Efficacy of potassium and magnesium in essential hypertension: a double-blind,placebo controlled,crossover study.

OBJECTIVE--To evaluate the antihypertensive activity of potassium given alone or in combination with magnesium in patients with mild hypertension. DESIGN--A double blind, randomised, placebo controlled, crossover trial of 32 weeks'' duration. SETTINGS--Cardiology outpatient department, Sassoon General Hospitals, Pune, India. PATIENTS--37 Adults with mild hypertension (diastolic blood pressure less than 110 mm Hg). INTERVENTION--Patients received either placebo or potassium 60 mmol/day alone or in combination with magnesium 20 mmol/day in a crossover design. No other drug treatment was allowed. MEASUREMENTS--Blood pressure and heart rate assessed at weekly intervals and biochemical parameters at monthly intervals. RESULTS--Potassium alone or in combination with magnesium produced a significant reduction in systolic and diastolic blood pressures (p less than 0.001) and a significant reduction in serum cholesterol concentration (p less than 0.05); other biochemical variables did not change. Magnesium did not have an additional effect. Urinary potassium excretion increased significantly in the groups who received potassium alone or in combination with magnesium. The drug was well tolerated and compliance was satisfactory. CONCLUSION--Potassium 60 mmol/day lowers arterial blood pressure in patients with mild hypertension. Giving magnesium as well has no added advantage.     

Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension.

OBJECTIVE--To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN--Exploratory study in which active treatment was preceded by placebo. SETTING--Inpatient unit of teaching hospital. PATIENTS--Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS--Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS--With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS--The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.     

Short term effect of captopril on microalbuminuria induced by exercise in normotensive diabetics.

OBJECTIVE--To investigate whether captopril has any effect on microalbuminuria induced by exercise in normotensive diabetic patients with early stage nephropathy. DESIGN--Randomised, double blind, crossover trial. SETTING--Outpatient department. PATIENTS--22 diabetics with stage II nephropathy (urinary albumin excretion rate less than 20 micrograms/min; 15 with type I diabetes and seven with type II), 32 patients with stage III nephropathy (urinary albumin excretion rate 20-200 micrograms/min; 14 with type I diabetes and 18 with type II), and 10 normal subjects. INTERVENTIONS--Four exercise tests on a cycle ergometer: the first two under basal conditions and the third and fourth after subjects had received captopril (two 25 mg doses in 24 hours) or placebo (two tablets in 24 hours). END POINT--Exercised until 90% of maximum heart rate achieved. MEASUREMENTS AND MAIN RESULTS--Mean urinary excretion one hour after the first two exercise tests was 21 micrograms/min in normal subjects, 101 micrograms/min in diabetic patients with stage II nephropathy, and 333 micrograms/min in those with stage III nephropathy. Similar results were obtained after placebo. After captopril the urinary excretion rate one hour after exercise was significantly decreased in diabetics with stage II (36 micrograms/min) and stage III (107 micrograms/min) disease compared with placebo but not in normal subjects. Systolic and diastolic pressures were similar in the three groups after placebo and captopril had been given. CONCLUSIONS--Captopril significantly reduces microalbuminuria induced by exercise in normotensive diabetics without affecting systemic blood pressure. Captopril may reduce renal intracapillary pressure.     

Relation between dose of bendrofluazide,antihypertensive effect,and adverse biochemical effects.

OBJECTIVE--To determine the relevant dose of bendrofluazide for treating mild to moderate hypertension. DESIGN--Double blind parallel group trial of patients who were given placebo for six weeks and then randomly allocated to various doses of bendrofluazide (1.25, 2.5, 5, or 10 mg daily) or placebo for 12 weeks. SETTING--General practices in Zealand, Denmark. PATIENTS--257 Patients with newly diagnosed or previously treated hypertension, aged 25-70, who had a mean diastolic blood pressure of 100-120 mm Hg after receiving placebo for six weeks. MAIN OUTCOME MEASURES--Reduction in diastolic blood pressure and changes in biochemical variables (potassium, urate, glucose, fructosamine, total cholesterol, apolipoprotein A I, apolipoprotein B, and triglyceride concentrations). RESULTS--All doses of bendrofluazide significantly reduced diastolic blood pressure to the same degree (10-11 mm Hg). Clear relations between dose and effect were shown for potassium, urate, glucose, total cholesterol, and apolipoprotein B concentrations. The 1.25 mg dose increased only urate concentrations, whereas the 10 mg dose affected all the above biochemical variables. CONCLUSION--The relevant range of doses of bendrofluazide to treat mild to moderate hypertension is 1.25-2.5 mg a day. Higher doses caused more pronounced adverse biochemical effects including adverse lipid effects. Previous trials with bendrofluazide have used too high doses.     

Quantification and kinetics of purine catabolism in Dalmatian dogs at low and high purine intakes

1. In eight Dalmatian dogs low and high purine intakes resulted in plasma urate levels from 25 to 185 mumol/l. 2. The relationship between purine intake and excretion of uric acid and allantoin per day was described by linear regression equations. 3. The elimination of endogenous purines was 1.8 mmol/day for urate and 1.7 mmol/day for allantoin. Exogenous purines increased renal excretion by 0.57 mmol/mmol. 4. Kinetic measurements with [2(-14)C]uric acid infused continuously into each of two dogs on low and high purine revealed increases of plasma pool (urate + allantoin) of 3.3 fold and entry rate of 4.0 fold. Conversion of urate into allantoin increased from 20 to 36%. 5. Renal elimination of catabolites increased 3.3 fold and exhalation rate of purine-CO2 379 fold. Extra-renal elimination at high purine intake was quantitatively similar to humans and closely related to pool size.     

Circadian changes in levels of magnesium in serum of healthy individuals]

Circadian changes in blood serum magnesium levels in healthy individuals. We examined circadian changes of the serum magnesium in 20 healthy subjects. Blood samples were taken every second hour during the 24 hours. Male serum magnesium concentrations increased from the lowest level (0.810 +/- 0.035 mmol/l) observed at 8.00 am to the highest level (1.028 +/- 0.084 mmol/l) at 6.00 pm. Female-we observed two peaks of serum magnesium concentrations: first at 8.00 pm (0.992 +/- 0.103 mmol/l) and second at 4.00 am. (0.982 +/- 0.094 mmol/l) with the lowest level at noon) 0.789 +/- 0.043 mmol/l. Differences between extreme levels were statistically significant.     

Controlled trial of biofeedback-aided behavioural methods in reducing mild hypertension.

Employees of a large industry were screened for the presence of coronary risk factors. A total of 204 employees, aged 35-64 years, with two or more such factors (serum cholesterol concentration greater than or equal to 6.3 mmol/l (243.6 mg/100 ml), blood pressure greater than or equal to 140/90 mm Hg, and current cigarette consumption greater than or equal to 10 cigarettes a day) were randomly allocated to a biofeedback group receiving training in relaxation and management of stress or a control group. Both groups received simple health education literature. After eight weeks of training, and again eight months later, the biofeedback group showed a significantly greater fall in systolic and diastolic blood pressures than the control group (p less than 0.001). Plasma renin activity and plasma aldosterone concentration were measured in a subsample at entry to the study and again at eight weeks and eight months; both showed a greater reduction in the biofeedback compared with the control group at eight weeks'' follow-up. The greater reduction in blood pressure in the subjects in the biofeedback group compared with the control group (11.0 mm Hg systolic and 8.8 mm Hg diastolic), persisting eight months after the training, suggests that relaxation-based behavioural methods might be offered as a first-time treatment to patients with mild 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.     

Urinary excretion of electrolytes during prolonged physical activity in normal man

Nine normal young male students were studied during 2 days of relative rest, during 2 days of physical training and again during the succeeding 2 days of relative rest. Twenty-four hour urine collections showed that sodium and potassium excretion were lower during the exercise days, while urinary aldosterone excretion was increased. No differences in the 24-h urinary excretion of creatinine, calcium, and magnesium were found between the resting and exercise days. Hemoglobin concentration, hematocrit and red cell counts were decreased at 14 h and 42 h after exercise; these findings together with the increased serum bilirubin concentration could result from hemolysis. Plasma renin activity, angiotensin II and aldosterone concentration were increased 14 h after exercise but returned to baseline 42 h after exercise. Our data shows that one should take into account previous exercise when interpreting results of certain of these tests.     

Treatment of arterial hypertension with tienilic acid,a new diuretic with uricosuric properties.

Tienilic acid--2,3-dichloro-4-(2-thienyl-carbonyl)phenoxyacetic acid--is a new diuretic with uricosuric properties. Nineteen patients with moderate arterial hypertension were treated for 5 consecutive weeks in a randomized fashion in a double-blind study with either tienilic acid or hydrochlorothiazide. Blood pressure was significantly reduced and to the same degree with both drugs. In 7 of the 11 patients receiving tienilic acid the daily dose was increased from 250 to 500 mg after 2 weeks, and in 2 of the 8 patients taking hydrochlorothiazide the daily dose was increased from 50 to 100 mg. Because of the potent uricosuric action of tienilic acid the mean serum urate concentration decreased from 6.3 to 3.3 mg/dL in the patients taking the drug. In contrast, the patients receiving hydrochlorothiazide the mean serum urate concentration increased from 6.1 to 7.8 mg/dL. Moderate hypokalemia of almost identical degree (mean serum potassium values 3.6 and 3.5 mmol/L) and mild metabolic alkalosis were observed in both groups. Tienilic acid had a marked hypocalciuric effect, which was of the same magnitude as the observed with hydrochlorothiazide. During the 5 weeks of treatment no significant change in renal or liver function was observed in either group. There were no hematologic complications and the drug was remarkably well tolerated. Tienilic acid, because of its unique character as a diuretic, hypouricemic and antihypertensive agent, should become the preferred drug for the treatment of arterial hypertension.     

Effect of long-term treatment with salmeterol on asthma control: a double blind,randomised crossover study.

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.     

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.     

Ciprofloxacin in the prevention and treatment of surgical infections]

A clinico-laboratory study on ciprofloxacin made by Bayer (Germany) was applied to patients with extended posttraumatic wounds and performed with the aim of preventing postoperative purulent complications in patients operated on the organs of the gastrointestinal tract. In the both groups ciprofloxacin was administered orally in doses of 500 and 1000 mg and intravenously in a dose of 200 mg. The results of the assay on ciprofloxacin sensitivity of the isolates from the wound excretion and urine showed that they were more sensitive to ciprofloxacin than to aminoglycosides and cephalosporins. 15 minutes after the intravenous administration the serum concentration of ciprofloxacin amounted to 7.5 +/- 0.9 micrograms/ml and in 6 hours it was equal to 0.45 +/- 0.45 micrograms/ml, the mean concentrations of ciprofloxacin being attained in the bile (8.7 +/- +/- 3.9 micrograms/ml), gallbladder wall (5.5 +/- 3.8 micrograms/g), liver (0.73 micrograms/g), muscles (1.93 micrograms/g) and tendon (0.15 microgram/g). After the oral administration in a dose of 500 mg ciprofloxacin was detected in the blood serum in an amount of 2.0 +/- 0.7 micrograms/ml in 1 hour and in an amount of 0.9 +/- 0.13 micrograms/ml in 6 hours. After the drug oral administration in a dose of 1000 mg the maximum concentrations were: 6.34 +/- 4.2 micrograms/ml on the average and 2.1 +/- 0.8 micrograms/ml in 6 hours (0.4 micrograms/g in the muscles, 1.4 micrograms/g in the skin and 0.34 micrograms/g in the bones). The study showed that ciprofloxacin was a highly efficient antimicrobial agent in the treatment of the complicated wound infections and the prophylaxis of the purulent complications during the postoperative period in the patients operated on gastrointestinal organs.     

Beta blockade,diuretics, and salt restriction for the management of mild hypertension: a randomised double blind trial.

Ninety four patients with mild hypertension (average supine diastolic blood pressure (phase V) 95-110 mm Hg) were allocated at random to receive restriction of dietary sodium (maximum allowed 70 mmol(mEq)/24 h) or a normal diet. In addition, they received in random order 25 mg chlorthalidone, 200 mg metoprolol (slow release), and a fixed combination of these two drugs. Each drug treatment was given for four weeks and alternated with four weeks of placebo. Forty four patients were allocated to sodium restriction (group 1) and 50 to normal diet (group 2). The mean 24 hour urinary sodium excretion in group 1 was 74 (SD 31) mmol(mEq)/24 h, and in group 2 132 (51) mmol/24 h. Compared with the screening blood pressure the average decrement of the supine blood pressure in group 1 was 16.0/8.6 mm Hg with placebo, 21.7/11.5 mm Hg with the diuretic, 28.5/17.8 mm Hg with the beta blocker, and 28.9/18.4 mm Hg with the combined agent; in group 2 these values were 13.3/6.1, 20.3/9.7, 21.3/12.9, and 29.4/16.8 mm Hg, respectively. There was a sharp decrease of the average potassium concentration during chlorthalidone and combination treatment periods (average value 3.3 mmol(mEq)/1). These results suggest that moderate salt restriction used as sole treatment has a limited though demonstrable blood pressure lowering effect but that when it is used as an adjuvant to beta blocker treatment its value is greatly enhanced.     

The effect of various ambient ammonia concentrations on the nitrogen metabolism of carp fry (Cyprinus carpio L.)

Authors studied how 125, 375 and 625 micrograms/l amounts of NH4Cl added to the water influenced the ammonia excretion of carp fry with an average weight of 2.4 g, compared to the control. During the course of the experiments the NH4N concentration, the pH and the temperature were measured for three days, twice daily. On the basis of our results the threshold concentration exerting harmful effects on the ammonia household of carp fry (disturbing the normal rate of metabolism in the fishes and decreasing their growth rate) is between 125 and 375 micrograms/l. NH4H (50-100 micrograms/l NH3). The ammonia concentrations exceeding 375 micrograms/l NH4+ (and 100 micrograms/l NH3, respectively) can be regarded as undesirable and harmful in frybreeding fish ponds. With regard to the ambient ammonia, a daily cycle developed in the excretion of ammonia: contrary to the control, a minimum in ammonia excretion was measured in the morning, while a maximum was measured in the afternoon.     

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.     

Magnesium levels in the body fluids of dam and fetal rabbits during the reproductive phase

Gestation- and lactation-dependent variations of magnesium concentrations were measured in the maternal and fetal body fluids and tissues of rabbits. Samples of serum, milk, and mammary gland were investigated. A decrease in magnesium in the maternal serum during the early gestation period from 0.80 mmol/l in the first week to 0.73 mmol/l in the third week was observed. In the last week of gestation a rapid increase of magnesium concentrations both in maternal (0.83 mmol/l) and fetal (2.84 mmol/l) serum was determined. An assumed active diaplacental transfer of magnesium from the doe to the fetus was indirectly established. An active transport mechanism for magnesium from the maternal serum into the mammary glands was enhanced by strong concentration gradients of approximately 1:33 between serum and milk.     

Blood lead concentration,blood pressure,and renal function.

Blood lead concentrations were related to blood pressure and indicators of renal function in a clinical survey of 7735 middle aged men from 24 British towns. There was no overall evidence that blood lead concentrations were associated with systolic or diastolic blood pressure (r = +0.03 and +0.01, respectively). In the 74 men with a blood lead concentration of 1.8 mumol/l (37.3 micrograms/100 ml) or more there was some suggestion of increased hypertension, but this did not reach significance. Blood lead concentration did not have any relation with serum creatinine concentration. Moderate increases in blood lead concentration were associated with small increases in mean serum urate concentration and small decreases in mean serum urea concentration; these associations were both reduced when alcohol consumption was taken into account. There is no indication that exposure to lead at concentrations commonly encountered in British men is responsible for impaired renal function or increased blood pressure.     

Hyperuricaemia in hypertension: role of alcohol.

Hyperuricaemia was present in 18 out of 73 men with untreated mild hypertension and was related significantly to alcohol intake, serum aspartate transaminase activity, and obesity. In the whole group the mean serum urate concentration correlated highly significantly with alcohol intake and activities of serum aspartate and alanine transferases but not with ponderal index, serum creatinine concentration, age, or blood pressure. Hypertension and hyperuricaemia are related at least in part through their common association with frequent alcohol use. A serum urate concentration exceeding 0.5 mmol/l (8--4 mg/100 ml) in a man with untreated hypertension is highly suggestive of heavy alcohol consumption. There was no evidence that hyperuricaemia had a deleterious effect on renal function.     

Reduction in blood pressure with a low sodium,high potassium,high magnesium salt in older subjects with mild to moderate hypertension.

OBJECTIVE--To examine the effect of a reduced sodium and increased potassium and magnesium intake on blood pressure. DESIGN--Randomised double blind placebo controlled trial. SETTING--General population of a suburb of Rotterdam. SUBJECTS--100 men and women between 55 and 75 years of age with untreated mild to moderate hypertension. INTERVENTIONS--During 24 weeks the intervention group received a mineral salt (sodium: potassium: magnesium 8:6:1) and foods prepared with the mineral salt. Controls received common salt and foods. MAIN OUTCOME MEASURE--Change in blood pressure. RESULTS--Complete follow up was achieved for 97 of the 100 randomised subjects. Systolic blood pressure (mean of measurements at weeks 8, 16, and 24) fell by 7.6 mm Hg (95% confidence interval 4.0 to 11.2) and diastolic blood pressure by 3.3 mm Hg (0.8 to 5.8) in the mineral salt group compared with the controls, with a 28% decrease in urinary sodium excretion and a 22% increase in urinary potassium excretion. Twenty five weeks after the study the difference in blood pressure between the groups was no longer detectable. CONCLUSION--Replacing common sodium salt by a low sodium, high potassium, high magnesium mineral salt could offer a valuable non-pharmacological approach to lowering blood pressure in older people with mild to moderate hypertension.