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.     

Moderate potassium chloride supplementation in essential hypertension: is it additive to moderate sodium restriction?

Twenty patients with mild or moderate essential hypertension and not receiving any drug treatment, who had been moderately restricting their sodium intake to around 70 mmol(mEq) a day for at least one month and whose mean blood pressure was then 163/103 mm Hg, were entered into a double blind, randomised crossover study to compare one month''s treatment with slow release potassium chloride tablets (64 mmol potassium chloride a day) with one month''s treatment with a matching placebo. Mean (SEM) urinary sodium excretion on entry to the study was 68 (6.8) mmol/24 h. Mean urinary potassium excretion increased from 67 (6.9) mmol(mEq)/24 h with placebo to 117 (4.6) mmol/24 h with potassium chloride. Supine and standing systolic and diastolic blood pressures did not change significantly with potassium chloride supplementation when compared with pressures while receiving placebo or before randomisation. In patients who are able moderately to restrict their sodium intake doubling potassium as a chloride salt has little or no effect on blood pressure.     

Effect of using nifedipine by patients with chronic congestive heart failure treated with digoxin and furosemide

Nifedipine was administrated to 25 patients with chronic congestive heart failure treated with digoxin and furosemide++, nifedipine (NF) in a daily dose of 30-80 mg for 14 days. Before and after the treatment with nifedipine chest X-ray, blood biochemical investigations, echocardiographic evaluation of the left ventricular function and submaximal exercise test were performed. Nifedipine induced significant decreases in the left ventricular systolic dimension, heart volume, blood serum potassium and uric acid concentrations and hematocrit . Resting and exertional heart rate, blood pressure, exercise power and duration, watt-pulse, myocardial oxygen demand index, ejection fraction, cardiac output, body weight, 24-hour urinary output, blood serum concentrations of urea, creatinine, sodium and chloride changed insignificantly following nifedipine administration. The obtained results suggest that long-term nifedipine treatment of patients who were already given digoxin and furosemide neither improve nor worsen their clinical status.     

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.     

The role of chloride in deoxycorticosterone hypertension: selective sodium loading by diet or drinking fluid

To evaluate the role of chloride in the pathogenesis of salt-dependent deoxycorticosterone (DOC) hypertension, we studied young Wistar rats chronically loaded with sodium bicarbonate (NaHCO(3)) or sodium chloride (NaCl) which were administered either in the diet or in the drinking fluid. Selective sodium loading (without chloride) increased blood pressure (BP) in DOC-treated animals only if NaHCO(3) was provided in the diet. In contrast, no significant blood pressure changes were induced by DOC treatment in rats drinking NaHCO(3) solution. Hypernatremia and high plasma osmolality occurred only in rats drinking NaCl or NaHCO(3) solutions. Compared to great volume expansion in NaCl-loaded DOC-treated rats, the degree of extracellular fluid volume expansion (namely of its interstitial fraction) was substantially lower in both NaHCO(3)-loaded groups in which significant hypokalemia was observed. NaHCO(3)-drinking rats without significant blood pressure response to DOC treatment represented the only experimental group in which blood volume was not expanded. In conclusion, our data confirm previous observations that NaHCO(3) loading is less potent in eliciting DOC hypertension than NaCl loading, but blood pressure rise in rats fed NaHCO(3) diet clearly demonstrated that selective sodium loading could potentiate the development of DOC hypertension if NaHCO(3) is offered within the appropriate dietary regimen. The reasons for the failure of NaHCO(3)-drinking rats to elevate blood pressure in response to chronic mineralocorticoid treatment are not obvious. However, the absence of a significant plasma volume expansion together with hypernatremia and increased plasma osmolality suggest a considerable degree of dehydration in these animals which fail to increase their fluid consumption compared to water drinking rats.     

Separate hemodynamic roles for chloride and sodium in deoxycorticosterone acetate-salt hypertension

It has been reported that both sodium and chloride ions must be ingested to induce the elevated blood pressure of deoxycorticosterone acetate (DOCA)-salt-sensitive hypertension. This study was designed to determine the separate roles of the sodium and chloride ions in the altered hemodynamics underlying the high blood pressure. DOCA pellets (75 mg) were implanted in uninephrectomized rats and the animals were then fed one of four diets: (i) high sodium chloride, (ii) high sodium-low chloride, (iii) high chloride-low sodium, or (iv) low sodium chloride. Blood pressures were measured weekly by tail-cuff plethysmography for 5 weeks and the animals were then subjected to a terminal experiment to measure cardiac output by thermodilution technique, renal blood flow by electromagnetic flow probe, and direct arterial pressure. Blood pressure in the DOCA-high NaCl group was significantly greater (P less than 0.05) compared with that of the DOCA-low NaCl group (160 +/- 3 mm Hg vs 124 +/- 2 mm Hg, respectively) at 5 weeks after treatment; all other groups were not significantly different from the DOCA-low NaCl group. Cardiac output was significantly greater in DOCA-treated rats consuming diets high in sodium (44 +/- 2 ml/min/100 g) or sodium chloride (40 +/- 2 ml/min/100 g) compared with animals consuming low sodium chloride (31 +/- 2 ml/min/100 g; P less than 0.01 for each comparison). Direct intraarterial blood pressure and renal blood flow were used to calculate renal vascular resistance. Renal vascular resistance was increased in those DOCA-treated rats consuming diets high in chloride (42 +/- 3 mm Hg/ml/min/100 g) and high sodium chloride (54 +/- 3 mm Hg/ml/min/100 g) compared with rats consuming low sodium chloride (30 +/- 3 mm Hg/ml/min/100 g; P less than 0.01 for each). It appears that elevations in cardiac output are associated with increased dietary sodium and act in synergy with the elevations in renal vascular resistance associated with increased dietary chloride. Increases in both cardiac output and renal vascular resistance are involved in the maintenance of elevated blood pressure in the DOCA-salt-sensitive model of hypertension.     

Simple treatment for chronic female infections

A prospective, double-blind, placebo-controlled crossover study of the use of quinine for nocturnal leg cramps was carried out in 8 elderly volunteer patients. The patients were randomly assigned to receive either placebo or 200 mg of quinine sulfate by mouth at bedtime. After 4 weeks of treatment and after a one-week washout period, the group taking quinine switched to placebo and vice versa for another 4 weeks. The differences in the number, duration, and severity of cramps and the side effects were compared. All of the patients had fewer cramps and decreased severity and duration of attacks while receiving quinine. Mild side effects developed in only 2 patients, and these subsided without treatment or discontinuing the medication. We conclude that quinine was effective in relieving nocturnal leg cramps in a selected group of elderly patients.     

Meta-analysis of efficacy of quinine for treatment of nocturnal leg cramps in elderly people.

OBJECTIVE--To assess quantitatively the efficacy of quinine (as quinine sulphate) compared with placebo in the treatment of nocturnal leg cramps. DESIGN--A meta-analysis of six randomised, double blind, crossover trials. SETTING--Randomised trials that were available as of April 1994. SUBJECTS--A total of 107 general ambulatory patients who suffered from regular nocturnal leg cramps from six clinical trials. RESULTS--Data from individual patients were used to calculate point estimates and 95% confidence intervals for each of the outcome measures reported by these studies. Treatment with quinine resulted in a significant reduction in the number of cramps for a four week period compared with placebo (8.83 fewer cramps; 95% confidence interval 4.16 to 13.49). Treatment with quinine reduced the number of nights with cramps by 27.4% (24.0% to 30.8%) compared with placebo. Treatment did not produce a significant change in the severity or duration of individual nocturnal leg cramps. Side effects were uncommon. CONCLUSIONS--The results indicate that quinine can prevent nocturnal leg cramps in general ambulatory populations. Given the possible serious side effects of treatment with quinine, the benefits and risks in patients taking this drug should be closely monitored.     

The effect of hypophysectomy on chloride balance in young-of-the-year bowfin, Amia calva

The effect of hypophysectomy on chloride balance was examined in young-of-the-year bowfin, Amia calva. Hypophysectomy resulted in decreased serum and total body chloride levels but not in serum and total body sodium levels. Hypophysectomy resulted in decreased chloride influx with no effect on chloride efflux or sodium fluxes. Prolactin therapy reversed the effect of hypophysectomy on electrolyte balance but caused a significant reduction in serum protein.     

Sodium and potassium in essential hypertension.

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.     

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.     

Role of catecholamines in hypotensive response to dieting.

The effect of dieting on blood pressure and catecholamine metabolism was assessed in 11 normotensive obese women by providing first a weight-maintenance regimen high in carbohydrate and then a low-energy diet. All dietary constituents other than carbohydrate were maintained constant throughout the 18-day study. The low-carbohydrate diet led within 48 hours to a 41% fall in the urinary output of 4-hydroxy-3-methoxy mandelate and a significant fall in systolic and diastolic blood pressure. Plasma noradrenaline concentrations also fell and the hypotensive effect of the diet continued despite a maintained total body sodium. Thus the fall in blood pressure appeared to be mediated by changes in catecholamine metabolism independent of sodium intake. This may explain both the usefulness of weight reduction in hypertensive patients and the fainting that occurs in some normotensive obese subjects taking slimming regimens low in carbohydrate.     

Long term reduction in sodium balance: possible additional mechanism whereby nifedipine lowers blood pressure.

OBJECTIVE--To assess the changes in sodium excretion and sodium balance after withdrawal of long term nifedipine. DESIGN--Single blind, placebo controlled study in patients receiving fixed sodium and potassium intakes. SETTING--Blood pressure unit of a teaching hospital in south London. PATIENTS--Eight patients with mild to moderate uncomplicated essential hypertension who had been taking nifedipine 20 mg twice daily for at least six weeks. INTERVENTIONS--Withdrawal of nifedipine and replacement with matching placebo for one week. MAIN OUTCOME MEASURES--Urinary sodium excretion and cumulative sodium balance, body weight, plasma atrial natriuretic peptide concentrations, plasma renin activity and aldosterone concentrations, and blood pressure. RESULTS--During nifedipine withdrawal there was a significant reduction in urinary sodium excretion (day 1: -62.7 mmol/24 h; 95% confidence interval -90.3 to -35.0) and each patient retained a mean of 146 (SEM 26) mmol sodium over the week of replacement with placebo. Body weight and plasma atrial natriuretic peptide concentrations increased during the placebo period and seemed to be associated with the amount of sodium retained. Systolic blood pressure rose from 157 (9) to 165 (9) mmHg (95% confidence interval of difference -7.1 to 22.1) when nifedipine was replaced with matching placebo, and the rise seemed to be related to the amount of sodium that was retained. CONCLUSIONS--Nifedipine causes a long term reduction in sodium balance in patients with essential hypertension. This long term effect may contribute to the mechanism whereby nifedipine lowers blood pressure.     

Moderate sodium restriction with angiotensin converting enzyme inhibitor in essential hypertension: a double blind study.

Fifteen unselected patients who had essential hypertension and whose average supine blood pressure when they were not receiving any treatment and their usual sodium intake was 162/107 mm Hg were treated with captopril 50 mg twice daily. After one month''s treatment their supine blood pressure had decreased to 149/94 mm Hg. They were then instructed to reduce their sodium intake to about 80 mmol(mEq)/day. After two weeks of moderate sodium restriction they were entered into a double blind randomised crossover study comparing the effect of 10 Slow Sodium tablets (100 mmol sodium chloride) with matching placebo tablets while continuing to take captopril and restrict sodium in their diet. After one month of taking placebo their mean supine blood pressure was 137/88 mm Hg with a urinary sodium excretion of 83 mmol/24 h, while after one month of taking Slow Sodium tablets their mean supine blood pressure was 150/97 mm Hg (p less than 0.001) with a sodium excretion of 183 mmol/24 h. The mean supine blood pressure during moderate sodium restriction therefore decreased by 9% and correlated significantly with the reduction in urinary sodium excretion. These results suggest that the combination of treatment with a moderate but practical reduction in sodium intake and an angiotensin converting enzyme inhibitor is effective in decreasing the blood pressure in patients with essential hypertension. This combined approach overcomes some of the objections that have been made to salt restriction alone and to converting enzyme inhibitors alone.     

Effect of the crude extract of Vernonia polyanthes Less. on blood pressure and renal sodium excretion in unanesthetized rats.

This study evaluated the effect of oral crude Vernonia polyanthes Less. hydroalcoholic extract administration (CHE, 0.5 and 1.0 g/kg body wt., daily for 7 days) on arterial blood pressure and renal sodium excretion in conscious rats. CHE administration decreased arterial blood pressure dose-dependently followed by a significant rise in creatinine clearance and a fall in fractional post-proximal sodium excretion was compared to the control group. These results suggest that blood pressure decrease induced by the oral crude Vernonia hydroalcoholic extract may be blunted by reduction of the post-proximal renal sodium excretion. Thus, the present study shows that Vernonia extract is a potential vasodilatation agent in normotensive rats without any effects on renal tubule autoregulation mechanisms.     

The importance of sodium and chloride ions for the development of DOCA-NaCl hypertension: a haemodynamic study

The role of sodium and its accompanying anion for the development of DOCA-salt hypertension was studied in uninephrectomized DOCA-treated weanling Wistar rats which were fed a diet containing either sodium chloride or sodium bicarbonate (170 mmol/kg). The blood pressure was increased in both groups of rats with sodium overload as compared to rats fed a low-salt diet only. A decreased cardiac output and substantially elevated systemic resistance were demonstrated in both groups of rats with high sodium intake in comparison with rats kept on a low-salt diet. However, these haemodynamic changes were more pronounced in rats with sodium chloride overload than in animals with a high sodium bicarbonate intake. On the other hand, the rigidity of major arteries which was estimated as the pulse pressure/stroke volume ratio, was increased only in rats fed a diet with sodium chloride but not in rats with sodium bicarbonate overload. Thus high sodium intake was responsible for the changes of systemic resistance in DOCA-treated animals and its action was only slightly augmented by a high chloride intake. In contrast to this, the chloride overload seemed to be essential for the induction of increased arterial rigidity.     

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.     

Lack of association of variants of the renal salt reabsorption-related genes SLC12A3 and ClC-Kb and hypertension in Mongolian and Han populations in Inner Mongolia

Abnormalities in renal sodium chloride and water reabsorption play important roles in the development of hypertension. Mutations in the genes involved in renal sodium chloride reabsorption can affect blood pressure. Recently, the R904Q variant of the sodium/chloride transporters, member 3 (SLC12A3) gene and the T481S variant of the chloride channel Kb (ClC-Kb) gene were found to be implicated in essential hypertension. We investigated a possible role of the SLC12A3 and ClC-Kb genes in the prevalence of essential hypertension in the Mongolian and Han ethnic groups. The study population comprised 308 unrelated Mongolians with essential hypertension, 271 Mongolian normotensives, 285 unrelated Han with essential hypertension, and 194 Han normotensives living in Inner Mongolia. The presence of the SLC12A3 R904Q and ClC-Kb-T481S polymorphisms was determined using TaqMan PCR. The risk factors for hypertension were age, body mass index, alcohol consumption, total plasma cholesterol, and low-density lipoprotein cholesterol. The genotype and allele frequencies of SLC12A3 R904Q and ClC-Kb-T481S were not significantly different between hypertensive patients and controls in the Mongolian (SLC12A3 R904Q, P = 0.471 and P = 0.494, ClC-Kb-T481S, P = 0.960 and P = 0.960, respectively) and Han (SLC12A3 R904Q, P = 0.765 and P = 0.777, ClC-Kb-T481S, P = 0.100 and P = 0.103, respectively) populations. There was no significant association between the SLC12A3 R904Q variant and the ClC-Kb-T481S variant and essential hypertension in either ethnic group.     

Urinary electrolyte excretion,alcohol consumption,and blood pressure in the Scottish heart health study.

As part of a study of risk factors for coronary heart disease 24 hour urine collections were obtained from 7354 men and women aged 40-59 selected at random from 22 districts throughout Scotland (Scottish heart health study). The mean of two standardised measurements of blood pressure was related to the reported consumption of alcohol and measurements of height, weight, pulse rate, and electrolyte excretion. Several significant correlations were found with both systolic and diastolic pressure, but only the coefficients for age, body mass index, and pulse rate were greater than 0.1. Alcohol consumption showed a weak positive correlation with blood pressure in men. Sodium excretion showed a weak positive correlation with blood pressure in both sexes, and potassium excretion showed weak negative correlations. In multiple regression analysis age, pulse rate, body mass index, alcohol consumption, and potassium excretion had significant independent effects but sodium excretion did not. Although measuring blood pressure twice on one occasion and 24 hour urinary sodium excretion only once may have weakened any potential correlation, the most likely explantation of these results is that the relation between sodium and blood pressure in the population is weak and that potassium and alcohol are of greater importance.     

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.