In-vivo intracellular pH at rest and during exercise in patients with essential hypertension.

BACKGROUND: Several studies in isolated cells have reported that intracellular pH (pHi) in individuals with essential hypertension may be relatively alkaline compared to normotensive individuals. Such an abnormality of pHi in hypertension would be consistent with enhanced sodium-hydrogen exchanger activity and may provide potential mechanisms by which hypertension and its complications could develop. OBJECTIVES: To determine in-vivo intracellular pH of skeletal muscle at rest and during recovery from exercise-induced acidosis in hypertensive and normotensive subjects. METHODS: Using 31-phosphorus magnetic resonance spectroscopy, pHi of the dominant flexor digitorum superficialis was measured in 20 Caucasian subjects (14 male) with essential hypertension and 20 normotensive controls matched for gender, age, race and body mass index. Measurements were made at rest and during the exercise and recovery periods of a stepped incremental maximal exercise protocol. The rate of pHi recovery from exercise-induced acidosis was calculated by linear regression over the first 210 s of recovery from the pHi time plots of respective subjects. RESULTS: Mean resting pHi in the hypertensive (7.05 +/- 0.04) and normotensive groups (7.06 +/- 0.04) were not significantly different. There was a significant effect of gender on pHi: mean pHi was 7.07 +/- 0.03 in males and 7.02 +/- 0.03 in females, respectively (P < 0.0005). The mean intracellular pH achieved by exercise was 6.74 +/- 0.31 in hypertensive individuals and not significantly different in normotensive individuals (6.68 +/- 0.19; P = 0.4). The mean rate of pHi recovery in the hypertensives was 0.08 +/- 0.03 pH units/min and not significantly different in normotensives (0.08 +/- 0.02; P = 0.4). CONCLUSIONS: These results contrast with previously documented abnormalities in the control of pHi in hypertension and demonstrate the absence of major in-vivo disturbances of pHi in skeletal muscle, both at rest and during recovery from exercise-induced acidosis, in essential hypertension. Therefore, it is possible that previously documented abnormalities of pHi and activity of the exchanger may be either specific to cell type or not present under in-vivo conditions.

Acute and sustained changes in sodium balance during nifedipine treatment in essential hypertension.

PURPOSE: To assess the changes in sodium excretion and sodium balance after initiation of nifedipine treatment and after withdrawal of nifedipine. PATIENTS: Eight patients with uncomplicated mild to moderate essential hypertension were entered in a single-blind, placebo-controlled study of 39 days' duration. METHODS: Two 7-day periods while on a fixed sodium intake of 150 mmol/day approximately 3 weeks apart. After 4 days of a placebo and fixed sodium intake, patients were given nifedipine GITS (gastrointestinal therapeutic system) once a day and carefully studied for the following 4 days. Thereafter, patients continued to receive nifedipine GITS, and approximately 3 weeks later they were studied again for a week while on a fixed sodium intake. Nifedipine administration was stopped and changes occurring after withdrawal were studied. RESULTS: Nifedipine caused a significant increase in sodium excretion with a cumulative loss of sodium of 38 mmol per subject within the first 4 days of treatment. The withdrawal of nifedipine treatment caused a significant decrease in sodium excretion and a cumulative retention of sodium of 42 mmol per subject within the first 4 days of withdrawal. CONCLUSION: Nifedipine causes an acute and a sustained reduction in sodium balance in patients with essential hypertension. This prolonged effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

A double-blind crossover study of the effect of concomitant diuretic therapy in hypertensive patients treated with amlodipine.

Twelve patients with essential hypertension who were already on treatment with the long-acting calcium antagonist amlodipine (5 mg once daily) were entered into a double-blind, randomized crossover study of the addition of one month's treatment with either bendrofluazide (5 mg once daily) or matching placebo. The addition of bendrofluazide did not cause any statistically significant fall in the supine blood pressure compared to treatment with placebo (147.6/90.1 +/- 4.8/2.8 v 150.8/92.6 +/- 4.3/2.3 mm Hg, respectively). Plasma potassium was significantly lower on bendrofluazide as compared to placebo (3.11 +/- 0.14 v 3.62v +/- 0.13 mmol/L, P less than .001) and 10 of 12 patients had a fall in plasma potassium while on diuretic. The results of this study suggest that a thiazide diuretic has little additive effect on blood pressure in patients already on the long-acting dihydropyridine amlodipine, and may cause hypokalemia.

Atrial natriuretic peptide, aldosterone, and plasma renin activity in peripartum heart failure.

Plasma concentrations of atrial natriuretic peptide and aldosterone and plasma renin activity were measured in patients with peripartum heart failure and in age matched healthy women post partum. Both groups had carried out traditional postpartum practices of salt consumption and body heating. Plasma concentrations (mean (SEM)) of atrial natriuretic peptide were significantly higher in the seven patients with peripartum heart failure (146.9 (24.3) pg/ml) than in the seven controls (4.4 (0.8) pg/ml). Both plasma aldosterone and plasma renin activity were suppressed in the patients with peripartum heart failure. After treatment for the heart failure plasma atrial natriuretic peptide fell considerably and there were associated increases in plasma aldosterone and plasma renin activity. The high plasma concentrations of atrial natriuretic peptide may have been a compensatory response to salt and water retention as well as to the heart failure. These high concentrations could also, in part, have suppressed the release of aldosterone and renin in an attempt to correct for volume overload.

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.

Does a diuretic cause a further fall in blood pressure in hypertensive patients already on nifedipine?

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.

Does nifedipine reveal a functional abnormality of arteriolar smooth muscle cell in essential hypertension--the effect of altering sodium balance.

Nifedipine, given to both normotensive and hypertensive subjects, caused a greater fall in blood pressure the higher the initial blood pressure. Increasing salt intake enhanced the acute blood-pressure-lowering effect of nifedipine in both normotensive and hypertensive subjects. In hypertensive subjects on longer-term treatment with nifedipine tablets, the addition of bendrofluazide caused no further significant fall in blood pressure. These findings provide circumstantial evidence that there may be a link between sodium intake, sodium balance, and inhibitor of sodium transport, and a functional abnormality of the smooth muscle cell to calcium-entry antagonists.

Captopril: contrasting effects of adding hydrochlorothiazide, propranolol, or nifedipine.

Because captopril alone does not control blood pressure in all patients with essential hypertension, studies were performed to assess the effect of sodium intake and of captopril combined with hydrochlorothiazide, propranolol, and nifedipine. Captopril given for 5 days to normotensive subjects having high, normal, and low sodium intakes reduced blood pressure the most in those on the lowest intake; the fall correlated with that in plasma angiotensin II. When 12 patients with moderate hypertension had hydrochlorothiazide added to captopril their blood pressure fell significantly. When propranolol was added to captopril, however, there was no further fall in blood pressure. When propranolol was added to captopril and a diuretic, pressures measured 4 and 6 h after the last dose of captopril showed reduced values compared with placebo; pressures measured 2 and 12 h after did not. Nifedipine added to captopril reduced blood pressure more than either drug alone. When renin and angiotensin are low, as they may be in essential hypertension, captopril is less effective; its effectiveness should increase if sodium is restricted. Both diuretics and nifedipine increase the effectiveness of captopril; propranolol does not, although it may prolong captopril's action. Experience in patients with resistant hypertension suggests that adding nifedipine to captopril may reduce the need for diuretics, while adding captopril to nifedipine may reduce the need for beta-blockers.

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.

Characteristics of a (Na+-K+)-ATPase inhibitor in extracts of tea.

Extracts of tea were examined for inhibitors of the sodium-potassium pump by investigating the effect of the extracts on 1) isolated preparations of (Na+-K+)-ATPase from hog brain and human blood cells; 2) the displacement of radioactive ouabain from its specific receptor on red blood cells, and 3) the uptake of radioactive rubidium in intact red blood cells. It has been found that extracts of tea were potent inhibitors of the purified hog brain (Na+-K+)-ATPase. However, the inhibition was not specific for the (Na+-K+)-ATPase and the extract of tea did not displace 3H-ouabain in a specific ouabain-receptor assay. Additionally, the tea extracts displayed only a small inhibitory effect on the uptake of 86Rb in intact red blood cells. These observations suggest that the material is not like digitalis and that, unlike cardiac glycosides, it may inhibit the activity of the (Na+-K+)-ATPase by interacting with the enzyme at intracellular sites.

[Moderate supplementation of potassium in essential hypertension]. / L'apport d'un complément modéré de potassium dans l'hypertension essentielle.

23 unselected patients with mild to moderate essential hypertension, whose average supine blood pressure after two months' observation on no treatment was 154/99 mm Hg, were entered into an eight week double blind randomised crossover study of one month's treatment with slow release potassium tablets (60 mmol/day) versus placebo without alteration of dietary sodium or potassium intake. By the fourth week mean supine blood pressure had fallen by 4% on potassium supplementation compared with placebo. Urinary potassium excretion increased from 62 +/- 4.7 mmol/24 h on placebo to 118 +/- 7.4 mmol/24 h on potassium. The fall in blood pressure was not related to urinary sodium excretion before entry to the trial or while on placebo. Moderate potassium supplementation caused a small but significant fall in blood pressure in patients with mild to moderate essential hypertension and could be additive to the effects of moderate sodium restriction. This increase in potassium intake could be achieved with a potassium-based salt substitute and a moderate increase in vegetable and fruit consumption. Moderate dietary sodium restriction with dietary potassium supplementation may obviate or reduce the need for drug treatment in some patients with mild to moderate hypertension.

Does increasing potassium intake lower blood pressure in essential hypertension?

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.

Does potassium lower blood pressure by increasing sodium excretion? A metabolic study in patients with mild to moderate essential hypertension.

Potassium chloride (96 mmol potassium/day) in the form of 12 Slow K tablets/day in 10 patients on an intake of 150 mmol sodium and 80 mmol potassium produced a cumulative sodium loss of 110 mmol by the 12th day of potassium supplementation. At the same time there was attenuation of the expected increase in plasma renin activity appropriate for such a sodium loss. The lack of rise in plasma renin activity and hence angiotensin II combined with sodium loss may account at least in part for the observed blood pressure fall. No change in ouabain-sensitive or total white cell sodium efflux rate constant was found. An effect of an increase in plasma potassium on the sodium pump cannot be excluded as the white cell sodium efflux rate constant was measured in a fixed external potassium concentration. There was no evidence from plasma noradrenaline measurements that increasing potassium intake reduces sympathetic activity in the resting state.

The acute response to nifedipine is related to pre-treatment blood pressure.

The acute response to nifedipine 5 mg was studied in 11 young normotensive subjects and 18 older normotensive subjects who were age matched with 33 patients with uncomplicated essential hypertension. There was an immediate fall in blood pressure which was significantly greater in the hypertensive subjects--10.4%--compared to the normotensive subjects where it was only 4.7%. The best predictor of response both in the hypertensive and normotensive subjects was the pre-treatment mean blood pressure. Multiple regression analysis showed that the addition of age and plasma renin activity made little effect. These results clearly demonstrate that, at least acutely, nifedipine becomes more effective the higher the blood pressure. They are compatible with the idea that nifedipine is partly working on a mechanism which is responsible for the high blood pressure and therefore becomes more effective the higher the blood pressure.

Moderate potassium supplementation in essential hypertension.

23 unselected patients with mild to moderate essential hypertension, whose average supine blood pressure after two months' observation on no treatment was 154/99 mm Hg, were entered into an eight week double blind randomised crossover study of one month's treatment with slow release potassium tablets (60 mmol/day) versus placebo without alteration of dietary sodium or potassium intake. By the fourth week mean supine blood pressure had fallen by 4% on potassium supplementation compared with placebo. Urinary potassium excretion increased from 62 +/- 4.7 mmol/24 h on placebo to 118 +/- 7.4 mmol/24 h on potassium. The fall in blood pressure was not related to urinary sodium excretion before entry to the trial or while on placebo. Moderate potassium supplementation caused a small but significant fall in blood pressure in patients with mild to moderate essential hypertension and could be additive to the effects of moderate sodium restriction. This increase in potassium intake could be achieved with a potassium-based salt substitute and a moderate increase in vegetable and fruit consumption. Moderate dietary sodium restriction with dietary potassium supplementation may obviate or reduce the need for drug treatment in some patients with mild to moderate hypertension.