volume, and total body water. Plasma levels of components of the renin-angiotensin system, atrial natriuretic peptide, and cellular sodium and transmembrane sodium efflux were also estimated. The overall frequency of the 460Trp mutation was 27.1%. In offspring and parent groups, we found no difference in the genotype or allele frequencies of the 460Trp mutation between subjects with high or low blood pressure. There was no overall association between the α-adducin genotypes and blood pressure variation. In offspring, the 460Trp mutation was not associated with any significant differences in body fluid volumes or exchangeable sodium; levels of plasma renin, angiotensin II, aldosterone, or atrial natriuretic peptide; intracellular sodium; or ouabain-sensitive transmembrane sodium efflux. These findings suggest that in our Scottish population, the α-adducin 460Trp polymorphism is not related to blood pressure and does not affect whole body or cellular sodium metabolism.

Relation of blood pressure with body and plasma electrolytes in Conn's syndrome.

Thirty-four patients with untreated Conns syndrome were studied in a metabolic ward. The final diagnosis in each case was based on the finding and removal of an adrenal cortical adenoma with histological features typical of the disorder. Compared with 34 age and sex-matched normal controls the untreated patients had increased plasma aldosterone concentration, increased blood pressure (183/112 mmHg), increased exchangeable sodium (116.7% of normal), hypokalaemia and increased plasma sodium concentration. Exchangeable potassium was lower than normal and plasma concentrations of active renin, total renin and angiotensin II were lower than normal mean values. Arterial pressure correlated significantly and positively with plasma and exchangeable sodium and there was a significant negative correlation with plasma potassium concentration. Partial regression analysis showed that the relation of exchangeable sodium with blood pressure did not depend on age or renal function but that the relation of blood pressure and plasma potassium could be attributed to the correlation of exchangeable sodium and blood pressure. Multiple regression analysis suggested that exchangeable and plasma sodium were the most important determinants of blood pressure in untreated patients. Spironolactone, amiloride and surgical removal of the adenoma corrected the electrolyte abnormality and usually lowered blood pressure. The fall in exchangeable sodium was related to the fall in blood pressure. The pattern of correlation found by multiple regression analysis in postoperative patients was similar to that in normal subjects. The findings are relevant to some of the mechanisms proposed for the hypertension of mineralocorticoid excess.

Glomerular Hyperfiltration, High Renin, and Low- Extracellular Volume in High Blood Pressure

Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (P<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (P<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.

Body Elemental Composition, with Particular Reference to Total and Exchangeable Sodium and Potassium and Total Chlorine, in Untreated and Treated Primary Hyperaldosteronism

The whole body content of sodium, potassium, chlorine, calcium, phosphorus and nitrogen was measured by neutron activation analysis in 13 patients with untreated primary hyperaldosteronism (Conns syndrome; aldosterone-secreting adenoma). Concurrently, exchangeable sodium and potassium were estimated by isotope dilution. Results were compared with values in the same patients during treatment with potassium-conserving diuretics and again after removal of the adenoma; and also with those in a series of 30 patients having untreated essential hypertension. Both total body and exchangeable sodium were high in Conns syndrome before treatment and were reduced by spironolactone or amiloride and by subsequent surgery. There was no evidence of alteration in the proportion of non-exchangeable sodium in this disease, in contrast to earlier reports. Total body and exchangeable potassium were low in untreated Conns syndrome and increased to normal after therapy: the proportion of non-exchangeable potassium was similar before and after treatment, and also similar to that in essential hypertension. Total body chlorine was increased before treatment in Conns syndrome and returned to normal with therapy; body calcium, phosphorus and nitrogen were normal throughout.

Body Sodium Blood Volume State in Essential Hypertension: Abnormal Relation of Exchangeable Sodium to Age and Blood Pressure in Male Patients

The circulatory volume and exchangeable sodium (NaE) were measured by the Berne group in 110 normal subjects and 120 patients with benign untreated essential hypertension. Total plasma volume (PV) and blood volume (BV) correlated with total NaE (r = 0.64–0.75, p < 0.001); these correlations were similar in normal and hypertensive subjects. PV, BV, and NaE related to body surface area averaged normal in the hypertensive population. PV and BV were unrelated to age or blood pressure in both normal and hypertensive subjects; NaE correlated positively with age (r = 0.25, p < 0.02) and arterial pressure (r = 0.25, p < 0.02) in essential hypertensive but not in normal subjects. These relationships in essential hypertension confirmed a previous observation by the Glasgow group. Moreover, a combined analysis of both study populations, with a total of 211 hypertensive patients, revealed significant correlations between NaE and age (r = 0.38, p < 0.001) or arterial pressure (r = 0.40, p < 0.001) in male but not in female subjects. The NaE was significantly decreased in hypertensive males less than 35 years old as compared with appropriate controls (95.8 ± 5.1 vs 99.1 ± 6.5%, p < 0.02). BV and body sodium content are on average normal in patients with benign essential hypertension. The NaE may even be decreased in young male patients. These observations do not support the concept that body sodium and fluid volume expansion represent the initial event leading to high blood pressure in patients with essential hypertension.

Are Idiopathic Hyperaldosteronism and Low-Renin Hypertension Variants of Essential Hypertension?

Most diseases are recognised by clinical, chemical, radiological, or pathological features present in that disease but not in other diseases or in normal people. Pernicious anaemia, cancer, stroke, and tuberculosis are diagnosed in this way. Essential hypertension is unusual in that apart from raised arterial pressure it has no characteristic or positive features. Diagnosis is reached negatively by exclusion of alternative diagnoses. A normal intravenous pyelogram is needed because an abnormal result suggests a renal cause for hypertension. Normal cortisol, catecholamines, aldosterone, and renin exclude other secondary forms of hypertension. This process of elimination would be justified if all patients excluded suffered from a disease qualitatively different from essential hypertension. We suggest here that two of the conditions excluded are not and that their exclusion alters the investigators view of essential hypertension. The evidence is based partly on a recent analysis (Davies et al., 1979) and partly on other work.

Renal artery stenosis with normal angiotensin II values. Relationship between angiotensin II and body sodium and potassium on correction of hypertension by captopril and subsequent surgery.

SUMMARY The case is reported of a young woman with severe hypertension, unilateral renal artery stenosis, variously normal or marginally high plasma concentrations of active renin, angiotensin II, aldosterone, sodium, and potassium; and normal total exchangeable and total body sodium and potassium. Arteriograms and ureter catheterization showed the stenosis to be severe, but the unstimulated renal vein renin and angiotensin II differential to be modest. Captopril caused an initial fall in angiotensin II and arterial pressure. During prolonged captopril treatment, plasma angiotensin II and aldosterone remained depressed; exchangeable and total body sodium and potassium were unaltered. Blood pressure fell further to normal levels during prolonged captopril treatment, while subsequent surgical correction of the renal artery stenosis was curative; absolute values of blood pressure and plasma angiotensin II were similar in both situations. The findings support, without proving, the concept that chronic modest elevation of angiotensin II may be responsible for sustained hypertension in unilateral renal artery stenosis. Patients of this type contrast sharply with those, also with severe renal artery stenosis or occlusion, who have gross elevation of renin, angiotensin II, and aldosterone, with sodium and potassium deficiency. Captopril or surgery are effective in both syndromes, but the manner of response to treatment differs markedly.

Failure of chronic administration of growth hormone to affect blood pressure, vascular reactivity and sodium metabolism in normal rats.

To examine the effects of exogenous growth hormone on the cardiovascular system and sodium metabolism, ovine growth hormone was given daily to female rats for 5 weeks. Growth hormone resulted in a significant increase in body mass compared with controls. However, blood pressure in the treated rats was not significantly different from that in controls. Following treatment, the baseline resistances and pressor responses of the isolated mesenteric beds did not differ between the two groups. In addition, exchangeable sodium, erythrocytic intracellular sodium and transmembrane sodium efflux rate constants were not altered significantly by growth hormone treatment. The failure to observe cardiovascular or sodium effects of growth hormone despite significant potentiation of growth is, at present, unexplained.

Arterial blood pressure and plasma and body electrolytes in idiopathic hyperaldosteronism: a comparison with primary hyperaldosteronism (Conn's syndrome) and essential hypertension.

Exchangeable and plasma electrolytes, blood pressure and aldosterone were measured in groups of patients with idiopathic hyperaldosteronism, primary hyperaldosteronism and essential hypertension and in normal subjects. In idiopathic hyperaldosteronism exchangeable sodium was higher than in both essential hypertensive and normal groups but lower than in primary hyperaldosteronism. Plasma sodium results were similar except that no difference existed between the two forms of hyperaldosteronism. Plasma potassium concentration was lower in idiopathic hyperaldosteronism than in either essential hypertensive or in normal groups, but higher than in primary hyperaldosteronism. Blood pressure correlated with age in all groups and with exchangeable sodium in hypertensive patients. This was also the case with exchangeable sodium:exchangeable potassium ratio, but blood pressure did not correlate with aldosterone in any group. In idiopathic hyperaldosteronism, as in essential hypertension, sodium and blood pressure correlated strongly in male and weakly in female patients. The analysis reveals important differences between idiopathic and primary hyperaldosteronism and also between idiopathic hyperaldosteronism and essential hypertension.