Plasma and tissue kallikrein-kinin systems during acute administration of frusemide in normotensive and hypertensive humans.

1. This study aims to further elucidate the role of the tissue and plasma kallikrein-kinin systems in blood pressure, electrolyte and volume homoeostasis. Components thereof and of the renin-angiotensin-aldosterone system were measured in conjunction with frusemide administration, in normotensive subjects and in patients with primary hypertension. 2. Frusemide increased plasma pre-kallikrein, angiotensin II and aldosterone concentrations and plasma renin activity, whereas the plasma level of tissue kallikrein remained unchanged. Basal values and the induced changes were similar in both groups. 3. Frusemide increased the urine volume and the excretion of Na+, K+, Mg2+, Cl-, aldosterone, prostaglandin E2 and tissue kallikrein. These changes were similar in both groups, but the total tissue kallikrein excretion was significantly lower in the hypertensive patients. Excretion of electrolytes and hormones was also measured during three 24 h urine collection periods and did not differ between the two groups. 4. Thus, acute administration of frusemide to hypertensive patients and normal subjects increased the plasma level of pre-kallikrein, possibly indicating less activation to kallikrein and subsequently less kinin generation in the blood stream. This also suggests a role for the plasma kallikrein-kinin system in the regulation of vascular tone and blood volume. Circulating tissue kallikrein does not seem to be acutely involved. 5. Urinary excretion of kallikrein is reduced in patients with primary hypertension after the administration of frusemide, apparently without affecting the renal excretory response.     

An Apparatus for Rapid Micro-Titration of Calcium in Serum with Edta

Abstract

In 10 patients with essential hypertension plasma (T-1824) and extracellular fluid volumes (⁸²Brdistribution space), mean blood pressure and serum potassium were determined before treatment, after 2 months of treatment with hydrochlorothiazide and 3 and 6 months of combined thiazide-triamterene treatment. During combined treatment, extracellular fluid volume and mean blood pressure were considerably decreased, whereas the plasma volume reduction was not significant. Serum potassium rose during combined treatment, but was still significantly reduced compared to the control levels. In conclusion, triamterene is a valuable supplement to thiazides in long-term antihypertensive treatment.     

Comparative study of pharmacokinetics and effects on urinary secretion of electrolytes of furosemide and furosemide-amiloride in healthy subjects]

A randomized cross over study was carried out in 12 healthy volunteers to investigate simultaneously the pharmacokinetics and the effects on urinary volume and electrolyte excretion after administration of single doses of 40 mg frusemide and a combination tablet containing both 40 mg frusemide and 5 mg amiloride. From a statistical analysis of plasma levels of frusemide and amiloride measured by HPLC methodology, no significant difference between the reference drug alone, frusemide, and the combination tablets was observed in mean peak plasma levels, mean times to peak or mean areas under the plasma concentration-time curves (AUC). Frusemide and the combination tablet both produced a rapid and powerful diuresis in the 0-2 hours postdose period and did not differ significantly in urine output at any time point. However a difference in natriuretic activity was observed between frusemide and the combination with the latter producing a significantly greater sodium excretion in the 0 to 2 hours period (p less than 0.05). Potassium retaining activity throughout the 24 hours was marked after the administration of the combination, the potassium excretion being significantly less (p less than 0.05) than either control of frusemide alone. There was also a significant correlation between plasma levels of frusemide and the time course of urine and electrolyte excretion in healthy subjects.     

RENAL EFFECTS OF NIFEDIPINE IN HEALTHY NORMOTENSIVE VOLUNTEERS. EFFECTS OF DOSE, FORMULATION, DURATION OF TREATMENT, AND CHLOROTHIAZIDE COADMINISTRATION

Renal effects of nifedipine were assessed in 3 groups of healthy normotensive volunteers. In the first group (N = 10), a single 20-mg dose of the slow-release formulation caused an increase in 8-h sodium excretion (P less than 0.025) and urine volume (P less than 0.005). Natriuresis (P less than 0.05) and diuresis (P less than 0.05) were still evident after 1 wk of pretreatment, but were significantly attenuated (P less than 0.05), in each case, compared to levels after a single dose. Natriuresis and diuresis after 2 wk of intake were indistinguishable from control levels. In another group of 8, a single 10 mg dose of the conventional formulation (capsule) effected natriuresis (P less than 0.01) and diuresis (P less than 0.001) similar to those associated with intake of a single 20-mg dose of the slow-release formulation. Natriuresis and diuresis associated with a 20-mg single dose of the conventional formulation were not different from control but were less than those following intake of the 10-mg dose (P less than 0.025 in each case). In the third group of 6, nifedipine, though weaker than chlorothiazide, promoted natriuresis (P less than 0.025) and diuresis (P less than 0.025) of the thiazide without augmenting its kaliuresis. In all the groups, there were no changes in creatinine clearance, and nifedipine did not alter kaliuresis. It is suggested that natriuretic and diuretic effects of nifedipine in healthy normotensive individuals are dependent on the dose employed, the formulation used, and the duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Humoral and hemodynamic effects of nitrendipine versus clonidine in patients with essential hypertension

A single-blind, randomized controlled study was conducted to assess and compare the antihypertensive effectiveness and the effects on glucose tolerance and renin-angiotensin-aldosterone balance of nitrendipine (Bay e 5009), a new dihydropyridine calcium antagonist, and clonidine. Twenty-six outpatients with uncomplicated mild to moderate essential hypertension were randomly allocated to receive 20 mg of nitrendipine or 0.25 mg of clonidine (slow-release formulation) daily for five weeks. One patient in the clonidine group dropped out. Both treatments significantly reduced systolic and diastolic blood pressures with negligible modifications in heart rate. However, diastolic blood pressure was reduced significantly more (P less than 0.001) with nitrendipine. Accordingly, 12 of 13 patients given nitrendipine attained the goal of diastolic pressure less than or equal to 90 mmHg, according to criteria of the Hypertension Detection and Follow-up Program, while only three of 12 patients in the clonidine group achieved this goal. Side effects were mild and transient in both treatment groups. No definite trends in plasma renin activity or plasma aldosterone concentration, or in blood glucose or immunoreactive insulin (measured both in fasting conditions and after an oral glucose tolerance test), were evident when baseline and posttreatment values were compared. The results of this study suggest that nitrendipine is an effective and safe antihypertensive agent and is devoid of adverse effects on glucose tolerance and renin-aldosterone homeostasis.     

Piretanide, a potassium stable diuretic, in the treatment of essential hypertension: a double-blind comparison of two formulations

In a randomized double-blind parallel group study the effects of two formulations of piretanide (standard tablet and slow-release capsule) were compared in patients with mild to moderate essential hypertension. Forty patients entered the study and thirty-seven completed it. Both formulations of piretanide produced a significant reduction in erect and supine blood pressure which was evident at 2 weeks and was maintained and further enhanced over the ensuing trial period. A mean maximal fall in supine diastolic pressure of 22% was observed in the piretanide tablet group, and of 20% in the slow-release piretanide group. Blood pressure fell more quickly at the beginning of treatment with the tablet preparation, such that there was a significant difference between the groups up to the fourth week. After this point the blood pressure lowering effect was very similar in both groups and there was a progressive reduction in supine blood pressures over the 12-week active-treatment period. Slow-release piretanide produced a smoother effect than the tablet formulation. There were no significant changes in serum potassium and serum magnesium in either treatment group. Minor changes were seen in some other biochemical and haematological variables but these were of no clinical significance. Three patients were withdrawn from the study because of side-effects: one because of an excessive antihypertensive response to the tablet formulation; and two because of allergic reactions to the slow-release preparation. Side-effects were otherwise mild and infrequent.     

The effect of intravenous frusemide on urine dopamine in normal volunteers: studies with indomethacin and carbidopa

1. The urine dopamine response to intravenous frusemide (30 mg) was investigated in 15 salt replete male volunteers. The effects of oral indomethacin (100 mg) and oral carbidopa (100 mg) given before intravenous frusemide were studied in the same group of subjects. 2. Frusemide produced a significant increase in urine dopamine output within 15 min. 3. Indomethacin attenuated the natriuretic and renin responses to frusemide, but did not alter urine dopamine output. 4. Carbidopa lowered urine dopamine to undetectable levels, but did not significantly affect the natriuretic and renin responses to frusemide. 5. We conclude that urine dopamine excretion after frusemide is not directly related to increased sodium excretion or renin response and it is not mediated by the prostaglandins. In addition, dopamine does not contribute to the renal actions of frusemide under normal conditions.     

Urinary kallikrein response to repeated frusemide injections in rats: effect of adrenalectomy and deoxycorticosterone acetate treatment

The effect of repeated intravenous injections of frusemide (0.17 mg/kg) on the urinary kallikrein excretion of normal, adrenalectomized and deoxycorticosterone acetate (DOCA)-treated adrenalectomized rats was studied. Adrenalectomy decreased baseline urinary kallikrein excretion, while DOCA treatment restored it to normal. Frusemide injections repeatedly increased urinary kallikrein excretion in the three groups of rats studied. Compared with control and DOCA-treated animals, adrenalectomized rats were less responsive. The excretion of urinary kallikrein was positively correlated with urine volume and with the excretion of sodium and potassium in all groups. The regression lines were shifted to the left in DOCA-treated adrenalectomized rats showing that mineralocorticoids enhance the effect of frusemide on urinary kallikrein excretion. The regression lines between urinary kallikrein excretion and the measured variables in adrenalectomized rats did not differ from those of control animals. We conclude that the response of urinary kallikrein to frusemide is influenced by the level of mineralocorticoid activity. The effect of frusemide on urinary kallikrein excretion does not appear to be a 'wash-out' of the enzyme since its influence did not subside after repeated injections.     

A fixed combination of metoprolol slow-release and chlorthalidone, given once daily, in the long-term treatment of arterial hypertension

A fixed combination of metoprolol slow-release 200 mg and chlorthalidone 25 mg was given once daily over a 3 months period in forty out-patients with mild-to-moderate arterial hypertension stage I or II WHO. The combination elicited a clear-cut antihypertensive effect lasting at least 24 hours after drug. As compared with pre-treatment values, systolic and diastolic blood pressures were gradually reduced within the first month of treatment, remaining nearly constant in the following 2 months. Treatment was well tolerated by all patients. Neither serum potassium nor any other laboratory test (creative, glucose, uric acid, etc) showed significant changes. In conclusion, slow-release metoprolol fixed association with chlorthalidone provides a safe and effective treatment of arterial hypertension even on a long-term basis. The once daily dosing schedule may considerably improve patient's compliance.     

Antihypertensive and biochemical dose-response study of tripamide

Tripamide is an experimental sulfonamide-derived diuretic antihypertensive agent. Twenty-four hospitalized patients with essential hypertension received placebo followed by 10, 25, 50, or 100 mg of tripamide daily in a randomized, double-blind design. All doses of tripamide significantly lowered standing arterial pressure. Changes in blood pressure, heart rate, and weight were not dose related, but the decrease in mean arterial pressure was significantly related to both age (P less than 0.02) and pretreatment blood pressure (P less than 0.05). Serum potassium levels were lowered significantly by the 25 and 100 mg daily doses of tripamide, whereas all doses of tripamide significantly reduced serum chloride levels and produced an increase in serum uric acid levels. Disparate time courses of antihypertensive and diuretic effects and the lack of a relationship between the increase in urine volume and the change in blood pressure suggest an additional antihypertensive action of tripamide or a delayed physiologic adaptation to volume depletion. Equal antihypertensive effects over the range of 10 to 100 mg/day, but greater hypokalemia at higher doses, suggest that future studies should employ the lower doses of tripamide.     

A MULTICENTRE, HOSPITAL STUDY OF THE EFFICACY AND SAFETY OF TERAZOSIN AND ITS EFFECTS ON THE PLASMA CHOLESTEROL LEVELS OF PATIENTS WITH ESSENTIAL HYPERTENSION

The safety, efficacy and the effect on the plasma total cholesterol of once-daily terazosin hydrochloride administered either as monotherapy or in combination with other antihypertensive therapy were evaluated in patients with mild-moderate uncontrolled essential hypertension in this U.K., open, multicentre hospital, 3-month study. Patients initially received 1 mg of terazosin as monotherapy or in addition to their current antihypertensive therapy followed by dose titration, if necessary, to a maximum of 10 mg over the first 6 weeks depending upon blood pressure control. Patients then continued treatment for a further 6 weeks on their optimum dosage. There were highly significant mean reductions in systolic and diastolic blood pressures at the end of 12 weeks for 439 patients of 18.5 and 14.0 mmHg (P less than 0.001), respectively, and were similar to the reductions shown when subgrouping the patients into either those 197 patients who were treated with terazosin as monotherapy (17.6/13.7 mmHg, P less than 0.001) or those 242 patients treated with terazosin in combination with other antihypertensive agents (19.3/14.2 mmHg, P less than 0.001). In addition, in a sub-group of 132 patients who had their mean total cholesterol measured at the end of 12 weeks' treatment, there was a significant reduction of -0.4 mmol/l (P less than 0.01). A similar significant mean reduction for total cholesterol was also shown when this subgroup was divided into those 50 patients who were treated with terazosin as monotherapy (-0.56 mmol/l, P less than 0.01), but not for those 82 patients treated with terazosin in combination with other antihypertensive agents (-0.3 mmol/l, P greater than 0.05 less than 0.1). No serious toxicity or safety problems were observed. Once daily administration of terazosin, either as monotherapy or in combination with other antihypertensive agents, proved to be safe and effective in reducing the blood pressure of patients with uncontrolled mild-moderate essential hypertension and favourably reduced the total plasma cholesterol level.     

中药足浴联合耳穴压豆治疗高血压临床疗效观察

目的:观察采用中药足浴疗法联合耳穴压豆治疗原发性高血压的临床效果。方法 :采用随机对照分组法,将80例确诊为1、2级原发性高血压患者分成两组,治疗组40例,采用中药足浴疗法联合耳穴压豆治疗;对照组40例,口服苯磺酸氨氯地平片治疗;观察两组血压变化,比较两组降压疗效和头晕、头痛症状积分变化情况。结果:两组患者血压较治疗前均明显降低(P0.05),治疗组降压总有效率为90.00%,对照组为87.50%,无显著差异(P0.05)。治疗组头晕、头痛症状改善优于对照组(P0.05)。均未出现不良反应。结论:中药足浴联合耳穴压豆对1、2级原发性高血压降压疗效显著,且可明显改善头晕、头痛症状。     

Intravenously administered frusemide increases glomerular permeability

1. The effects of frusemide on glomerular permeability were investigated in eight proteinuric patients by measuring the fractional protein and dextran clearances and correlating these observations with changes in renal haemodynamics. 2. Frusemide increased significantly the fractional albumin and IgG clearances. The fractional dextran clearances of molecules with a radius greater than or equal to 5.4 nm also increased significantly after frusemide injection. Pretreatment with indomethacin partly inhibited the increments in clearances of macromolecules. 3. The changes in the fractional protein clearances correlated significantly with those of inulin clearance There was also a high degree of correlation between the changes in fractional protein clearances and prostanoid excretion. 4. The data obtained suggest that frusemide increases glomerular permeability by influencing the effective pores of the glomerular capillary wall. The increased permeability possibly is due to changes in prostanoid synthesis.     

Reduced high density lipoprotein in stroke: relationship with elevated triglyceride and hypertension

Lipids and lipoproteins were analysed in forty-one survivors of stroke, aged less than 65 years, and the same number of age and sex matched controls without vascular disease. The stroke subjects had no evidence of coronary artery or peripheral vascular disease. High density lipoprotein cholesterol was significantly lower (1.19 +/- 0.06 mmol/l) in the stroke subjects than the controls (1.47 +/- 0.07 mmol/l). Triglyceride was also elevated in the stroke subjects, but this was confined to those who were taking antihypertensive treatment which included beta-blockers and/or thiazides. The low levels of high density lipoprotein in stroke were independent of hypertension or its treatment. Thus low levels of high density lipoprotein appear to be associated with cerebrovascular disease, while elevated triglyceride is a complication of anti-hypertensive therapy.     

Which hypertensive patient requires diuretic therapy?

Over the last decade the role of diuretics as first-line agents for the treatment of hypertension has diminished substantially. The present review encourages the reader to reconsider the current trend for a decline in the use of these inexpensive antihypertensive drugs whose efficacy is well documented. Diuretics have been used in 16 placebo controlled studies with over 13,000 patients as first-line drugs to lower blood pressure. These drugs were shown to reduce total mortality by 11%, cerebrovascular events by 34% and coronary morbidity by 29%. The magnitude of blood pressure reduction with low-dose thiazide diuretics is comparable to that of a therapy with high-dose thiazides, without the serious metabolic side effects observed with the higher dosage. In combination with other antihypertensive agents, diuretics counteract the compensatory regulatory responses, such as volume expansion and edema formation. Moreover, it has been shown that a combination with low-dose thiazides may not only further decrease blood pressure but also reduce cerebrovascular and coronary mortality. Advantages of diuretics in the treatment of hypertension can be appreciated in special clinical conditions, for instance in patients with edema, heart failure, renal failure, nephrotic syndrome and portal hypertension. Low-dose diuretics still have a place as first-line drugs for the treatment of mild, uncomplicated essential hypertension. Moreover, as opposed to other blood pressure lowering agents, there is sufficient scientific evidence for the primary preventive effect of low-dose thiazide.     

Addition of indapamide to frusemide increases natriuresis and creatinine clearance,but not diuresis,in fluid overloaded ICU patients

BackgroundFluid and sodium overload are a common problem in critically ill patients. Frusemide may result in diuresis in excess of natriuresis. The addition of indapamide may achieve a greater natriuresis, and also circumvent some of the problems associated with frusemide. The objective of this study was to examine the effect of adding indapamide to frusemide on diuresis, natriuresis, creatinine clearance and serum electrolytes.MethodsFluid overloaded ICU patients were randomised to either intravenous frusemide (Group F) or intravenous frusemide and enteral indapamide (Group F + I). Comprehensive exclusion criteria were applied to address confounders. 24 hour urine was analysed for electrolytes and creatinine. Serum electrolytes were measured before and 24 hours after administration of diuretics.ResultsForty patients (20 in each group) were included in the study. The groups were similar in their baseline characteristics. Over the 24 h study period, patients in Group F + I, had a larger natriuresis (P = 0.01), chloride loss (P = 0.01) and kaliuresis (P = 0.047). Patients in Group F + I also had a greater 24 hour urinary creatinine clearance (P = 0.01). The 24 hour urine volume and fluid balance was similar between the groups. Patients in Group F had an increase in serum sodium (P = 0.04), while patients in Group F + I had a decrease in both serum chloride (P = 0.01) and peripheral oedema (P < 0.001) during the study duration.ConclusionIn fluid overloaded ICU patients, addition of indapamide to frusemide led to a greater natriuresis and creatinine clearance. Such a strategy might be utilised in optimising sodium balance in ICU patients.     

Chlorthalidone alone or in fixed combination with slow-release metoprolol in the management of arterial hypertension: a long-term study of 545 patients

In a double-blind trial, 545 out-patients with essential hypertension received 25 mg/day chlorthalidone alone (274 patients) or in fixed combination with 200 mg/day slow-release metoprolol (271 patients) for 8 weeks. Both treatments significantly (P less than 0.001) decreased systolic and diastolic blood pressure; 45.6% of patients receiving chlorthalidone and 82.5% receiving combined therapy had a diastolic blood pressure of less than 95 mmHg. Patients not controlled by chlorthalidone or chlorthalidone plus metoprolol subsequently received chlorthalidone plus metoprolol (137 patients) or chlorthalidone plus metoprolol plus a third drug (34 patients), respectively, for 8 weeks. A total of 79.5% of patients receiving chlorthalidone plus metoprolol and 61.8% receiving chlorthalidone plus metoprolol plus a third drug had a diastolic blood pressure of less than 95 mmHg. Only 5.9% of patients experienced mild to moderate side-effects. Plasma potassium levels significantly (P less than 0.01) decreased during the first 8 weeks only. It is concluded that a diuretic alone or in fixed combination with a beta-blocker is effective in the long-term treatment of arterial hypertension.     

Interaction of diuretics and non-steroidal anti-inflammatory drugs in man

1. The influence of four diuretics on renal prostaglandins was investigated in a study designed in two parts (A and B): A, 24 normal subjects on a constant sodium intake received frusemide (80 mg daily), or hydrochlorothiazide (100 mg), or triamterene (200 mg) or spironolactone (300 mg); B, the same subjects were pretreated for 3 days with indomethacin (150 mg daily), which was continued during the 3 day administration of the respective diuretics and during a 2 day post-diuretic period. 2. In study A, only triamterene provoked a rise in urinary prostaglandins E2 and F2 alpha (+ 474 +/- SEM 92%, P less than 0.01, and + 192 +/- 7%, P less than 0.01). In study B, prostaglandins were significantly inhibited in all subjects. After indomethacin, the natriuretic effect of frusemide and spironolactone was reduced by 80 +/- 12% (P less than 0.01) and 54 +/- 11% (P less than 0.001), whereas the natriuresis induced by hydrochlorothiazide and triamterene was unchanged. No correlation was found between urinary PGE2 and F2 alpha and natriuresis. 3. When triamterene was associated with indomethacin, two subjects developed reversible acute renal failure. 4. Plasma renin activity and urinary aldosterone were stimulated by the four diuretics in study A, but their response was blunted in study B. Urinary antidiuretic hormone was not modified by diuretics but was suppressed by indomethacin. 5. Diflunisal, a structurally unrelated nonsteroidal anti-inflammatory drug, given to 12 of the subjects provoked similar interactions with frusemide, hydrochlorothiazide and spironolactone. 6. The results suggest that prostaglandins contribute to the natriuretic effects of frusemide and spironolactone, but not to those of hydrochlorothiazide and triamterene.     

Effect of indapamide on urinary calcium excretion in patients with and without urinary stone disease

BACKGROUND: Indapamide is an antihypertensive agent similar to thiazides, but with some different effects. Thiazide and thiazide-like diuretics are useful in preventing recurrent urinary stone formation due to their hypocalciuric effects. OBJECTIVE: To determine the hypocalciuric and other effects on certain laboratory parameters of indapamide 1.5 mg in different patient groups. METHODS: Four groups of patients recruited from urology and nephrology outpatient departments were experiencing non-hypercalciuric urinary stone disease (group 1), idiopathic hypercalciuria (group 2), urinary stone disease with hypercalciuria (group 3), and essential hypertension (group 4). In all patients, fasting serum uric acid, calcium, sodium, potassium, cholesterol, triglyceride, parathyroid hormone (PTH) values, and morning second-spot urine calcium and creatinine levels were assessed before and 8 weeks after treatment with indapamide. RESULTS: Urinary calcium excretion was reduced significantly in all groups: group 1 from 0.10 +/- 0.02 to 0.07 +/- 0.03 (mean +/-SD; 30% reduction; p < 0.001), group 2 from 0.30 +/- 0.15 to 0.15 +/- 0.10 (50% reduction; p < 0.001), group 3 from 0.35 +/- 0.15 to 0.20 +/- 0.10 (43% reduction; p < 0.001), and group 4 from 0.10 +/- 0.03 to 0.08 +/- 0.02 (20% reduction; p < 0.0010). These results should be interpreted with caution since no control group was included in this study. Mean serum uric acid and triglyceride levels were significantly increased, and mean PTH and potassium levels and diastolic and systolic blood pressure were significantly decreased in all groups. Few temporary adverse effects, such as dizziness and fatigue, were noticed and none of them caused discontinuation of treatment. CONCLUSIONS: Indapamide 1.5 mg/day is effective in decreasing calciuria in patients with non-hypercalciuric urinary stone disease, idiopathic hypercalciuria, urinary stone disease with hypercalciuria, and essential hypertension. This could be achieved with few adverse effects similar to those of thiazides and indapamide 2.5 mg. Indapamide decreased the PTH levels in all groups. Long-term clinical benefits of these effects should be evaluated prospectively with further randomized studies.