Effect of magnesium on blood pressure.

Twenty patients receiving long term diuretic treatment for arterial hypertension (18 patients) or congestive heart failure (two patients) received magnesium supplementation as aspartate hydrochloride 15 mmol/day for six months. Both systolic and diastolic pressures decreased significantly, by a mean of 12/8 mm Hg. No significant changes were recorded in plasma or urinary electrolytes except for magnesium, 24 hour urinary volumes, or body weight after treatment. The effect of magnesium on blood pressure may be direct or through influences on the internal balance of potassium, sodium, and calcium.     

Regulation of arterial pressure: role of pressure natriuresis and diuresis

The importance of the renal pressure natriuresis and diuresis mechanisms in long-term control of body fluid volumes and arterial pressure has been controversial and difficult to quantitate experimentally. Recent studies, however, have demonstrated that in several forms of chronic hypertension caused by aldosterone, angiotensin II (AngII), vasopressin, or norepinephrine and adrenocorticotropin, increased renal arterial pressure is essential for maintaining normal excretion of sodium and water in the face of reduced renal excretory capability. When renal arterial pressure was servo-controlled in these models of hypertension, sodium and water retention continued unabated, causing ascites, pulmonary edema, or even complete circulatory collapse within a few days. Apparently, other mechanisms for volume homeostasis, such as the various natriuretic and diuretic factors that have been postulated, are not sufficiently powerful to maintain fluid balance in the absence of increased renal arterial pressure when renal excretory function is reduced in these forms of hypertension. The intrarenal mechanisms responsible for pressure natriuresis and diuresis are not entirely clear, but they seem to involve small increases in glomerular filtration rate and filtered load as well as reductions in fractional reabsorption in proximal and distal tubules. During chronic disturbances of arterial pressure additional factors, especially changes in AngII and aldosterone formation, act to amplify the effectiveness of the basic renal pressure natriuresis and diuresis mechanisms in regulating arterial pressure and body fluid volumes.     

Relation between arterial pressure,dietary sodium intake,and renin system in essential hypertension.

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.     

Influence of non-steroidal anti-inflammatory drugs on diuretic treatment of mild to moderate essential hypertension.

In an open triple crossover study in 10 patients with mild to moderate essential hypertension the influence was investigated of adding indomethacin 50 mg, naproxen 250 mg, or sulindac 200 mg, each twice daily for four weeks, to diuretic treatment with hydrochlorothiazide 50 mg a day. After two weeks'' treatment with indomethacin a slight increase in blood pressure was observed, whereas both sulindac and naproxen tended to enhance the antihypertensive effect of hydrochlorothiazide. After treatment for four weeks, however, the effects of all three drugs on blood pressure appeared to be blunted. Furthermore, body weight increased significantly during treatment with indomethacin but not during treatment with naproxen or sulindac. No significant changes were found for various biochemical variables, including concentrations of plasma electrolytes and serum creatinine and albumin, plasma renin activity, plasma aldosterone concentration, and 24 hour urinary excretion of sodium and potassium, with the exception, however, of an increase in plasma potassium concentration during treatment with indomethacin. These observations suggest that the interaction of indomethacin, naproxen, and sulindac with diuretic treatment in mild to moderate essential hypertension is transient and of minor clinical importance.     

Plasma Renin Activity and Blood Pressure in 89 Patients Receiving Maintenance Haemodialysis Therapy

Blood pressure, plasma renin activity, plasma sodium concentration, plasma potassium concentration, dietary sodium intake, and duration of dialysis have been measured under standard conditions in 89 patients on maintenance haemodialysis. No significant relation was found between plasma renin activity and blood pressure. Statistically significant correlations were found between plasma renin activity and plasma sodium concentration and between plasma renin activity and dietary sodium intake.Only one patient was found to have uncontrollable hypertension associated with a markedly raised plasma renin activity. Reasons are given for not performing bilateral nephrectomy in this patient. We believe the low incidence of uncontrollable hypertension and hyperreninaemia in our patients to be due to their slow introduction to haemodialysis, thus preventing violent swings in body weight, blood pressure, and renin secretion.Although plasma renin activity did fall with duration of dialysis, all 15 patients who have been on maintenance dialysis for longer than five years have normal levels.     

Calcium antagonists in hypertension: relation to abnormal sodium transport.

Leucocyte sodium efflux rate constants and intracellular electrolyte contents were estimated in 13 patients with untreated essential hypertension. There was no correlation between intracellular sodium or potassium content or efflux rate constant and blood pressure. The patients were then treated with oral nifedipine and blood pressure controlled. Sodium efflux rate constants and electrolyte contents were estimated one and three months after the start of treatment. There was a significant fall in blood pressure, but mean sodium efflux rate constant and intracellular sodium content were unchanged. There was no correlation between the fall in blood pressure, initial sodium efflux, or intracellular sodium content. These data do not support the hypothesis that the sodium pump and intracellular sodium content have a direct role in generating raised blood pressure, or that treatment of hypertension with calcium antagonists corrects a fundamental alteration of calcium-sodium exchange across the cell membrane.     

Spironolactone in essential hypertension: evidence against its effect through mineralocorticoid antagonism.

The effect of a six-week course of spironolactone 300 mg/day was examined in 25 unselected patients with essential hypertension. In the blood spironolactone produced a significant rise in urea and potassium concentrations and a fall in sodium and bicarbonate concentrations. In six patients blood pressure was normal at the end of the course, while in five patients there was almost no change. Studies of the effects of spironolactone on various indices usually affected by mineralocorticoids-namely, blood electrolytes, total body potassium, and rectal electrical properties-showed no differences between responding and non-responding patients. Mineralocorticoid excess therefore seems to be rarely responsible for essential hypertension and the influence of spironolactone cannot at present be fully explained.     

State-dependent expression of pressure diuresis in conscious rats

In 1967, Guyton and Coleman modeled pressure diuresis as the underlying, essential, long-term mechanism that regulates arterial pressure when sodium intake changes. Other mechanisms that influence renal function interact with pressure diuresis to achieve sodium balance and determine the blood pressure. Increases in sodium intake suppress sodium conserving mechanisms and activate natriuretic mechanisms; decreases in sodium intake have the opposite effect. If the Guyton-Coleman model is correct, then pressure diuresis should be more readily detected in animals on a high-salt diet than in animals on a low-salt diet. We measured spontaneous changes in arterial pressure and urine flow in conscious rats fed low-salt (0. 4% NaCl) and high-salt (8.0% NaCl) chow. For 10 rats fed a high-salt diet, arterial pressure and urine flow were positively correlated in 19 of 32 (59%) trials. In 10 rats fed a low-salt diet, a positive correlation was observed in 10 of 33 (30%) trials. Chi-square analysis revealed that differences in Na+ content of the diet were significantly associated with the probability of a positive relationship between blood pressure and urine flow. These results support the hypothesis that the expression of pressure diuresis across time is dependent on the state of sodium balance.     

Atrial natriuretic peptides in essential hypertension: basal plasma levels and relationship to sodium balance.

The identification of the atrial natriuretic peptides (ANP) as a new hormonal system has provided a new perspective on the mechanisms controlling renal sodium excretion and abnormalities in sodium homeostasis. The present article focuses on the potential importance of ANP (ANF 99-126) in essential hypertension with particular reference to circulating ANP levels and the relationship between the ANP and the renin-angiotensin system in the control of sodium balance and blood pressure. There is now considerable evidence demonstrating that a substantial proportion of patients with essential hypertension have raised circulating ANP levels. Given the known biological actions of ANP, these raised levels point to important compensatory mechanisms. This is further supported by studies during alterations in dietary sodium intake, as sodium restriction high-lighted important relationships between ANP and the renin angiotensin system. The potential importance of ANP in essential hypertension is strengthened by recent demonstration of natriuretic and antihypertensive actions associated with small increases in circulating ANP as induced by administration of exogenous ANP. Furthermore, the recent development of orally active inhibitors of ANP metabolism now provides a basis to determine the therapeutic importance of specific manipulation of endogenous ANP levels in patients with essential hypertension.     

Association of GNB3 C825T polymorphism with plasma electrolyte balance and susceptibility to hypertension

The role of G-protein activation in cardiovascular disorders is well-known. G-protein β3 subunit (GNB3) C825T polymorphism is associated with increased intracellular signal transduction. We investigated the role of the variant in plasma sodium and potassium concentrations and association with hypertension. 345 healthy controls and 455 patients with essential hypertension were enrolled. Plasma renin activity and aldosterone concentration were measured. The variant, typed by SNaPshot, was analyzed on an ABI Prism 3100 Genetic Analyzer and GeneScan. The TT genotype and T allele were over-represented in the patients (p < 0.001, p < 0.0001). Multiple-logistic regression disclosed that the risk of hypertension was significantly greater for TT (p < 0.0001, OR = 6.1, CI = 2.9-12.7). One-way ANOVA revealed that hypertensive T-allele carriers (CT+TT), compared to non-carriers (CC), had a greater body mass index (BMI), mean arterial pressure (MAP) and PAC (p = 0.01, p = 0.01, p < 0.0001, respectively); while the patients with 825TT risk genotype showed higher plasma sodium and lower potassium (p < 0.0001, each). The results strongly emphasize, not only the role of C825T polymorphism by the induction of increased G-protein activity and enhancement of Na/h exchangers, but also the association with higher plasma sodium and lower potassium levels, high BMI and susceptibility to hypertension.     

Exchangeable body sodium in normal man: analysis of various frames of reference

Exchangeable sodium is a reliable measure of body sodium contents. Since fat tissue contains significantly less sodium per unit of weight than other tissues, leanness of an individual may considerably affect exchangeable body sodium. Thus, subjects of different body size can be compared only when body build is considered. To evaluate various frames of reference, we analysed the relationship between exchangeable sodium as determined by isotope dilution and various parameters of body size. Body weight, body height, body surface area, and leanness index correlated significantly with exchangeable sodium, the closest relationship having been obtained with body surface area (r = 0.790; p less than 0.001). When analysing males and females separately (n = 18 and 36, resp.), best parallelism of regression lines was also obtained with body surface area. It is concluded that exchangeable sodium should be referred to unit of body surface area, expressing each individual's value as percent of the normal predicted value calculated from the regression equations y = 1388x + 370 and y = 1554x - 196 for males and females, respectively.     

Nutritional management of hypertension: past, present, and future

A succinct overview of the nutritional management of hypertension, past, present, and future is presented. Prior to 1945, the low sodium diet and the rice-fruit diet were shown to be effective in reducing the blood pressure to normal levels in 35-40% of hypertensive patients. Between 1945 and the present, many studies were made on the effects of alcohol, water hardness, obesity, moderate restriction of sodium with increased potassium intake, increased dietary calcium, low animal and high unsaturated fat intake, and increased amounts of fiber in the diet. Criticisms are made of the very small magnitude, even if statistically significant, of blood pressure decreases and the too-short control periods in many instances, and also concerning the assumption of use of 24-h urinary sodium as an accurate index of the sodium intake, and of urinary creatinine as a physiological reference standard against the excretion of sodium. The author mentions, for possible future research, long-term studies of the effects of diets moderately restricted in sodium and high in potassium, of reducing weight and increasing physical activity in obese hypertensives, and of low animal and high polyunsaturated fat diets in patients with mild essential hypertension.     

Circadian variations of catecholamines and blood pressure in patients with pseudohypoparathyroidism and hypertension

The relationship between 24-h recumbent blood pressure levels and secretory patterns of catecholamines was investigated in 4 patients with pseudohypoparathyroidism (PsHP) and hypertension and in 9 patients with essential hypertension. A clear circadian rhythm of blood pressure and catecholamines was documented in both groups with lowest levels of blood pressures and catecholamines occurring during sleep. During the 24-h period of recumbency mean arterial blood pressure (MAP) was correlated (r = 0.63, p less than or equal to 0.01) with plasma norepinephrine (N) in the patients with essential hypertension, but this correlation was weaker in patients with PsHP (r = 0.38, p less than or equal to 0.05). MAP was more closely related to plasma epinephrine (E) (r = 0.62, p less than or equal to 0.01) than to plasma NE in patients with PsHP. Plasma NE and E levels were considerably lower in patients with PsHP than in patients with essential hypertension throughout the 24-h recumbent period. The sleep-related decline in blood pressure and NE was less than in patients with essential hypertension. These results suggest that while the sympathetic nervous system may have a role in hour-to-hour maintenance of blood pressure in patients with PsHP and hypertension, it does not appear to be responsible for the elevated arterial pressure in these patients. Factors other than those investigated, such as obesity, alterations in sodium homeostasis of refractoriness of the vascular smooth muscle to the vasodilatory effect of PTH may be involved in the pathogenesis of hypertension in PsHP.     

Sodium restriction and blood pressure in hypertensive type II diabetics: randomised blind controlled and crossover studies of moderate sodium restriction and sodium supplementation.

OBJECTIVE--To determine the effect of moderate dietary sodium restriction on the hypertension of non-insulin-dependent (type II) diabetes. DESIGN--Randomised parallel controlled study of moderate sodium restriction for three months compared with usual diabetic diet, followed by randomised double blind crossover trial of sustained release preparation of sodium for one month versus placebo for one month in patients continuing with sodium restriction. SETTING--Patients attending diabetic outpatient clinic of city hospital. PATIENTS--Thirty four patients with established type II diabetes complicated by mild hypertension (systolic blood pressure greater than 160 mm Hg or diastolic pressure greater than 95 mm Hg on three consecutive occasions). Patients already taking antihypertensive agents (but not diuretics) not barred from study provided that criteria for mild hypertension still met. Conditions precluding patients from study were diabetic or hypertensive nephropathy, cardiac failure, and pregnancy. INTERVENTIONS--After run in phase with recordings at seven weeks, three weeks, and time zero patients were allocated at random to receive moderate dietary sodium restriction for three months (n = 17) or to continue with usual diabetic diet. Subsequently nine patients in sodium restriction group continued with regimen for a further two months, during which they completed a randomised double blind crossover trial of sustained release preparation of sodium (Slow Sodium 80 mmol daily) for one month versus matching placebo for one month. END POINT--Reduction in blood pressure in type II diabetics with mild hypertension. MEASUREMENTS AND MAIN RESULTS--Supine and erect blood pressure, body weight, and 24 hour urinary sodium and potassium excretion measured monthly during parallel group and double blind crossover studies. After parallel group study sodium restriction group showed significant reduction in systolic blood pressure (supine 19.2 mm Hg, erect 21.4 mm Hg; p less than 0.001) and mean daily urinary sodium excretion (mean reduction 60 mmol/24 h). There were no appreciable changes in weight, diabetic control, or diastolic pressure. No significant changes occurred in controls. In double blind crossover study mean supine systolic blood pressure rose significantly (p less than 0.005) during sodium supplementation (to 171 mm Hg) compared with value after three months of sodium restriction alone (159.9 mm Hg) and after one month of placebo (161.8 mm Hg). CONCLUSIONS--Moderate dietary restriction of sodium has a definite hypotensive effect, which may be useful in mild hypertension of type II diabetes.     

Evidence for a raised concentration of a circulating sodium transport inhibitor in essential hypertension.

A cytochemical technique that measures the ability of plasma to stimulate guinea-pig renal glucose-6-phosphate dehydrogenase (G6PD) activity in vitro, which is a marker of its ability to inhibit Na+-K+-adenosine-triphosphatase (Na+-K+-ATPase), was used in 19 patients with essential hypertension and 23 normotensive, healthy subjects. The ability of plasma to stimulate G6PD was significantly greater in the hypertensive patients when they were taking their normal sodium diet than in the normotensive subjects, and was significantly correlated with blood pressure. The ability of plasma to stimulate G6PD was inversely correlated with plasma renin activity in the hypertensive patients and increased with age and sodium intake in the normotensive subjects. These results support the hypothesis that essential hypertension, and also perhaps the increase in blood pressure with age in communities that consume large quantities of salt, is in part due to an increase in a circulating concentration of an inhibitor of Na+-N+-ATPase.     

Chronic activation of plasma renin is log-linearly related to dietary sodium and eliminates natriuresis in response to a pulse change in total body sodium

Responses to acute sodium loading depend on the load and on the level of chronic sodium intake. To test the hypothesis that an acute step increase in total body sodium (TBS) elicits a natriuretic response, which is dependent on the chronic level of TBS, we measured the effects of a bolus of NaCl during different low-sodium diets spanning a 25-fold change in sodium intake on elements of the renin-angiotensin-aldosterone system (RAAS) and on natriuresis. To custom-made, low-sodium chow (0.003%), NaCl was added to provide four levels of intake, 0.03-0.75 mmol.kg(-1).day(-1) for 7 days. Acute NaCl administration increased PV (+6.3-8.9%) and plasma sodium concentration (~2%) and decreased plasma protein concentration (-6.4-8.1%). Plasma ANG II and aldosterone concentrations decreased transiently. Potassium excretion increased substantially. Sodium excretion, arterial blood pressure, glomerular filtration rate, urine flow, plasma potassium, and plasma renin activity did not change. The results indicate that sodium excretion is controlled by neurohumoral mechanisms that are quite resistant to acute changes in plasma volume and colloid osmotic pressure and are not down-regulated within 2 h. With previous data, we demonstrate that RAAS variables are log-linearly related to sodium intake over a >250-fold range in sodium intake, defining dietary sodium function lines that are simple measures of the sodium sensitivity of the RAAS. The dietary function line for plasma ANG II concentration increases from theoretical zero at a daily sodium intake of 17 mmol Na/kg (intercept) with a slope of 16 pM increase per decade of decrease in dietary sodium intake.     

Comparison of chlorthalidone and spironolactone in low--renin essential hypertension.

Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given spironolactone, 400 mg/d, or chlorthalidone, 100mg/d, in a double-blind, random-sequence, crossover trial. The sequence of treatments was placebo for 2 months, one active drug for 2 months, placebo again for 1 month and the other active drug for 2 months. With both active treatments the average systolic, diastolic and mean arterial pressures decreased significantly. The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment. Body weight, 24--hour urinary excretion of sodium, the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug. Both drugs reduced the body weight and increased the stimulated plasma renin level activity. Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level. Three patients experienced orthostatic dizziness during spironolactone therapy, but no adverse symptoms were observed with chlorthalidone therapy. Thus, spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension.     

Dietary sodium restriction for mild hypertension in general practice.

Eighteen patients with stable mild hypertension (mean blood pressure 144/93 mm Hg) restricted their sodium intake for eight weeks while taking part in a double blind randomised crossover trial of slow sodium and placebo tablets. Mean 24 hour urinary sodium excretion was 143 mmol(mEq) during the period on slow sodium and 87 mmol during the period on placebo. Five patients were unable to reduce their sodium intake below 120 mmol, but the others had a mean 24 hour urinary sodium excretion of 59 mmol during the period on placebo. There was no significant difference in blood pressure between the slow sodium and placebo treatment periods, although the study had a power of 99% to detect a difference of 5 mm Hg in mean arterial pressure between the two periods. Moderate dietary sodium restriction does not lower blood pressure in patients with this degree of hypertension.     

Evidence for a circulating sodium transport inhibitor in essential hypertension.

The active sodium transport of white cells and red cells obtained from patients with essential hypertension was impaired. Incubating white cells from normotensive subjects in serum obtained from patients with essential hypertension caused an impairment in sodium transport in the white cells of normotensive subjects similar to that found in the white cells of hypertensive patients. The impairment in sodium transport was due to a fall in the ouabain-sensitive component of the total sodium efflux rate constant. These results show that the serum of patients with essential hypertension contains a substance which influences sodium transport and that it has ouabain-like activity. They also suggest that it is this substance which causes the impairment in sodium transport in the leucocytes of patients with essential hypertension. These findings support the hypothesis that the rise in blood pressure in patients with essential hypertension is due to an increased concentration of a circulating sodium transport inhibitor which is continuously correcting a tendency for sodium retention by the kidney.     

Genetic and familial factors in essential hypertension and related traits

The health significance of essential hypertension “high blood pressure of undefined origin” is well established. It is a major factor contributing to coronary heart disease, stroke, and kidney failure. It directly affects about one in five Americans. Factors which are known to be associated with blood pressure include: body composition as it relates to overall mass and fat mass; physiological variables involving the sympathetic and parasympathetic nervous systems; biochemical variables such as renin, aldosterone, kallikrein, lipids, and lipoproteins, etc.; environmental variables such as sodium intake, heavy metals, and noise; and psychological variables involving personality type and mental stress. There is a definite, well-established genetic involvement in hypertension, but specific genetic mechanisms remain a mystery. Familial aggregation occurs for many of the associated traits listed above. For some, specific polymorphic major genes have been identified, but for others genetic factors are unidentified. Essential hypertension is undoubtedly a heterogeneous group of diseases with the common end result of elevated blood pressure. Because of its health significance, there is considerable interest in identifying genetic mechanisms resulting in essential hypertension. One area that currently shows some potential for the identification of a specific genetic mechanism is related to the transmembrane transport of sodium and potassium cations.