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[Changes in body fluid spaces in hypertension patients treated with different diuretics].

Body fluid spaces: total body fluid volume, extracellular fluid volume, circulating plasma volume, intracellular and interstitial fluid volumes were studied in 60 patients with essential hypertension, stage IIB. The studies were performed prior and following a two-week treatment with diuretics ( furosemid , oxodolin , hydrochlorothiazide, brinaldix ). The patients were divided into 3 groups. I--patients whose total body fluid volume was considerably increased due to intracellular fluid. They had the highest blood pressure level. Treatment with diuretics was the most effective in this group and was accompanied by intracellular fluid reduction and slight circulating plasma volume decrease. II--patients whose fluid spaces did not differ from those of normal subjects. Treatment with diuretics was effective and accompanied by simultaneous reduction in intracellular and interstitial fluid volumes. III--patients with reduced interstitial fluid volume and raised circulating plasma/interstitial fluid ratio. Treatment with diuretics was ineffective and accompanied by intracellular fluid level reduction and fluid passage from the vascular bed into the interstitial space. Furosemid and oxodolin were most effective decreasing intracellular fluid volume, hydrochlorothizide --reducing interstitial fluid volume and brinaldix was equally effective decreasing both fluid volumes.

Adult↗

Hemodynamic and endocrine changes associated with captopril in diuretic-resistant hypertensive patients.

To evaluate the therapeutic efficacy of oral angiotensin-converting enzyme inhibition with low-dose (average 30 mg/day) captopril in diuretic-resistant hypertension, its long-term cardiocirculatory action was determined by dye-dilution method and venous-occlusion forearm plethysmography in 11 uncontrolled patients taking a thiazide diuretic. Significant declines in mean blood pressure (average 12.4 +/- 1.4 percent) and systemic vascular resistance (28.7 +/- 3.2 percent) accompanied an increase in cardiac output (24.8 +/- 4.1 percent). Forearm vascular resistance (16.0 +/- 2.7 percent) decreased considerably, but the decrease in limb vascular resistance did not parallel the fall in systemic vascular resistance in magnitude (p less than 0.01), indicating that arteriolar dilatation occurred on a selective basis. Plasma renin activity increased after therapy as plasma aldosterone levels consistently fell, while plasma norepinephrine concentrations were not changed. There was a direct correlation between pretreatment plasma renin activity and the magnitude of the decline in systemic vascular resistance (p less than 0.05). These findings suggest that the inhibition of angiotensin-converting enzyme with captopril in diuretic-resistant hypertensive patients improves cardiocirculatory function through selective dilatation. The reordering of regional blood flow, which appears to result from release of angiotensin-mediated vasoconstriction as well as the suppression of aldosterone, may underlie the prolonged benefit observed in these patients. This oral vasodilator in very low dose appears to represent an effective adjunct for the treatment of hypertension refractory to diuretics.

Adult↗

The renin-angiotensin-aldosterone system and blood pressure during oxprenolol treatment in hypertensive patients pretreated with diuretics.

The interrelationship between PRA, urinary aldosterone excretion, and blood pressure was studied in 11 patients with essential hypertension while receiving a diuretic (1st week) and subsequently a diuretic + oxprenolol (2nd week). The diuretic reduced blood pressure and body weight but increased PRA and aldosterone. Oxprenolol reduced PRA on the 1st day but to a lesser extent on the 7th day. Blood pressure was decreased 1 day after oxprenolol administration, but to a greater extent on the 7th day. Blood pressure decrements were independent of renin suppression, but directly correlated to aldosterone changes. These data suggest that the hypotensive effect of oxprenolol in patients receiving diuretic treatment is independent of its suppression of renin. Aldosterone suppression may instead contribute to the hypotensive effect of the drug.

Adult↗

Diuretics, magnesium, potassium and sodium.

Diuretics increase renal magnesium excretion and, when chronically administered, decrease intracellular magnesium levels. This deficiency reduces active transport of potassium into the cell and intracellular potassium decreases irrespective of serum potassium levels. Potassium supplementation or the co-administration of potassium-sparing diuretics cannot maintain intracellular potassium at normal levels when intracellular magnesium is reduced. The effects of chronic magnesium supplementation have not been adequately studied. Maintenance of the diuretic dose at an effective minimum and curtailing sodium intake when diuretics are chronically prescribed are the simplest and safest manoeuvres which can be undertaken in order to prevent the occurrence of events usually ascribed to hypokalaemia and in fact principally due to low intracellular potassium which is associated with magnesium deficiency.

Diet, Sodium-Restricted↗

[Antihypertensive and diuretic effects of indapamide in normotensive and hypertensive rats (author's transl)].

Antihypertensive and diuretic actions of indapamide (SE-1520) were investigated in rats and compared with those of trichlormethiazide (TCMT). In normotensive rats, indapamide in a dose of 100 mg/kg p.o. did not show a significant effect on the blood pressure. In DOCA-saline and uni-nephrectomized DOCA-saline hypertensive rats, indapamide above 1 mg/kg and TCMT above 3 mg/kg with single oral or repetitive administration for 2 weeks reduced the blood pressure level. In spontaneously hypertensive rats (SHR), both indapamide and TCMT lowered the blood pressure with single doses above 10 mg/kg or repetitive doses above 3 and 10 mg/kg, respectively. In the diuretic test using normal rats, indapamide in doses ranging from 0.1 to 30 mg/kg increased urine volume and urinary electrolyte excretion. TCMT showed a more potent diuretic action at a lower dose level. In SHR, indapamide and TCMT produced a greater urine volume and electrolytes excretion. Indapamide inhibited the carbonic anhydrase activity and the potency was about 1/25 of that of acetazolamide in vitro. The antihypertensive activity of indapamide was more potent than that of TCMT and the reverse order to that of their diuretic potencies. It is suggested that the mechanism of antihypertensive effect of indapamide is different from that of TCMT.

Animals↗

The effect of diuretics on extrarenal potassium tolerance.

A potassium loading study was performed in acutely nephrectomized rats to determine the extrarenal effects of diuretics on potassium tolerance. Four diuretics were evaluated: hydrochlorothiazide, furosemide, bumetanide, and spironolactone. Following an intravenous potassium load (0.17 mEq/100 g over one hour), plasma potassium concentration rose by 2.69 +/- 0.26 to 3.67 +/- 0.20 mEq/L in all groups. There was no difference in the observed increment in plasma potassium concentration between animals receiving diuretics and control animals. These results demonstrate that, at the doses used, diuretics do not impair extrarenal potassium disposal in the rat.

Animals↗

Furosemide renal excretion rate and the effects of the diuretic on different tubular sites are modified by endogenous dopamine in normohydrated rats.

The present study was designed to explore the involvement of endogenous dopamine in furosemide excretion and in the actions of the diuretic on tubular sodium reabsorption. The dose-response relationship for the diuretic effect of furosemide given as i.v. bolus injections (0.2-7.5 mg.kg-1) was studied by clearance technique in pentobarbital-anesthetized rats treated with vehicle, benserazide (BZ) (25 mg.kg-1 i.v.) or SCH 23390 (50 micrograms.kg-1 + 10 micrograms.kg-1.min-1 i.v.). Furosemide induced the maximal diuresis 15 to 30 min after i.v. administration. The diuretic response was dose-dependent and was reduced in the animals treated with BZ and SCH 23390. Fractional sodium excretion was also increased by furosemide from 1.8 to 7.5% during the same period. This effect was reduced by both BZ or SCH 23390 by 35 to 50%. The effects of furosemide on proximal and distal renal tubules were dissected by measuring the renal lithium clearance (CLi+). Furosemide effective on proximal tubular sites (measured by FENa+ prox = CLi+/Cln) were completely abolished by BZ and SCH 23390, whereas both drugs reduced furosemide effects on distal tubular sites (measured by FENa+ distal = CNa+/CLi+) by 20 to 40%. Furosemide excretion rate during the peak response to the diuretic was measured in the urine. BZ and SCH 23390 diminished furosemide excretion by 45 to 80% as compared with vehicle-treated animals. The furosemide tubular effects and the proximal and distal functions measured by CLi+ determined during the peak response were correlated to the maximal excretion rate of furosemide in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Diuretic enhanced duplex Doppler sonography in 33 children presenting with hydronephrosis: a study of test sensitivity, specificity and precision.

PURPOSE: We assessed the value of diuretic enhanced Doppler sonography in the diagnosis of pediatric renal obstruction as well as its reproducibility, sensitivity and specificity. MATERIALS AND METHODS: We studied 33 children (68 kidneys) by standard diagnostic techniques and diuretic Doppler sonography. A total of 20 obstructed kidneys was compared to 48 without obstruction and we performed surgery on 13. An average of 2.3 resistive index measurements were made per test and 436 total resistive index values were assessed by Student's t distribution and chi-square analysis before and after surgical repair. The assessor was blinded to the clinical diagnosis. RESULTS: The obstructed mean resistive index before (0.71) and after (0.74) furosemide administration differed significantly from the nonobstructed mean resistive index (0.65, p < 0.02). Postoperative mean resistive index (0.68) was not affected by the diuretic and did not differ from the mean resistive index of nonobstructed kidneys. Resistive index test sensitivity was 76% and specificity was 88%. The precision for 3 values per test was +/- 0.11. CONCLUSIONS: When at least 3 values are obtained per test, diuretic Doppler sonography predicts the actual resistive index average with 98% confidence limits 90% of the time.

Adolescent↗

Loop diuretics act directly on adenylate cyclase in rat renal tubular basolateral membranes.

We have reported previously that loop diuretics, especially azosemide and ethacrynic acid, may act not only on the AVP receptor site, but also on the post-AVP receptor site in rat renal tubular basolateral membranes. The purpose of this study was to examine whether loop diuretics (furosemide, azosemide, ethacrynic acid) affect the post-AVP receptor components, using GTP-gamma S, forskolin and cholera toxin as tools acting distal to the receptor. Adenylate cyclase activity stimulated by 10(-9)M AVP was inhibited more potently by azosemide and ethacrynic acid than by furosemide at the concentration of 10(-3) M. Azosemide and ethacrynic acid at concentrations above 10(-4) M also significantly decreased the enzyme activity that was stimulated by 10(-7) M GTP-gamma S and 10(-5)M forskolin, while significant inhibition by furosemide was observed only at 10(-3)M. In addition, the inhibitory effect of these loop diuretics on cholera toxin-stimulated enzyme activity was almost similar to the results observed in AVP-, GTP-gamma S- or forskolin-stimulated the enzyme activity. From these results, we conclude that loop diuretics, especially azosemide and ethacrynic acid, directly affect adenylate cyclase in part as well as the AVP receptor site.

Adenylyl Cyclases↗

[Molecular structure of luminal diuretic receptors].

Since day to day sodium and water intake is more or less constant, the output by urinary sodium excretion is the key to maintain extracellular fluid volume within physiologic ranges. To achieve this goal, the kidneys ensure that most of the large quantities of filtered sodium are reabsorbed, a function that takes place in the proximal tubule, the loop of Henle and the distal tubule, and then the kidneys adjust the small amount of sodium that is excreted in urine in such a way that sodium balance is maintained. This adjustment occurs in the collecting duct. Three groups of diuretic-sensitive sodium transport mechanisms have been identified in the apical membranes of the distal nephron based on their different sensitivities to diuretics and requirements for chloride and potassium: 1) the sulfamoylbenzoic (or bumetanide)-sensitive Na+:K+:2CI- and Na+:CI- symporters in the thick ascending loop of Henle; 2) the benzothiadiazine (or thiazide)-sensitive Na+:CI- cotransporter in the distal tubule; and 3) the amiloride-sensitive Na+ channel in the collecting tubule. The inhibition of any one of these proteins by diuretics results in increased sodium urinary excretion. Recently, the use of molecular biology techniques, specially the functional expression cloning in Xenopus laevis oocytes, has led to the identification of cDNA's encoding members of the three groups of diuretic-sensitive transport proteins. The present paper reviews the primary structure and some aspects of the relationship between structure and function of these transporters as well as the new protein families emerging from these sequences. It also discusses the future implications of these discoveries on the physiology and pathophysiology of kidney disease and sodium retaining states.

Amino Acid Sequence↗

Diuretic and antihypertensive effects of 2-aminoethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK-447).

2-Aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride or MK-447, is a chemically novel diuretic agent which produced diuretic and saluretic effects in rats, dogs and chimpanzees. At doses ranging from 0.1 to 10 mg/kg p.o. (0.32-32 mumol/kg) MK-447 was more effective then furosemide at the same or higher doses in increasing the excretion of Na+, K+ and Cl- in rats and dogs. At single oral doses, MK-447 had antihypertensive activity in spontaneously hypertensive rats and renal hypertensive dogs. Other diuretics are known to lower arterial pressure in these models only by repeated administration. The antihypertensive and diuretic effects of MK-447 in spontaneously hypertensive rats were reduced by indomethacin.

Animals↗

New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-one derivatives as diuretics.

A series of new 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e] pyrimidin-5-ones 3-substituted and/or 8,9-hydrogenated was prepared and tested for their diuretic, natriuretic and kaliuretic activities on male Wistar rats at a dosage of 25 mg/kg or less. Diuretic and saliuretic activities were strongly influenced by substituents in 3-position. Quantitative structure-activity relationships show that electron withdrawn substituents in 3-position enhance both diuretic and saliuretic activities at 25 mg/kg. Global analysis of the variations introduced on pyridine, pyrimidine and thiazole rings of this tricyclic system showed an increases of diuretic and natriuretic activities when the formal charge on N9a and C9b increases. Potassium ion excretion also increases, although not as drastically a in the earlier cases. Regression equations were calculated by partial least squares method (PLS) and validated by the cross-validation (leave-one-out) technique.

Animals↗

Diabetes mellitus in treated hypertension: incidence, predictive factors and the impact of non-selective beta-blockers and thiazide diuretics during 15 years treatment of middle-aged hypertensive men in the Primary Prevention Trial Göteborg, Sweden.

The objective of this study was to analyse predictive factors for the development of diabetes mellitus during long-term treatment of hypertension and to compare the diabetogenic potential of thiazide diuretics and non-selective beta-adrenoceptor blockers. The study population comprised 686 hypertensive men, aged 47-54 years, who were followed for 15 years. Patients were treated with either thiazide diuretics or beta-adrenoceptor blockers as monotherapy or in combination with one another or alternative other antihypertensive drugs. During the first part of the study, i.e. during the 1970s, only non-selective beta-adrenoceptor blockers were used. The average yearly incidence of the development of diabetes mellitus during follow-up was 1.3%. In univariate analysis body mass index, serum triglyceride level, radiographic heart enlargement and beta-blocker therapy were significantly associated with the development of diabetes mellitus. Predictors selected by stepwise Cox regression were body mass index, radiological heart enlargement and beta-blocker therapy. Two subgroups with patients treated with nonselective beta-adrenoceptor blockers but not with thiazide diuretics during the first five years of follow-up (the beta-blocker group; n = 93) or with thiazide diuretics but not with nonselective beta-adrenoceptor blockers during the first five years of follow-up (the thiazide-group; n = 96) were identified. The relative risk for developing diabetes mellitus was significantly higher in the beta-blocker group being 6.1 after 10 years and 3.5 after 15 years treatment in comparison with the thiazide group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

[Comparative evaluation of the effectiveness of diuretics].

The study was conducted in 118 patients with cardiac and pulmonary lesions, aged 18 to 75 years. Among the diuretics the leading role belongs to Uregyt, and Lasix, as judged by their natriuretic and diuretic action, then follow Nuvorit, Hypothiaside and Brinaldix. Renese (polythiaside) produces the same diuretic effect as Nuvorit and Hypothiaside. Renese, Hypothiaside, Lasix and Uregyt enhance kaliuresis and often reduce potassium blood plasma concentrations, while Nuvorit and Brinaldix increase kaliuresis least of all, and often increase the potassium blood plasma level. Within two days of discontinuing Thriamterene nearly all body potassium that was retained under the effect of this drug is excreted. Nuvorit, Hypothiaside, Renese, Brinaldix, Lasix, Uregyt cause similar changes in the acid-base balance (respiratory and metabolic alkalosis), and produce no effect upon the acid-base balance rather seldom. Lasix and Uregyt cause metabolic alkalosis more often than other diuretics. Apart from that, Hypothiaside also causes respiratory acidosis in 1/4 of the patients.

Adolescent↗

Loop diuretics affect transcellular electrolyte transport in cells of the distal convoluted tubule.

Although loop diuretics act preferentially on sodium chloride absorption in the thick ascending limb of the loop of Henle in the nephron, high concentrations of some loop diuretics also impair sodium absorption in the distal convoluted tubule (DCT). To characterize further the inhibitory effect of these agents on sodium absorption in the DCT, the action of torsemide and furosemide on cell sodium, chloride and potassium concentrations was examined in individual DCT cells of the kidney cortex and also, for comparison, in proximal convoluted tubule cells. In addition, initial cell uptake rates of rubidium, an index of in vivo Na+/K(+)-ATPase activity, were studied. Both diuretics caused a significant reduction of intracellular sodium concentration and rubidium uptake in DCT cells but not in connecting tubule, principal, intercalated or proximal tubule cells. These findings are consistent with the concept that both diuretics reduce transcellular sodium absorption in DCT cells by impairing sodium entry across the apical cell membrane and, as a consequence, sodium extrusion by primary active Na+/K+ (Rb+) exchange across the basolateral membrane.

Animals↗

Diuretics potentiate angiotensin converting enzyme inhibitor-induced acute renal failure.

Previous studies suggest that angiotensin converting enzyme (ACE) inhibitors cause reversible acute renal failure (ARF) in patients with hypertension, congestive heart failure (CHF), and renal disease. These patients often receive diuretics concomitantly with ACE inhibitors. The purpose of this study was to examine whether ACE inhibitors alone produce ARF or whether they do so when used in combination with diuretics. The medical records of patients taking ACE inhibitors without or with diuretics were reviewed. Complete data from 74 patients were obtained and the data were analyzed. These 74 patients had a diagnosis of hypertension, CHF or diabetes mellitus. BUN and serum creatinine values before, during, and after discontinuation of ACE inhibitor therapy for a mean period of 8.7 months were collected. Seventy-four patients were divided into two groups: Group A (n = 41) patients who received ACE inhibitors alone; Group B (n = 33) patients who received a combination of an ACE inhibitor and a diuretic. ARF developed in 1 of 41 (2.4%) Group A patients compared to 11 of 33 (33%) Group B patients. This group difference was highly significant (P < .001). In Group A, mean serum creatinine before (1.24 +/- .34 mg/dl) was identical to that 1.23 +/- .33 mg/dl) after 8.7 months of ACE inhibitor therapy, whereas in Group B, post-mean serum creatinine (3.11 +/- 2.27 mg/dl) was significantly (P < .01) higher than pre-mean serum creatinine (1.65 +/- .85 mg/dl). CHF patients had a higher rate of ARF than patients with other diagnoses. Urinary electrolytes showed that 4 of 6 Group B patients had chloride concentration less than 20 mEq/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

Acute and chronic diuretic treatment selectively affects vascular permeability in the unanesthetized normal rat.

Diuretics are widely used antihypertensive agents, and although their renal actions have been well characterized, the extent of their vascular effects remains to be defined. Because hypertension is associated with numerous vascular complications whose incidences are not always lowered once blood pressure is regulated, this study was undertaken to evaluate the effects of five selected diuretics on capillary permeability to see if they could contribute in some way to these vascular abnormalities. Extravasation of Evans blue dye (EB: 20 mg/kg) injected in the caudal vein of male Wistar rats was used to assess capillary permeability to albumin. Indapamide (0.04 mg/kg), cicletanine (2.0 mg/kg), amiloride (0.3 mg/kg), hydrochlorothiazide (0.5 mg/kg) and furosemide (0.5 mg/kg) were administered by acute i.v. injection or by 10-day "chronic" gavage. EB extravasation was increased in the upper bronchi, lung parenchyma and kidney after acute administration of indapamide (54, 41 and 31%, respectively) and hydrochlorothiazide (45, 41 and 19%, respectively), and increased in all tissues but the duodenum (upper bronchi, lung parenchyma, heart, liver, kidney and muscle; 57-118%) after furosemide. In contrast, capillary permeability was reduced after acute cicletanine in the heart (31%), duodenum (49%) and muscle (58%) and after amiloride in the heart (25%) and muscle (63%). Pretreatment with indomethacin abolished most changes in EB extravasation induced by acute injection of the diuretics. After 10-day gavage, however, changes in capillary permeability were null after amiloride or hydrochlorothiazide treatment, attenuated after cicletanine or furosemide or even reversed after indapamide. Arterial pressure was not affected by diuretic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

New 2-aryl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-4-one derivatives as diuretics.

2-Aryl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-4-one derivatives having various substituents at the 4'-position, H or methyl at 1,3-positions and nitro or amino at 6-position were prepared and tested for their diuretic, natriuretic and kaliuretic activities on male Wistar rats at a dosage of 25 mg/kg or less. 2-(3-Pyridyl) derivatives were inactive. 1,3-Dimethyl-6-nitro-2-phenyl derivatives (1) were active depending on the electronic character of the 4'-substituent but at the same time were sodium-sparing. However, 1(H),3(H)-6-nitro-2-phenyl derivatives (2) were generally inactive as diuretics but active as potassium-sparing drugs. 6-Amino-1(H),3(H)-2-phenyl derivatives (4) were active as diuretics depending on dipolar moment of the substituent at the 4'-position, and induced moderate potassium release. The 6-amino-2-(4-trifluoromethylphenyl)-1, 2,3,4-tetrahydropyrido [2,3-d]pyrimidin-4-one (4f) remained active up to a dosage of 3 mg/kg. The structure-activity relationships were carried out in light of the adaptative least squares (ALS) method and discriminant functions for diuretic compounds were established.

Animals↗