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Background and Methods: Clinical disturbances of the circulating sodium concentration are both a cause and a consequence of cerebrovascular disease. We examined the relationship between serum sodium level and risk of stroke and major ischaemic heart disease in a prospective study of 7690 middle-aged males drawn from general practices in 24 British towns followed over a 9.5-year period., Results: The mean serum sodium level was 141.5 mmol/l and 375 males on antihypertensive treatment were excluded from the analyses. A significant inverse trend was seen between serum sodium and risk of stroke up to 144 mmol/l; above this the risk of stroke was increased. Those with levels of 143-144 mmol/l showed over a 70% reduction in risk of stroke compared with those with levels of < or = 140 mmol/l. The inverse relationship between sodium and stroke up to 144 mmol/l was seen in males with and without pre-existing ischaemic heart disease or stroke, in normotensives and untreated hypertensives, and in non-smokers and current smokers. A weak but significant inverse association was seen between serum sodium and diastolic but not systolic blood pressure. The association between serum sodium level and stroke remained significant after adjustment for diastolic blood pressure and other factors associated with stroke: age, smoking, social class, body mass index, physical activity, heavy drinking, presence of diabetes, blood glucose and pre-existing ischaemic heart disease. No association was seen between serum sodium level and risk of ischaemic heart disease after adjustment for other risk factors. All-cause and non-cardiovascular mortality were significantly increased at serum sodium levels of < or = 138 mmol/l, probably due to an association between lung cancer and hyponatraemia., Conclusion: These findings suggest that sodium concentration may be related to risk of stroke even at levels of sodium usually regarded as normal.

The circulatory volume and exchangeable sodium (NaE) were measured by the Berne group in 110 normal subjects and 12 patients with benign untreated essential hypertension. Total plasma volume (PV) and blood volume (BV) correlated with total NaE (r = 0.64-0.75, p less than 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 less than 0.02) and arterial pressure (r = 0.25, p less than 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 less than 0.001) or arterial pressure (r = 0.40, p less than 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 less than 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.

Measurements of exchangeable sodium, arterial pressure and plasma concentrations of active renin, angiotensin II, aldosterone, sodium and potassium were made in 35 hypertensive patients with renal artery stenosis, 30 having unilateral renal arterial lesions. Plasma urea was below 7 mmol/l in 24 of the patients with unilateral lesions. In these and in the whole group of 35 patients there were significant inverse correlations between exchangeable sodium and diastolic blood pressure and between plasma sodium concentration and diastolic pressure. Six patients had hyponatraemia with a plasma sodium concentration less than 135 mmol/l. All were sodium-deplete with secondary hyperaldosteronism, three also having malignant-phase hypertension. Twelve of the patients with unilateral renal artery stenosis underwent bilateral ureteric catheterization. Sodium excretion was greater from the contralateral kidney than from the affected kidney and the rate of sodium excretion from the former, but not from the latter, was significantly related to arterial pressure. The relation of diastolic blood pressure and exchangeable sodium is the opposite of the positive correlation found in essential hypertension and Conn's syndrome. In renal artery stenosis the inverse correlation could result from a natriuretic effect of increased arterial pressure occurring mainly in the contralateral kidney.

Measurements of total body sodium and potassium, and of components of the renin-angiotensin-aldosterone system, were made in a group of women who developed hypertension while taking oestrogen-progestagen oral contraceptives. The results were compared with similar measurements made in age-matched women with essential hypertension. Total body sodium and potassium were normal in both groups. Plasma renin-substrate was significantly elevated in the women taking oral contraceptives, while concentrations of active renin were similar and normal in both groups. Thus plasma angiotensin II was significantly elevated in the pill users; overall the product of renin and renin substrate concentrations correlated significantly with angiotensin II. The rise in plasma angiotensin II in conjunction with normal total body sodium could therefore contribute to the increase in blood pressure induced by oestrogen-progestagen oral contraceptives.

Angiotensin II (Ang II) stimulated the growth of cultured vascular smooth muscle cells in a dose-dependent manner; a small but significant increase being seen at 10(-9) mol/l, whereas 10(-5) mol/l produced a 166% increase compared with control cells. Saralasin blocked the Ang II-mediated increase in cell number. Amiloride-sensitive Na+-H+ exchange was characterized (Km = 18 mmol/l, Vmax = 0.27 pH units/30 s) in cell monolayers using the fluorescent probe biscarboxyethylcarboxy fluorescein. Angiotensin II (10(-7) mol/l) produced a small overall net intracellular alkalinization. Raising intracellular pH via Na+-H+ activation might be one of the ways in which Ang II increases cell growth.

The whole body content of sodium, chlorine and potassium has been measured in 30 patients with essential hypertension, using the techniques of in vivo neutron activation analysis and whole body counting. Total exchangeable sodium and potassium were also measured, and found to be well correlated with the total body amounts of these elements. Comparable measurements on normotensive subjects could not be obtained, but results for both elements were similar to those expected on the basis of published values for healthy normal body composition. Similarly, no abnormality was found in the average body content of the other major elements (chlorine, calcium, phosphorus and nitrogen). We therefore have no evidence that essential hypertension is associated with any abnormality in the mean body content of these elements. However, there was some evidence of a relationship between body sodium and blood pressure in this study group.

1. Exchangeable sodium (NaE), plasma electrolytes and arterial pressure were measured in 121 normal subjects and 91 patients with untreated essential hypertension (diastolic greater than 100 mmHg), 21 of whom had low-renin hypertension. Plasma concentrations of renin, angiotensin II and aldosterone were measured in all hypertensive patients, total body sodium, total body potassium and exchangeable potassium (KE) in some patients. 2. Mean NaE was not different in normal and hypertensive subjects provided the two groups were matched for leanness index. In the subgroup of young hypertensive patients aged 35 years or less mean NaE was below normal. NaE was not related to arterial pressure in normal subjects but in hypertensive patients there were positive and significant correlations of arterial pressure with NaE and with total body sodium. 3. NaE and total body sodium increased with age in hypertensive but not in normal subjects. Partial regression analysis suggested that the correlation of NaE with arterial pressure was not explained by an influence of age. 4. Mean NaE was not increased and mean KE was not decreased in patients with low-renin hypertension. 5. Plasma potassium concentration, KE and total body potassium correlated inversely and significantly with blood pressure in hypertensive patients. These correlations were more marked in young than in old patients. 6. Multiple regression analysis showed that the combination of NaE and plasma potassium concentration 'explained' more of the variation of systolic blood pressure in hypertensive patients than it did in normal subjects. Plasma potassium concentration 'explained' more of the variation in young hypertensives and NaE 'explained' more in older patients. 7. Our findings suggest than changes of plasma and body potassium are important in the earlier stages of essential hypertension and that changes of body sodium become important later.

1. Total-body neutron-activation analysis in vivo was carried out in 11 hypertensive subjects to measure simultaneously the total body content of sodium, chlorine, calcium, phosphorus and nitrogen. 2. There was a highly significant correlation between total body sodium measured by activation analysis and total exchangeable sodium measured by a standard isotope-dilution technique (r = 0.92, P less than 0.001). Exchangeable sodium averaged 80.3% of total body sodium. 3. The measured values of chlorine, calcium, phosphorus and nitrogen were similar to those for healthy subjects reported by others. 4. Activation analysis in vivo appears promising as an additional tool for investigating sodium metabolism in hypertension, as it is the only method available for determining the total body content of this element. The radiation dose (1 rem) is sufficiently low to permit repeated measurements in the same subject.

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 (Conn's 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 Conn's 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 Conn's 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 Conn's syndrome and returned to normal with therapy; body calcium, phosphorus and nitrogen were normal throughout.

A study was carried out of arterial pressure and body content of electrolytes in 91 patients with essential hypertension and 121 normal controls. Exchangeable sodium was found to be positively correlated with arterial pressure in the patients, the correlation being closest in older patients; values of exchangeable sodium were subnormal in young patients; and plasma, exchangeable, and total body potassium correlated inversely with arterial pressure in the patients, the correlations being closest in young patients. Three hypotheses were proposed to explain the mechanisms relating electrolytes and arterial pressure in essential hypertension--namely, a cell-salt hypothesis, a dietary salt hypothesis, and a kidney-salt hypothesis. It was concluded that two mechanisms probably operate in essential hypertension. In the early stages of the disease blood pressure is raised by an abnormal process related more closely to potassium than to sodium. A renal lesion develops later, possibly as a consequence of the hypertension. This lesion is characterised by resetting of pressure natriuresis and is manifest by an abnormal relation between body sodium and arterial pressure and by susceptibility to increased dietary sodium intake.

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.

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.

The effect of the angiotensin II antagonist saralasin on plasma aldosterone, plasma angiotensin II and blood pressure was studied in six normal supine subjects both before and during sodium depletion. Before sodium depletion, infusion of saralasin produced no consistent changes; during sodium depletion, infusion of the angiotensin antagonist caused a fall in plasma aldosterone and an increase in plasma angiotensin II in each subject. It is concluded that angiotensin II plays a major part in stimulating aldosterone secretion during sodium depletion in man.

It is reported that dietary deprivation of sodium in young rats produces changes of sodium balance and aldosterone excretion which persist when normal sodium intake is restored. To test this further, sodium intake was reduced 10-fold in rats. In the first experiment sodium intake was reduced for 5 weeks in rats aged 3 weeks. Systolic blood pressure, heart rate and plasma renin concentration increased and growth rate was reduced. Sodium intake was then increased for 10 weeks. Blood pressure, heart rate and plasma renin concentration fell and growth rate increased but body weight did not regain control values. As compared with controls, plasma concentrations of aldosterone and corticosterone did not increase after the 10-week period. Thus, sodium depletion did not produce an irreversible change in aldosterone but it did raise arterial pressure. Further experiments confirmed the pressor effect in young and adult rats. Blood pressure was measured in the tail in these experiments but the increase in pressure was not a technical artifact as measurements made in the tail correlated well with measurements made simultaneously by intra-arterial catheter. Catheters were inserted under general anaesthetic for this comparison of pressure and rats previously deprived of sodium showed a significantly higher mortality rate due to the anaesthesia and surgery involved. Thus, a 10-fold reduction of dietary sodium raises blood pressure in young and adult rats and it may increase mortality from a minor surgical procedure. It does not produce irreversible changes in aldosterone.

The possibility that the responsiveness of plasma aldosterone concentration to angiotensin II alters with changes in sodium balance was investigated in male beagle dogs under conditions of controlled sodium and potassium intake. Angiotensin II was infused at four different rates (usually 3, 6, 12, and 24 ng/kg/min), each for 1 h, 1) after periods of normal sodium diet (32 mEq/day), 2) after moderate sodium depletion (negative cumulative sodium balance 25-58 mEq), 3) after severe sodium depletion (65-116 mEq negative cumulative sodium balance), and 4) after sodium loading (150-212 mEq positive sodium balance), daily potassium intake remaining constant (26 mEq/day) throughout. Angiotensin II/aldosterone dose-response curves after moderate sodium depletion were both elevated and steepened in comparison with those found during normal sodium intake. Severe sodium depletion was associated with even greater elevation of dose-response curves, but individual aldosterone responses to angiotensin II were irregular and unpredictable. Sodium loading significantly diminished aldosterone responsiveness to angiotensin II. Blood pressure increments during angiotensin II infusion were attenuated by sodium depletion.

Blood pressure, exchangeable sodium content, sodium metabolic balance, and plasma concentrations of active renin, angiotensin II, and aldosterone were measured in seven normal men and 10 essential hypertensive men of similar age and weight. The measurements were made under two circumstances: during a 2- to 3-day period of normal sodium intake of 145-150 mmol/24 h and during a 2- to 3-day period of sodium depletion produced by 40 mg frusemide and a dietary sodium intake less than 10 mmol/24 h. Mean arterial pressure decreased in nine of the 10 hypertensive subjects but increased in six of the seven normotensive subjects during sodium depletion. Blood pressure changed more for a given change in exchangeable sodium level in hypertensive subjects than in normotensive subjects, despite a similar loss of sodium in the two groups. Changes in blood pressure varied markedly in the hypertensive group. Patients showing the greatest fall in arterial pressure had the least rise in plasma active renin concentration and, not significantly, the least rise in plasma aldosterone level. These findings are compatible with a model of pressure natriuresis which is altered more in normal subjects during changes in dietary sodium content, thereby preventing a rise in arterial pressure. Failure of this compensatory mechanism in hypertensive subjects may raise blood pressure.

Angiotensin II, infused intravenously, increased plasma aldosterone concentration in two of six anephric subjects taking their usual dietary quantities of sodium. After 3 days of dietary sodium restriction and weight-reducing hemodialysis, the aldosterone response to infused angiotensin II in the two previously reactive subjects was enhanced, while the four previously unreactive subjects also showed a rise in plasma aldosterone. Before and after sodium depletion the anephric subjects were less responsive than normal subjects. Even when sodium-depleted, the anephrics showed no further rise in plasma aldosterone when arterial plasma angiotensin II was increased by infusion to concentrations greater than 50-199pg/ml, in contrast to sodium-depleted normals who show progressive aldosterone responses with plasma angiotensin II concentrations up to at least 370pg/ml. Before the infusion of angiotensin II, arterial plasma renin, angiotensin II, and aldosterone were detectable in the anephrics, but were unchanged by dietary sodium restriction or weight-reducting hemodialysis. Sodium depletion caused significant falls in weight, plasma sodium, and blood pressure, but no changes in plasma potassium or cortisol. Increases in blood pressure in relation to increments of arterial plasma angiotensin II were unaffected by sodium depletion, as might be expected in the absence of a rise in endogenous angiotensin II.

1. Arterial pressure and exchangeable sodium (NaE) were measured in patients with Conn's syndrome, essential hypertension, renal artery stenosis and chronic renal failure. Comparison was made with a control group. Urine sodium excretion was measured separately from the two kidneys in patients with renal artery stenosis. 2. Compared with control, mean NaE was significantly increased in Conn's syndrome, and was normal in essential hypertension, renal artery stenosis and chronic renal failure. 3. The correlation of arterial pressure with NaE was positive and significant in Conn's syndrome, essential hypertension and chronic renal failure. 4. In contrast the correlation was significantly negative in unilateral renal artery stenosis. Patients with lowest NaE had hyponatraemia, hypokalaemia and secondary hyperaldosteronism. 5. Urinary sodium excretion from the unaffected kidney in unilateral renal artery stenosis correlated positively with arterial pressure, possibly reflecting the phenomenon of pressure-natriuresis. Patients subsequently responding least well to surgery excreted least sodium from the untouched kidney for a given arterial pressure. 6. The findings suggest important roles for arterial pressure in the regulation of sodium balance (predominant in renal artery stenosis), and for sodium balance in the regulation of arterial pressure (predominant in Conn's syndrome). The observations in essential hypertension are compatible either with an exact balance between these mechanisms or with the existence of some other mechanism raising blood pressure.