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.     

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.     

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.     

Plasma norepinephrine concentrations: No differences among normal volunteers and low,high or normal renin hypertensive patients

Plasma norepinephrine concentrations were measured by a sensitive radioenzymatic method in 51 patients with essential hypertension and 26 age-matched normal volunteers under conditions of ad libitum sodium intake, after volume expansion by infusion of saline intravenously, and after volume contraction by administration of furosemide orally. The hypertensive patients were classified into low, normal and high renin groups both by renin-sodium indexing and by their renin response to furosemide and saline administration. Plasma norepinephrine concentrations were similar among normal volunteers and patients with low, normal or high renin hypertension while the people were either recumbent or after they stood for 5 min. These and other results do not support the hypothesis that abnormal activity of the sympathetic nervous system accounts for the low or high renin values seen in many hypertensive patients.     

Acute effects of angiotensin-converting enzyme inhibitor on erythrocyte sodium ion transport in essential hypertension.

The acute effects of angiotensin-converting enzyme inhibitor, captopril, on sodium ion transport systems were investigated in essential hypertensive and normotensive subjects. The passive sodium efflux through the erythrocyte membrane was significantly higher and erythrocyte sodium-potassium cotransport was lower in patients with essential hypertension when compared with normal subjects. However, sodium-potassium pump activity and sodium-lithium countertransport did not differ significantly between the hypertensive patients and the normal subjects. Immediately after captopril administration, erythrocyte passive sodium efflux and sodium-potassium cotransport returned to normal levels in the hypertensive subjects. Although the plasma renin activity and plasma aldosterone concentration were altered by captopril, they did not correlate with changes in any sodium transport system. These results suggest that the changes in sodium transport systems which occur immediately after captopril administration may contribute, at least in part, to its antihypertensive action.     

Renin in hypertension: how important as a risk factor?

An analysis of the plasma renin levels in relation to the incidence of severe cardiovascular complications (coronary thrombosis, stroke, ruptured aortic aneurysm) was made in 325 patients with various types of hypertension. These patients had one to four measurements of plasma renin activity taken under standard conditions of sodium intake and posture in the period 1963-68. The follow-up was 5 to 10 years in the four groups of hypertensive patients (essential hypertension, malignant hypertension, hypertension secondary to renal parenchymatous disease and hypertension caused by, or associated with, renal artery obstruction). For all 325 patients, the incidence of such complications was 23.6, 20.4 and 44.7% in the low, normal and high renin groups. These findings are at variance with the claim that renin constitutes a serious risk factor in hypertensive patients, especially if it is isolated from other parameters such as the level of diastolic pressure, the adequacy of kidney function, the effectiveness of dietary and drug management of hypertension, and especially the presence or absence of atherosclerotic lesions of the large vessels at the time of the renin determination.     

Salt intake and depletion increase circulating levels of endogenous ouabain in normal men

High-salt diets elevate circulating Na+ pump inhibitors, vascular resistance, and blood pressure. Ouabain induces a form of hypertension mediated via the alpha2-Na+ pump isoform and the calcium influx mode of the vascular sodium calcium exchanger (NCX). Whereas elevated levels of an endogenous ouabain (EO) and NCX have been implicated in salt-sensitive hypertension, acute changes in sodium balance do not affect plasma EO. This study investigated the impact of longer-term alterations in sodium balance on the circulating levels and renal clearance of EO in normal humans. Thirteen normal men consumed a normal diet, high-salt diet, and hydrochlorothiazide (HCTZ), each for 5-day periods to alter sodium balance. EO and other humoral and urinary variables were determined daily. On a normal diet, urinary sodium excretion (140 +/- 16 meq/day), plasma EO (0.43 +/- 0.08 nmol/l) and urinary EO excretion (1.04 +/- 0.13 nmol/day) were at steady state. On the 3rd day of a high-salt diet, urine sodium excretion (315 +/- 28 meq/day), plasma EO (5.8 +/- 2.2 nmol/l), and the urinary EO excretion (1.69 +/- 0.27 nmol/day) were significantly increased, while plasma renin activity and aldosterone levels were suppressed. The salt-evoked increase in plasma EO was greater in older individuals, in subjects whose baseline circulating EO was higher, and in those with low renal clearance. During HCTZ, body weight decreased and plasma renin activity, aldosterone, and EO (1.71 +/- 0.77 nmol/l) rose, while urinary EO excretion remained within the normal range (1.44 +/- 0.31 nmol/day). Blood pressure fell in one subject during HCTZ. HPLC of the plasma extracts showed one primary peak of EO immunoreactivity with a retention time equivalent to ouabain. High-salt diets and HCTZ raise plasma EO by stimulating EO secretion, and a J-shaped curve relates sodium balance and EO in healthy men. Under normal dietary conditions, approximately 98% of the filtered load of EO is reabsorbed by the kidney, and differences in the circulating levels of EO are strongly influenced by secretion and urinary excretion of EO. The dramatic impact of high-salt diets on plasma EO is consistent with its proposed role as a humoral vasoconstrictor that links salt intake with vascular function in hypertension.     

Effect of somatostatin on plasma renin activity and blood pressure in patients with essential hypertension

The effects of somatostatin on plasma renin activity (PRA) and blood pressure were evaluated in patients with essential hypertension (EH) and in normotensive subjects. All subjects examined were hospitalized and placed on a diet containing 7-8 g/day sodium chloride and received an intravenous infusion of somatostatin (500 microgram/20 ml of saline, for 60 min) in the basal condition. During somatostatin infusion, the mean blood pressure (MBP) remained unaffected in all patients with EH and the normotensive subjects, while the PRA decreased slightly in the EH group. When the patients with EH were classified according to their renin levels (low, normal and high), parallel significant decreases in MBP and PRA were found only in the high renin group during the somatostatin infusion. No significant change in MBP and PRA was observed in the other groups including the normotensive subjects. To assess the activity of synthetic somatostatin, the plasma levels of growth hormone (GH) and cyclic AMP were measured. These levels were lowered significantly during the infusion and the GH levels showed a rebound 15 min after cessation of the infusion. The cyclic AMP returned to the basal levels, but no rebound was observed. The above data indicate that the fall in blood pressure in the high renin group in the basal condition was probably due in part to reduced renin release by somatostatin, and the maintenance of high blood pressure especially in high renin EH.     

Relevance of Salt,Water, and Renin to Hypertension in Chronic Renal Failure

Blood pressure control was examined in 75 patients with end-stage renal failure treated by regular twice-weekly haemodialysis. Dietary sodium was restricted and extracellular fluid was removed by ultrafiltration until blood pressure was normal or signs of salt depletion were observed. Failure of these measures constituted an indication for nephrectomy. Of the 75 patients, 18 were never hypertensive, 46 had hypertension which could be corrected by salt and water depletion, and 11 had persistent hypertension which could not be controlled in this way. Nine of these 11 patients underwent bilateral nephrectomy; in each of the seven in whom the post operative result could be evaluated the blood pressure returned rapidly to normal.Plasma renin activity, measured in 34 subjects, was raised above normal in six out of nine patients whose blood pressure could not be controlled by salt and water depletion and in one of the 11 patients whose blood pressure could be so controlled, but was within the normal range in all nine normotensive patients. The mean level of plasma renin activity in the first group was significantly higher than that of each of the other two groups.There was a significant correlation between hypertension during dialysis and after transplantation, suggesting that, in addition to renin, there is a non-renal factor which predisposes certain patients to hypertension in the presence of salt and water excess.     

Response of plasma aldosterone to orthostatism during follicular and luteal phases of the normal menstrual cycle

The responses of plasma aldosterone (A) and plasma renin activity (PRA) to orthostatism have been evaluated in 47 women during the follicular and/or luteal phase of the menstrual cycle. Three postmenopausal women and 51 men were also studied for control. Fourteen cycling women and 11 men were studied on a low sodium diet (20 mEq/day) while the rest of the subjects were on normal sodium intake. In addition, 18 women (including those postmenopausal) and 17 men were studied after intravenous administration of 20 mg frusemide. The response of A to orthostatism in women during luteal phase on normal sodium diet with or without frusemide was much greater than in men or women during follicular phase (p less than 0.01) or menopuase (p less than 0.05). However, no differences between groups could be observed in A response while on a low sodium diet. PRA response was similar during follicular of luteal phase fo the cycle as well as in men either on low or normal sodium intake with or without frusemide.     

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.     

Immunoradiometric assay of active renin versus determination of plasma renin activity in the clinical investigation of hypertension, congestive heart failure, and liver cirrhosis

We compared the determination of plasma renin activity (PRA) and the direct immunoradiometric measurement of active renin (AR) as ways of assessing the activity of the renin-angiotensin system in normal volunteers and in patients with hypertension, heart failure, or liver failure. The levels of plasma renin substrate, angiotensinogen, and the ratio of PRA to AR concentration did not differ in the normal volunteers and the patients with essential or renovascular hypertension. However, compared to the volunteers, patients with severe heart or liver failure had markedly reduced plasma renin substrate levels, which led to a considerable underestimation of AR concentration when it was measured by PRA.     

Relationships among urinary kallikrein, mineralocorticoids and human hypertensive disease.

Urinary kallikrein excretion is reduced in patients with hypertension of unknown etiology. In addition, the excretion of this renal, kinin-forming enzyme was found to be elevated in hypertensive patients with primary aldosteronism. Aldosterone regulates kallikrein excretion, as normal subjects show increased kallikrein excretion in response to a low sodium intake, high potassium intake, or the synthetic mineralocorticoid, fludrocortisone, whereas kallikrein excretion falls during treatment with spironolactone. The relationship between kallikrein excretion and aldosterone activity may directly reflect the intrarenal activity of the kallikrein-kinin system, as determined by studies of kallikrein levels from isolated renal cells or of plasma kinin levels in man in response to postural changes or saline loads. Some patients with essential hypertension do not show a normal increase in kallikrein excretion in response to low dietary sodium intake despite an apparently normal aldosterone response, suggesting that there may be a defect in the renal kallikrein-kinin system in these patients. Whether these findings are of pathogenetic significance in human hypertensive disease remains to be determined.     

Immediate plasma renin response to propranolol: differentiation between essential and renal hypertension.

The immediate short-term effect on plasma renin activity of intravenous injection of propranolol was studied in 31 normal subjects and 166 hypertensive patients. In patients with essential hypertension and normal subjects plasma renin activity fell considerably within 15 minutes; the fall was directly proportional to initial plasma renin levels. In contrast, in patients with renal hypertension the fall was much less pronounced or totally absent. These differences in response to propranolol provide, though presently only on a group basis, a biochemical means of differentiating between patients with renal hypertension and those with essential hypertension. The observations also indicate that, unlike normal subjects and patients with essential hypertension, in patients with renal hypertension sympathetic activity plays no part in the control of basal plasma renin levels.     

Role of the renin-angiotensin system during alterations of sodium intake in conscious mice

The present studies were performed to quantify circulating components of the renin-angiotensin-aldosterone axis and to determine the functional importance of this system during alterations in sodium intake in conscious mice. Increasing sodium intake from approximately 200 to 1,000 microeq/day significantly decreased plasma renin concentration from 472 +/- 96 to 304 +/- 83 ng ANG I. ml(-1). h(-1) (n = 5) but did not alter plasma renin activity from the low-sodium level of 7.7 +/- 1.1 ng ANG I. ml(-1). h(-1). Despite the elevated plasma renin concentration, plasma ANG II in mice on low-sodium level averaged 14 +/- 3 pg/ml and was significantly suppressed to 6 +/- 1 pg/ml by high-sodium intake (n = 7). Consistent with the modulation of ANG II, plasma aldosterone significantly decreased from 41 +/- 8 to 8 +/- 3 ng/dl when sodium intake was elevated (n = 6). In a final set of experiments, the continuous infusion of ANG II (20 ng. kg(-1). min(-1)) led to a mild salt-sensitive increase in mean arterial pressure from 108 +/- 2 to 131 +/- 2 mmHg as sodium intake was varied from low to high (n = 7). In vehicle-infused mice, mean arterial pressure was unaltered from 109 +/- 2 mmHg when sodium intake was increased (n = 6). These studies indicate that the physiological suppression of circulating ANG II may be required to maintain a constancy of arterial pressure during alterations in sodium intake in normal mice.     

Pharmacological evidence for involvement of the sympathetic nervous system in the increase in renin secretion produced by a low sodium diet in rats

To determine the degree to which increased sympathetic activity contributes to the increase in renin secretion produced by a low sodium diet, the beta-adrenergic blocking drug propranolol or saline vehicle was injected through indwelling jugular cannulas in rats fed a normal diet and rats fed a low sodium diet for 9 days. Plasma renin activity (PRA) and plasma renin concentration (PRC) were elevated by the low sodium diet, and these values were reduced 42-45% by propranolol, although they were still higher than in the normal diet controls. Plasma corticosterone was moderately elevated in cannulated rats on regular diet, compared to decapitated controls, but corticosterone did not differ between cannulated and decapitated rats on low salt diet; propranolol reduced plasma corticosterone. However, PRA and PRC were comparable in cannulated rats and decapitated controls on both the normal and the low sodium diets, and propranolol did not produce a significant reduction in PRA and PRC in rats fed the normal diet. This indicates that the effects of propranolol on PRA and PRC in the low sodium rats were not simply due to reduction of a stress-induced increase in renin secretion. The results indicate that increased sympathetic activity makes a substantial contribution to the increase in renin secretion produced by 9 days of dietary sodium restriction.     

Impairment of renal sodium excretion in tropical residents – phenomenological analysis

There is evidence of impaired renal sodium excretion in salt-sensitive African Blacks. A decreased rate of renal sodium chloride (NaCl) excretion, low plasma renin activity and a tendency to elevated blood pressure are the hallmarks of salt sensitivity. Recent evidence indicates that increased proximal and distal tubular fluid reabsorption in some tropical residents may explain the impaired sodium excretion in these people. In this study of a cohort population, we speculated that subjects selected from that population might be salt-sensitive. We therefore measured the sodium balance in 10 normotensive male subjects over 10 consecutive days, after they had ingested a normal or a high amount of sodium, as NaCl (salt) in their diet. We quantified their renal sodium excretion rate by phenomenological analysis of their sodium balance data. We also measured plasma renin activity for 7 consecutive days in a separate group of 6 male and 4 female subjects in order to assess the state of their renin/angiotensin system. We selected all our subjects from a cohort population of 269 subjects randomly selected from a community known to have a high prevalence of primary hypertension. Our data on two separate groups of subjects from the same cohort population revealed delayed renal sodium excretion with t _1/2 of about 5 days, compared to published data for normal individuals with t _1/2 of less than 24 h. Also, plasma renin activity levels were low. Hence, our subjects are salt-sensitive. Quantification of their renal impairment is important for various reasons: it heightens one’s appreciation of the problem of salt retention in African Blacks who are salt-sensitive and it also underlines the importance of the need for further research into the benefits of dietary salt restriction for reducing cardiovascular mortality in African populations, as has been done in some Western countries. Received: 4 March 1999 / Accepted: 12 May 1999     

Effect of nifedipine treatment on the renin-aldosterone system and secretion of cortisol and growth hormone in patients with essential hypertension]

The effect of treatment of hypertension with nifedipine on plasma renin activity, blood serum level of aldosterone in the course of renin test, and cortisol and growth hormone concentrations after stimulation with insulin hypoglycemia was followed during two weeks of treatment in 40 patients with essential hypertension. No significant differences in the secretion of the hormones studied, as compared to the patients with the normal arterial blood pressure, were found. After nifedipine treatment no significant changes in the secretion of aldosterone, cortisol and growth hormone were observed despite a significant fall in the arterial blood pressure while there was a moderate stimulatory effect on renin secretion. The results obtained indicate that nifedipine has only small effect on the hormonal system of patients with essential hypertension.     

Effect of treatment with enalapril maleate on the levels of circulating catecholamines, beta endorphins, prostaglandins, and concentration of sodium in erythrocytes in patients with essential hypertension

An effect of enalapril maleate on the activity of renin-angiotensin-aldosterone system and sympathetic reactivity, erythrocyte prostaglandin and sodium levels as well as blood beta-endorphin was investigated in 28 patients with the essential arterial blood hypertension. It was found that enalapril maleate significantly increased plasma renin activity, decreased plasma norepinephrine and its 24-hour excretion, and decreased erythrocyte beta-endorphin and sodium levels. Blood epinephrine and aldosterone levels and their daily excretion remained unchanged similarly to prostaglandins. The above results suggest that a decrease in sympathetic system activity and intracellular sodium concentration may play a role in the hypotensive action of enalapril maleate related to the inhibition of angiotensin II formation.     

Some Effects of a Low Sodium Diet High in Potassium on the Renin-Angiotensin System and Plasma Electrolyte Concentrations in Normal Dogs

Eight normal male Beagle dogs received 0.7 mmol Na+/kg/day for 5 weeks and 4.0 mmol Na+/kg/day in one 3 week control period preceding and another similar period following the low sodium period. The dogs received 6.8 mmol K+/kg/day throughout the study. The median plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were higher in the low sodium period than in the following control period (0.67 versus 0.28 ng/ml/h, p < 0.0001) and (204 versus 31 pg/ml, p < 0.0001). PRA and PAC quickly stabilized on a new steady level in response to altered intake of sodium chloride. The angiotensin-converting enzyme (ACE) activity was not changed by the altered intake of sodium chloride. The plasma concentrations of sodium and chloride were increased during the low sodium period. This could be due to an indirect effect of the high potassium intake of the dogs. Potassium leads to an increased secretion of aldosterone and thereby to an increased retention of sodium and chloride in the kidney. The possible implications of a high potassium content in a low sodium diet are discussed.