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To study the relationship between pre-dialysis plasma sodium and blood pressure (BP), we performed an audit of patients who were on stable haemodialysis at St Bartholomew's and The Royal London Hospital from 1 June 2009 to 15 June 2010. There were 651 patients with 7445 dialysis sessions where both plasma biochemistry and BP were measured before haemodialysis. We found a significant association between plasma sodium and both systolic and diastolic BP. A 1 mmol l(-1) increase in plasma sodium was related to 0.65/0.36 mm Hg increase in BP (P<0.001 for both systolic and diastolic BP) after adjusting for potential confounding factors, including weight gain between dialyses and plasma albumin, both of which are crude indices of extracellular fluid volume. A separate analysis excluding individuals who were on BP treatment showed a similar relationship, with a 1-mmol l(-1) increase in plasma sodium associated with 0.82/0.56 mm Hg increase in BP (P<0.001 for both, N=177). These results provide further support for the accumulating evidence that plasma sodium has an important role in regulating BP, which may be independent of extracellular volume. Our findings in conjunction with other evidence suggest that small changes in plasma sodium could be an important mechanism for the beneficial effects of lower dialysate sodium and lower salt intake on BP in haemodialysis patients.

To study the relationship between salt intake and blood pressure in children and adolescents, we analysed the data of a large cross-sectional study (the National Diet and Nutrition Survey for young people), which was carried out in Great Britain in 1997 in a nationally representative sample of children aged between 4 and 18 years. A total of 1658 participants had both salt intake and blood pressure recorded. Salt intake was assessed by a 7-day dietary record. The average salt intake, which did not include salt added in cooking or at the table, was 4.7+/-0.2 g/day at the age of 4 years. With increasing age, there was an increase in salt intake, and by the age of 18 years, salt intake was 6.8+/-0.2 g/day. There was a significant association of salt intake with systolic blood pressure as well as with pulse pressure after adjusting for age, sex, body mass index and dietary potassium intake. An increase of 1 g/day in salt intake was related to an increase of 0.4 mm Hg in systolic and 0.6 mm Hg in pulse pressure. The magnitude of the association with systolic blood pressure is very similar to that observed in a recent meta-analysis of controlled trials where salt intake was reduced. The consistent finding of our present analysis of a random sample of free-living individuals with that from controlled salt reduction trials provides further support for a reduction in salt intake in children and adolescents.

Over 70 years ago, potassium was found to have a natriuretic effect and was used in patients with heart failure. However, it took many years for its role in the control of blood pressure to be recognized. Recently, epidemiological and clinical studies in man and experimental studies in animals have shown that increasing potassium intake towers blood pressure and that communities with a high potassium intake tend to have lower population blood pressures. Several studies have shown an interaction between salt intake and potassium intake. However, the recent DASH-Sodium (Dietary Approaches to Stop Hypertension) study demonstrates an additive effect of a low salt and high potassium diet on blood pressure. Increasing potassium intake may have other beneficial effects, for example, reducing the risk of stroke and preventing the development of renal disease independent of its effect on blood pressure. A high potassium intake reduces calcium excretion and could play an important role in the management of hypercalciuria and kidney stone formation, as well as bone demineralization. Potassium intake may also play an important role in carbohydrate intolerance. A reduced serum potassium increases the risk of lethal ventricular arrhythmias in those at risk, i.e. patients with ischemic heart disease, heart failure or left ventricular hypertrophy, and increasing potassium intake may prevent this. In this article, we address the evidence for the important role of potassium intake in regulating blood pressure and other beneficial effects of potassium which may be independent of and additional to its effect on blood pressure.

Prospective comparisons of different drug classes have shown that differences in blood pressure control, rather than differences between drug classes, have the over-riding influence on overall outcome. The same studies have also reinforced the need, in the majority of patients, to use combinations of drugs in order to achieve the target of <140/85 mmHg. By contrast, most patients in routine practice receive single agents and consequently fail to achieve target blood pressure. This failure reflects in part the emphasis in individual studies and subsequent guidelines on comparison of individual drugs. In this article we show how the consistency of both theory and a broad range of evidence permits a didactic approach to combination therapy. Our advice is based on the growing recognition that essential hypertension and its treatment fall into two main categories. Younger Caucasians usually have renin-dependent hypertension that responds well to angiotensin-converting-enzyme inhibition or angiotensin receptor blockade (A) or ss blockade (B). Most other patients have low-renin hypertension that responds better to calcium channel blockade (C) or diuretics (D). These latter drugs activate the renin system rendering patients responsive to the addition of renin suppressive therapy. Coincidence of the initials of these main drug classes with the first four letters of the alphabet permits an AB/CD rule, according to which recommended combinations are one drug from each of the "AB" and "CD" categories of drugs. However, the diabetogenic potential of the older "B" and "D" classes leads us to advise against combining "B" and "D" in older patients, and to recommend "A" + "C" + "D" as standard triple therapy for resistant hypertension.

Two recent meta-analyses of randomised salt reduction trials have concluded that there is little purpose in reducing salt intake in the general population. However, the authors, as with other previous meta-analyses, included trials of very short duration (eg 1 week or less) and trials of acute salt loading followed by abrupt reductions to very low salt intake (eg from 20 to less than 1 g of salt/day). These acute salt loading and salt depletion experiments are known to increase sympathetic tone, and with salt depletion cause a rise in renin release and, thereby, plasma angiotensin II. These trials are not appropriate, therefore, for helping to inform public health policy, which is for a more modest reduction in salt intake, ie, from a usual intake of approximately 10 to approximately 5 g of salt per day over a more prolonged period of time. We carried out a meta-analysis to assess the effect of a modest salt reduction on blood pressure. Our data sources were MEDLINE, EMBASE, Cochrane library, CINAHL, and the reference lists of original and review articles. We included randomised trials with a modest reduction in salt intake and a duration of 4 or more weeks. Meta-analysis, meta-regression, and funnel plots were performed. A total of 17 trials in hypertensives (n=734) and 11 trials in normotensives (n=2220) were included in our study. The median reduction in 24-h urinary sodium excretion was 78 mmol (equivalent to 4.6 g of salt/day) in hypertensives and 74 mmol in normotensives. The pooled estimates of blood pressure fall were 4.96/2.73+/-0.40/0.24 mmHg in hypertensives (P<0.001 for both systolic and diastolic) and 2.03/0.97+/-0.27/0.21 mmHg in normotensives (P<0.001 for both systolic and diastolic). Weighted linear regression analyses showed a dose response between the change in urinary sodium and blood pressure. A reduction of 100 mmol/day (6 g of salt) in salt intake predicted a fall in blood pressure of 7.11/3.88 mmHg (P<0.001 for both systolic and diastolic) in hypertensives and 3.57/1.66 mmHg in normotensive individuals (systolic: P<0.001; diastolic: P<0.05). Our results demonstrate that a modest reduction in salt intake for a duration of 4 or more weeks does have a significant and, from a population viewpoint, important effect on blood pressure in both hypertensive and normotensive individuals. This meta-analysis strongly supports other evidence for a modest and long-term reduction in population salt intake, and would be predicted to reduce stroke deaths immediately by approximately 14% and coronary deaths by approximately 9% in hypertensives, and reduce stroke and coronary deaths by approximately 6 and approximately 4%, in normotensives, respectively.

Hypertensive (n=93) and normotensive (n=39) white individuals were given a high sodium intake of approximately 350 mmol/d for 5 days followed by a low sodium intake of 10 to 20 mmol/d for 5 days. With this acute and large reduction in salt intake, no significant change was seen in blood pressure in the normotensive individuals, but blood pressure decreased in the hypertensive individuals. Compared with normotensive subjects, hypertensive patients had a 7/7-mm Hg greater fall in blood pressure (P<0.05 for systolic and P<0.01 for diastolic, adjusted for age), with similar changes in urinary sodium excretion. From the high-salt to low-salt diet, plasma renin activity rose from 0.90 to 5.99 ng. mL(-1). h(-1) in normotensives, whereas in hypertensives it rose from 0.73 to only 3.14 ng. mL(-1). h(-1) (P<0.05 between hypertensives and normotensives). Plasma aldosterone rose by 1396 pmol/L in normotensive subjects and by 511 pmol/L in hypertensive patients (P<0.05). Significant inverse correlations were obtained for all subjects between the fall in blood pressure from the high-salt to low-salt diet and the rise in plasma renin activity and aldosterone that occurred in addition to the absolute level on the low-salt diet. These results demonstrate that the larger fall in blood pressure with an acute reduction in salt intake in hypertensives compared with normotensives is, at least in part, due to a less-responsive renin-angiotensin-aldosterone system in the hypertensive patients.

The height of the blood pressure is one of the most important determinants of strokes and heart attacks, the two most common causes of death and disability in the western world. In undeveloped communities that do not have access to salt, blood pressure remains low throughout life in comparison with that in developed countries, where blood pressure is higher and increases inexorably with increasing age. An understanding of why blood pressure increases could lead to better preventive strategies, and thereby to a major reduction in cardiovascular disease. Much evidence suggests that salt intake plays an important role in elevating blood pressure. At the same time, elegant cross-transplantation experiments on inherited hypertension in rats and more circumstantial evidence in humans suggests that an inherited abnormality in the kidney, combined with our high salt intake, is likely to explain the development of high blood pressure in individuals. At the same time, studies now show that modest reductions in salt intake cause large decreases in blood pressure in hypertensive individuals and smaller, but very important from a public health perspective, decreases in blood pressure in normotensive people. A large effort is now required to persuade the salt, soft drink, and food manufacturers to reduce the unnecessarily high salt content of processed food.

Nutrition plays a very important role in regulating blood pressure. If we reverted to our evolutionary diet the problem of high blood pressure would disappear. However, this is unlikely and we, therefore, need to identify the most important factors in our diet that predispose to high blood pressure and, therefore, to vascular disease. Studies clearly demonstrate the very important role of our current intake of salt in our diet as being the major factor in regulating blood pressure in populations. Other dietary factors have also been identified as playing an important role, particularly potassium intake and fruit and vegetable consumption. A more healthy diet, that is a diet with much less salt and increased potassium through an increase in fruit and vegetable consumption, a reduction in fat intake with substitution of saturated by monounsaturated fat, a reduction in meat and dairy products with an increase in fish consumption will have large effects on blood pressure but, at the same time, will decrease other cardiovascular risk factors, particularly cholesterol and glucose intolerance. This healthier diet will reduce cardiovascular disease and is similar to the diet now being advocated for the prevention of some forms of cancer. Diet is by far the most important environmental factor determining our longevity and for those who wish to live longer, a change in diet as early in life as possible will have substantial effects.

The evidence linking salt intake to high blood pressure has become stronger. At the same time, there is increasing evidence that salt has other adverse effects independent of its effects on blood pressure.

The objectives of this study were to assess relations between ACE gene I/D polymorphism, essential hypertension, plasma renin activity and aldosterone in white (European descent) and black (Afro-Caribbean descent) peoples. Measurements were carried out on a total of 320 subjects (210 white: 116 men, 94 women; 110 black: 65 men, 45 women); all were on their usual sodium intake; none was on anti-hypertensive therapy and none had secondary hypertension. Genomic DNA was isolated from blood cells and ACE I/D genotype was established using polymerase chain reaction. Plasma hormones were measured by radioimmunoassay and blood pressure (BP) with an ultrasound sphygmomanometer. All subjects were grouped into normotensive, borderline and hypertensive according to WHO guidelines. The distribution of the I/D genotype in the white people was approximately 1:2:1; by contrast, in the Afro-Caribbean people there was a significantly higher frequency of the D allele (chi 2P = 0.04). Within the white people there was no significant association between ACE genotype and high BP; however, within the black people there was a positive association between the frequency of the D allele and increasing BP ( chi 2 for trend P = 0.03). In either group, there were no associations between ACE I/D genotype and plasma renin activity and aldosterone suggesting that ACE genotype does not contribute to the expression of the circulating renin-angiotensin system. This study highlights differences in ACE I/D polymorphism between white and black peoples and suggests the possibility of racial differences in the association between ACE genotype and BP.

Hormonal and renal effects of candoxatril, a neutral endopeptidase 24.11 inhibitor, were investigated in eight subjects equilibrated on a low sodium diet (10 mmol sodium per day) and a high sodium (350 mmol per day) diet. After candoxatril treatment, plasma ANP increased to a maximum at 2-4 h and declined to baseline within 24 h. The increases were relatively greater on the high sodium diet, which was also associated with increases in urinary sodium, with highest values at 4h. On the low sodium diet, the magnitude of the changes was significantly lower (24 h cumulative sodium excretion was 11.4 +/- 5.5 mmol on the low sodium diet and 73.1 +/- 25.6 mmol on the high sodium diet; P < 0.01). There were no significant effects on urinary potassium excretion, creatinine clearance or haematocrit. After candoxatril treatment there were reductions in PRA, especially on the low sodium diet. On either diet there were no effects on systemic blood pressure. These results demonstrate that dietary sodium intake is an important determinant of the renal and hormonal responses to neutral endopeptidase inhibition.

Objective: To examine the changes in plasma brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and blood pressure in patients with essential hypertension on a low, normal and high sodium intake., Design and Methods: Twelve patients with mild-to-moderate essential hypertension were studied. Plasma, urinary and blood pressure measurements were made with the patients on their usual sodium intake, then on the fifth day of a low (10 mmol/day) and on the fifth day of a high (350 mmol/day) sodium intake, the sequence being allocated randomly., Results: Plasma levels of BNP and ANP increased significantly on the high sodium intake compared with when the patients were on their normal diet. The mean blood pressure on the high sodium intake was not significantly different from that with the patients on their normal diet. In contrast, plasma BNP and ANP decreased on the low sodium intake, but were not significantly different compared with when the patients were on their normal diet. However, there was a significant reduction in the mean blood pressure on the low sodium intake compared with when the patients were on their normal diet. Compared with the normal diet, BNP and ANP plasma levels showed similar percentage decreases on the low sodium intake and similar percentage increases on the high sodium intake., Conclusions: These findings suggest that BNP and ANP are released in response to a common stimulus during changes in dietary sodium intake. The changes in plasma BNP and ANP observed with sodium restriction and sodium loading indicate the potential importance of BNP and ANP as a dual peptide system contributing to the maintenance of sodium balance and blood pressure regulation in patients with essential hypertension, during changes in dietary sodium intake.

Background: The role of cardiac extrinsic innervation in the regulation of sodium balance and blood pressure is controversial., Methods and Results: We performed a double-blind study of endocrine and blood pressure responses to 5 days of low- (LS, 10 mmol/d) and 5 days of high- (350 mmol/d) sodium intake in 12 cardiac transplant recipients, 12 matched healthy subjects, and 12 matched subjects with untreated essential hypertension. In transplant recipients on low sodium, supine blood pressure was 137/94 +/- 8/4 (mean +/- SEM) mm Hg and plasma atrial natriuretic peptide (ANP) was 59.3 +/- 6.3 pg/mL; on high sodium, blood pressure was 148/97 +/- 5/3 mmHg (P < .05 for systolic pressure versus LS), and ANP was 94.3 +/- 10.6 pg/mL (P < .01 versus LS), respectively. Plasma ANP for those on each diet was significantly higher in the cardiac transplant recipients than in healthy or hypertensive controls; relative changes in plasma ANP in changing from low- to high-sodium diet were similar in each group. Urinary sodium excretion by the fifth day of each diet was similar in each group. Suppression of plasma renin activity and aldosterone by high-sodium diet was blunted in cardiac transplant recipients compared with healthy subjects (respectively, plasma renin activity: 1.41 +/- 0.30 versus 0.68 +/- 0.21 ng.mL-1 x h-1, P < .05; aldosterone: 391 +/- 35 versus 166 +/- 21 pmol/L, P < .05)., Conclusions: These results suggest that extensive denervation of the heart does not result in major abnormalities in regulation of large changes in sodium intake and that intact cardiac innervation is not required for plasma ANP responses to altered sodium intake. Blood pressure after cardiac transplantation is sensitive to reduced sodium intake.

Both epidemiologic and clinical studies have suggested that an increase in potassium intake may lower blood pressure. However, the results of prospective clinical trials looking at the effect of oral potassium supplements on blood pressure have yielded conflicting results. For this reason, we reviewed 19 clinical trials examining the same end-point and involving a total of 586 participants (412 of whom had essential hypertension). Overall, the results of the trials indicate that oral potassium supplements significantly lower systolic blood pressure [-5.9 mmHg, -6.6 to -5.2 mmHg (mean, 95% confidence interval)] and diastolic blood pressure (-3.4 mmHg, -4.0 to 2.8 mmHg). The magnitude of the blood pressure lowering effect is greater in patients with high blood pressure (-8.2 mmHg, -9.1 to -7.3 mmHg for systolic and -4.5 mmHg, -5.2 to -3.8 mmHg for diastolic blood pressure) and appears to be more pronounced the longer the duration of the supplementation (P less than 0.05 and P less than 0.01 for systolic and diastolic, respectively). Based on this analysis, an increase in potassium intake should be included in the recommendations for a non-pharmacological approach to the control of blood pressure in uncomplicated essential hypertension.

We studied the effect of amlodipine, a long-acting dihydropyridine calcium antagonist, on blood pressure, urinary sodium excretion, plasma renin activity, aldosterone and atrial natriuretic peptide in six patients (aged 47-63 yrs) with essential hypertension. Patients were placed on a fixed sodium intake of 150 mmol/day. After a control period, amlodipine 10 mg/day was given for two weeks. There was a gradual reduction in supine BP over the first two days of treatment, from 165/103 +/- 5/4 mmHg to 137/92 +/- 6/4 mmHg (P less than 0.001) and BP remained at this level during treatment. Three days after amlodipine was stopped the BP was still reduced at 136/87 +/- 5/4 mmHg but was back to pretreatment levels two weeks later. Plasma amlodipine rose after two weeks of treatment to 29.7 +/- 4.7 ng/ml but had only decreased to 15.0 +/- 3.4 ng/ml three days after the treatment was withdrawn. During the first two days of treatment there was no evidence of an increase in urinary sodium excretion and when amlodipine was withdrawn there was no evidence of sodium retention. Plasma renin activity increased from 1.26 +/- 0.30 to 2.99 +/- 0.68 ng/ml/h (P less than 0.001) and plasma atrial natriuretic peptide fell from 19.3 +/- 7.0 to 11.4 +/- 3.8 pg/ml (P less than 0.03) with two weeks of treatment. This study demonstrates that amlodipine is a long-acting calcium antagonist with a slow onset of action and a slow end of action after withdrawal. This makes it difficult to detect alterations in sodium balance when assessed by changes in urinary sodium excretion. However, one explanation for the increase in plasma renin activity and fall in atrial natriuretic peptide is a small reduction in total body sodium.

There is increasing circumstantial evidence that the very high sodium diet combined with low potassium intake that most Western communities now eat may be, at least in part, responsible for the prevalence of high blood pressure. This circumstantial evidence combined with animal evidence has been considered sufficient in some countries to make a general recommendation to reduce sodium intake. If high sodium intake is an important cause of high blood pressure, it is not clear at the present time how it may do so. In this report, evidence is reviewed for one hypothesis suggesting an inherited defect in the kidney's ability to excrete sodium in patients who are going to develop essential hypertension, together with evidence for a raised concentration of an inhibitor of sodium transport. In patients with established hypertension, moderate restriction of sodium intake appears to lower blood pressure and moderate potassium supplementation to also lower blood pressure. While further evidence is required, particularly long-term studies, it would seem prudent to recommend to patients with essential hypertension or a strong family history of hypertension that they restrict dietary sodium intake moderately and increase dietary potassium intake by the consumption of more fruits and vegetables and, perhaps, the use of a potassium-based salt substitute. This regimen could obviate or reduce the need for drug treatment in some patients with mild to moderate hypertension.

1. Captopril given for 5 days caused a fall in blood pressure in normotensive subjects. The percentage fall in mean supine pressure was greatest on a low sodium diet (10 mmol/day), 19.6%, least on a high sodium diet (350 mmol/day), 11%, and in between on a normal sodium diet (120 mmol/day), 16.5%. 2. Captopril caused a marked fall in plasma aldosterone in normal subjects on all three sodium intakes. 3. Captopril caused an increase in sodium excretion on the normal (120 mmol/day) and low (10 mmol/day) sodium diet but not the high sodium diet. 4. These results suggest that the renin--angiotensin--aldosterone system is a normal mechanism for maintaining blood pressure and aldosterone secretion in normotensive man. The system may also be involved in the maintenance of sodium balance. 5. These results may lead to a better understanding of the role of the renin--angiotensin--aldosterone system in the maintenance or causation of high blood pressure in essential hypertension.

A non-sulfhydryl-containing inhibitor of angiotensin-converting enzyme (MK421) was given as a single dose in a randomised double-blind cross-over trial using 20 mg and 5 mg of MK-421 or matched placebo to nine normotensive volunteers receiving a sodium intake of 150 mmol (mEq) daily. The two dosages of MK-421 caused similar, significant falls in supine and standing blood pressure, which were maximum four to six hours after dosing (9.5-11.0% fall). With this fall in blood pressure there was a significant fall in activity of angiotensin-converting enzyme and in concentrations of plasma angiotensin II and aldosterone and a rise in plasma renin activity. Placebo caused no significant change in blood pressure or blood measurements. The study showed that MK-421 inhibits angiotensin-converting enzyme activity and lowers blood pressure in normotensive subjects. It strongly suggested that the renin system plays an important part in maintaining blood pressure in normotensive subjects receiving normal sodium intake. The results also suggest that this non-sulfhydryl-containing converting-enzyme inhibitor will be an effective blood-pressure-lowering drug in patients with blood pressure. A single dose of 5 mg was as effective at lowering blood pressure as a single dose of 20 mg.

1 The blood pressure lowering effect of xipamide, a non-thiazide diuretic given for 6 weeks was compared in a randomised cross-over trial with that of cyclopenthiazide in 14 patients with essential hypertension. 2 Xipamide 10 or 20 mg given once daily was as effective in lowering supine blood pressure as daily cyclopenthiazide 0.5 mg. There was no difference in the blood pressure lowering effect of 10 mg xipamide daily for 2 weeks compared to 20 mg daily given for a further 4 weeks. 3 Plasma potassium was reduced by both drugs, but markedly more after both 10 mg and 20 mg xipamide than after cyclopenthiazide 0.5 mg. By the sixth week of treatment 13 of 14 patients on xipamide but only 6 of 14 on cyclopenthiazide has plasma potassium concentrations of, or less than, 3.5 mmol/l. The fall in plasma potassium was significantly greater and the final plasma potassium concentration was significantly lower after either dose of xipamide than after cyclopenthiazide. 4 These results suggest that 10 mg or 20 mg of xipamide daily is effective in lowering blood pressure in hypertensive patients but is associated with hypokalaemia. In view of recent evidence linking diuretic-induced hypokalaemia with cardiac dysrhythmias in patients with essential hypertension we would suggest that thiazide diuretics be used in preference to xipamide for the routine management of essential hypertension. Our results also suggest that the currently recommended dose of xipamide (20 mg) for the treatment of hypertension is excessive, and lower amounts than 10 mg per day might possibly be as effective in lowering blood pressure with less adverse metabolic consequences.

Twenty-three unselected patients with mild to moderate essential hypertension whose average supine blood pressure after 2 months of observation on no treatment was 154/99 mm Hg were entered into an 8-week double-blind randomised crossover study of 1 month's treatment with slow release potassium tablets (64 mmol/day) versus placebo without alteration of dietary sodium or potassium intake. By the fourth week mean supine blood pressure had fallen by 4% with potassium supplementation compared with placebo. In a separate metabolic study the effect of 12 slow release potassium tablets (98 mmol/day) was studied in 12 patients with mild essential hypertension who had a fixed sodium and potassium intake. The increase in potassium intake caused immediate natriuresis with an average cumulative sodium loss of 110 mmol per patient. In spite of this loss of sodium there was no rise in plasma renin activity, but there was a significant increase in plasma noradrenaline level. On an average western diet containing approximately 150 mmol of sodium/day, potassium chloride supplementation causes a small but worthwhile fall in blood pressure in many patients with essential hypertension. It is likely that part of the mechanism of this fall in blood pressure is related to the increase in potassium intake causing a loss of sodium with no compensatory rise in renin release.

Six patients with essential hypertension underwent a randomized cross over design study to investigate the effect of supplementing a 10 mmol/day sodium diet for a period of 5 days with either 120 mmol sodium chloride (Slow Sodium, Ciba, Horsham, UK) or 122 mmol sodium in the presence of other anions, mainly phosphate (Phosphate, Sandoz, Feltham, UK). With both sodium salts, urinary sodium excretion was increased. The calculated amount of sodium retained was similar for both the sodium chloride and sodium phosphate periods. However, with the addition of sodium chloride to the low-salt diet, there were increases in supine mean blood pressure whereas with the addition of sodium phosphate no change in mean blood pressure occurred. The supine mean blood pressure after supplementation with sodium chloride (119.8 +/- 4.3 mmHg) was significantly greater than that after sodium phosphate (113.3 +/- 4.5 mmHg), similarly, the standing mean blood pressure was greater after addition of sodium chloride than of sodium phosphate (122.3 +/- 4.20 versus 115.4 +/- 3.0 mmHg). With both salts there were similar but non-significant increases in weight and reductions in plasma renin activity (PRA) and plasma aldosterone (PA).

Captopril, given for 5 days to normotensive healthy subjects caused a significant fall in blood pressure. The fall in mean supine blood pressure was greater on a low sodium diet (10 mmols/day) - 19.6% and was less on a high sodium diet (350 mmols/day) - 11% compared to the normal sodium intake (120 mmols/day) when the fall in blood pressure was 16.5%. Patients with essential hypertension who were studied on their normal diet had a similar fall in blood pressure for a given plasma renin activity. It seems likely that the predominant mechanism whereby captopril lowers blood pressure is through the inhibition of the formation of angiotensin II. If this is so, our results suggest that the renin system is an important control of both normal and high blood pressure when on a normal sodium intake.

The effect of digoxin (0.25 mg t.d.s.) given orally for 5 days, on sodium excretion, plasma renin activity, plasma aldosterone and blood pressure has been studied in 6 normotensive subjects, on a constant sodium intake. Average serum digoxin level measured in 5 subjects on the 5th day of treatment was in the upper range of the therapeutic level (1.92 +/- 0.3 nmol/l). Red cell sodium content increased from 9.75 +/- 1.2 mmol/l of cells in the control period to 15.3 +/- 1.7 mmol/l of cells on the 5th day of digoxin treatment when measured in 4 of the 6 subjects. In spite of this evidence of inhibition of the red cell sodium pump, there was no detectable change in sodium excretion, blood pressure, plasma renin activity and aldosterone.

The effect of the addition of a diuretic, bendrofluazide, for 1 month was studied in 12 hypertensive patients who were already on treatment with nifedipine tablets (20 mg b.i.d.) When nifedipine was maximally effective, that is, at 2 hours after the last dose, the diuretic had no further blood-pressure-lowering effect. These results suggest that unlike most other blood-pressure-lowering agents, there is little point in giving a diuretic to patients who are already on nifedipine, and if blood pressure is not controlled on nifedipine alone, it may be more effective to add either a beta blocker or a converting enzyme inhibitor. This has the advantage of avoiding the metabolic problems of diuretics.

Eighteen unselected patients with untreated mild to moderate essential hypertension, whose average supine blood pressure after 2 months' observation on no treatment was 154/103 mmHg, were entered into a double-blind randomized crossover study of 1 month's treatment with calcium lactate gluconate (40 mmol of elemental calcium/day) and treatment with placebo for a further month. Despite a significant increase in total plasma calcium (P less than 0.01) and in 24-h urinary excretion of calcium (P less than 0.025) while taking calcium lactate gluconate, there was no fall in blood pressure with calcium supplementation compared to treatment with placebo.

Forty-one patients with mild essential hypertension, 36 patients with severe hypertension, and 28 normotensive subjects were studied on a high sodium intake of 350 mmol/day for five days and low sodium intake of 10 mmol/day for five days. The fall in mean arterial pressure on changing from the high-sodium to the low-sodium diet was 0.7 +/- 1.7 mm Hg in normotensive subjects, 8 +/- 1.4 mm Hg in patients with mild hypertension, and 14.5 +/- 1.4 mm Hg in patients with severe hypertension. The fall in blood pressure was not correlated with age. Highly significant correlations were obtained for all subjects between the ratio of the fall in mean arterial pressure to the fall in urinary sodium excretion on changing from a high- to a low-sodium diet and (a) the level of supine blood pressure on normal diet, (b) the rise in plasma renin activity, and (c) the rise in plasma aldosterone. In patients with essential hypertension the blood pressure is sensitive to alterations in sodium intake. This may be partly due to some change either produced by or associated directly with the hypertension. A decreased responsiveness of the renin-angiotensin-aldosterone system shown in the patients with essential hypertension could partly account for the results.

Patients with essential hypertension were sodium deprived by five days on a 10 mM sodium diet and were then infused with an incremental infusion of saralasin, a competitive inhibitor of angiotensin II. Patients with normal renin hypertension showed no change in lying or standing blood pressure during the infusion of saralasin. Angiotensin II is not, therefore, directly maintaining blood pressure in these patients when sodium deprived by diet, and is therefore unlikely to be playing any direct role in maintaining their blood pressure on their normal sodium intake. Patients with low renin hypertension showed a significant rise in blood pressure during saralasin infusion. Saralasin may be a further method of distinguishing low renin hypertensives from other hypertensives if they are infused when sodium deprived by diet.