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PubMed1990

Loop diuretic-sensitive potassium flux pathways of rat glomerular mesangial cells.

Glomerular mesangial cells are smooth muscle-like contractile cells that mediate hormonal regulation of glomerular filtration. To gain better understanding of ionic events that accompany contraction/relaxation of these cells, flux pathways of K+ and their regulation by vasoactive agents were investigated in cultured rat mesangial cells using 86Rb+ as a tracer. Of total 86Rb+ influx (16.6 +/- 0.6 nmol x mg protein -1 x min-1), 46% was inhibited by 2 mM ouabain. Loop diuretics inhibited 43% of ouabain-insensitive 86Rb+ influx (3.9 +/- 0.2 nmol x mg protein-1 x min-1). Half-maximum inhibition was observed at 2 and 0.4 microM for furosemide and bumetanide, respectively. Loop diuretic-sensitive 86Rb+ influx was dependent on extracellular Na+ and Cl-; a hyperbolic dependency on extracellular Na+ was noted with apparent Michaels constant of 39 mM while a sigmoidal dependency on extracellular Cl- was present, which, assuming 1:1:2 stoichiometry for Na(+)-K(+)-Cl-, produced an apparent mean affinity constant of 64 mM. Moreover, a fraction of amiloride-insensitive 22Na+ influx was found to be sensitive to furosemide and dependent on extracellular K+ and Cl-, further indicating the presence of Na(+)-K(+)-Cl- cotransport. Efflux of 86Rb+ followed first-order kinetics, of which 60% was inhibitable by furosemide. Manipulations of extracellular osmolarity revealed that these furosemide-sensitive 86Rb+ flux pathways were coordinately regulated in response to osmotic stress. Concentration-dependent stimulation of Na(+)-K(+)-Cl- cotransport-mediated 86Rb+ influx was induced by two vasoconstrictors, angiotensin II (ANG II) and arginine vasopressin (AVP), and by a vasodilator, atrial natriuretic peptide (ANP).(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed1985

Role of citrate excretion in acid-base balance in diuretic-induced alkalosis in the rat.

Studies were performed to assess the role of changes in the excretion of citrate, a metabolic precursor of bicarbonate, in acid-base balance in diuretic-induced metabolic alkalosis. Rats on a low-chloride diet with sodium sulfate added were studied during a base-line period, 3 days of furosemide administration, and 4 days post-furosemide. During the period of furosemide administration, net acid excretion and plasma bicarbonate concentration increased. In the post-furosemide period, net acid excretion remained higher than base line but plasma bicarbonate concentration did not increase further. Citrate excretion was significantly higher in the post-furosemide period than in base line. Studies substituting sodium neutral phosphate or sodium bicarbonate for dietary sodium sulfate demonstrated greater increases in net acid excretion post-furosemide and, again, no increase in plasma bicarbonate concentration during this period. Citrate excretion was greater than in the sulfate group. The increment in citrate excretion was proportional to the base "load," defined with respect to changes in net acid excretion and/or dietary bicarbonate. Thus, in these studies alterations of base excretion in the form of citrate play an important role in acid-base balance during diuretic-induced metabolic alkalosis.

Acid-Base Equilibrium↗
PubMed1989

Reversible downregulation of thiazide diuretic receptors by acute renal ischemia.

Receptors for thiazide diuretic drugs in the rat renal cortex have recently been identified through the binding of [3H]metolazone, a potent diuretic with a thiazide-like mechanism of action. The present studies describe the rapid and reversible alterations that occur in thiazide receptors following acute renal ischemia in the rat. The apparent density of thiazide receptors in kidney membranes as measured by the binding of [3H]metolazone was reduced by 90% following 10 min of renal ischemia produced by clamping the renal pedicle. With release of the clamp and subsequent reperfusion for 10 min, thiazide receptor density returned to within 40% of control levels. Ischemia did not alter apparent affinity of receptors for [3H]-metolazone. Sections prepared from renal cortex and incubated in oxygenated media in vitro displayed similar rapid changes in thiazide receptors. Hypoxia of 10- to 30-min duration produced by incubating sections in vitro in nitrogen-saturated media caused a significant decrease in [3H]metolazone binding that was reversible with return to oxygenated media. Similar decreases were obtained in oxygenated sections that were incubated with mitochondrial inhibitors, dinitrophenol and rotenone, but not in sections incubated with ouabain. These results indicate that renal thiazide receptors undergo a rapid and reversible form of regulation and that controlling mechanisms are dependent on metabolic energy.

Acute Disease↗
PubMed1990

Comparative effects of diuretics and atrial peptide in chronic caval dogs.

Anesthetized chronic caval dogs with ascites were given atrial natriuretic peptide (ANF) at 75 ng.kg-1.min-1 iv and were characterized as to natriuretic response [n = 21; urinary excretion rate of Na (UNaV): 28-362 mu eq/min] or lack of response (n = 14; UNaV: 0-10 mu eq/min). Sixteen normal dogs showed an increment in UNaV between 38 and 288 mu eq/min following the same dose of ANF. Both caval "responders" and "nonresponders" were equivalent with regard to pre- and post-ANF hemodynamics and renal function. When various diuretic agents (glucagon, acetazolamide, furosemide, thiazide, amiloride) were administered, equivalent natriuretic responses were obtained between both groups of caval dogs and the controls. An acute saline load (7% body wt), however, produced a greater natriuresis in controls than in caval dogs, but in this latter group the response was similar in responders and nonresponders. When six caval dogs each were initially pretreated with either amiloride or ANF, and then treated with a second agent, an additive natriuretic effect was obtained. These results suggest that tubular resistance to diuretics in caval dogs is unique to ANF, and this peptide appears to act at an additional Na transport site separate from amiloride-inhibitable channels.

Amiloride↗
PubMed1992

A comparison of the effect of inhaled diuretics on airway reflexes in humans and guinea pigs.

The effects of nebulized diuretics on citric acid-induced cough and airway obstruction in guinea pigs and capsaicin-induced cough and increase in airway resistance in humans have been studied. Half-maximum inhibition of cough in the guinea pig was produced by 1.3 mM furosemide and 0.25 mM hydrochlorothiazide. Cough was inhibited by 78 +/- 9% by 3 mM furosemide (P less than 0.05) and 89 +/- 11% by 3 mM hydrochlorothiazide (P less than 0.01). At the same time, airway obstruction was inhibited by 50 +/- 9% (P less than 0.001) and 42 +/- 15% (P less than 0.05), respectively. Nebulized furosemide (3 mM) was without effect on the airway obstruction produced by inhaled histamine or acetylcholine in the guinea pigs. Intravenously administered furosemide (270 nmol/kg) did not affect citric acid-induced responses. In humans, aerosolized furosemide (9 mM) and hydrochlorothiazide (3.4 mM) reduced the percent increase in respiratory resistance from 22.1 +/- 3.7 and 15.6 +/- 3.4 to 10.5 +/- 4.9 and 9.4 +/- 3.3%, respectively (P less than 0.05), but were without effect on cough due to capsaicin. Thus both furosemide and hydrochlorothiazide inhibited airway obstruction in the guinea pig and reduced the capsaicin-induced increase in airway resistance in humans. However, whereas coughing was inhibited in the guinea pig, neither drug affected cough in humans. This difference in the action of the loop diuretic and thiazide, which interact differently with Na(+)-K(+)-Cl-transport within the airway mucosa, on the cough and airflow obstruction in guinea pig and humans supports the view that different sensory limbs are involved in these reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1981

Thiazide diuretics inhibit contractions of isolated smooth muscles.

The interaction between thiazide diuretics and contractile responses produced by 5-hydroxytryptamine, acetylcholine, noradrenaline and angiotensin II, has been examined on isolated rat uterus and guinea pig aorta. Hydrochlorothiazide, polythiazide and cyclopenthiazide inhibited the contraction of isolated tissue induced by the spasmogens. These data demonstrated that the tested diuretics possess antagonistic activity on contractions induced by various spasmogens.

Animals↗
PubMed1983

Structure activity correlation for diuretic furosemide congeners.

The structure activity correlation of several groups of anthranilic acid derivatives was studied. 59 compounds, most of them possessing the anthranilic acid moiety, were synthesized and tested for diuretic and saluretic activities. Equations correlating the biological activities of these compounds with their physicochemical constants suggest positive dependence of the diuretic activity on log P (octanol:water partition coefficient). It is concluded that, within limits, the variation in biological activity is primarily governed by the lipophilicity of the molecule, and further increase in log P value will not enhance this activity.

Animals↗
PubMed1994

Characterization of ATP-sensitive potassium channel-blocking activity of ZENECA ZM181,037, a eukalemic diuretic.

ZENECA ZM181,037 is a novel eukalemic diuretic from a series of 1,1-diarylcarbin-1-01-2 amines. In contrast to the standard diuretic hydrochlorothiazide, the blood pressure-lowering effect was not observed with ZENECA ZM181,037 in spontaneously hypertensive rats. ZENECA ZM181,037 demonstrated a K+ channel-blocker profile. In the isolated rat aorta stimulated with 20 mmol/l KCl, both the d- and l-enantiomer of ZENECA ZM181,037 antagonized the relaxation of cromakalim with mean pKB values of 6.4 and 6.7, respectively. In the isolated guinea-pig portal vein and urinary detrusor muscle, both enantiomers enhanced the spontaneous myogenic activity at concentrations of 1 mumol/l and higher, in addition to antagonizing the effect of cromakalim. ZENECA ZM 181,037, similar to glibenclamide, prevented a significant increase in 86Rb+ by cromakalim in both portal vein and detrusor muscle strips; however, ZENECA ZM181,037, dissimilar to glibenclamide and tolbutamide, did not increase plasma glucose when given orally to dogs. Thus, ZENECA ZM181,037 is a blocker of the ATP-sensitive K+ channel (KATP) in vascular and nonvascular tissues. In view of the profound saluresis produced by ZENECA ZM181,037, the lack of antihypertensive effect appears to result from its blocking activity on KATP in vascular tissues.

Acetamides↗
PubMed1987

Loop diuretics.

Loop diuretics such as furosemide, piretanide, and bumetanide bind reversibly to the Na+2Cl-K+ carrier. This transporter is responsible for the uptake of Cl- into the thick ascending limb segment. As a consequence, these compounds reduce or abolish NaCl reabsorption in this nephron segment and lead to a decreased interstitial hypertonicity and thus to a reduced water absorption. Apart from these profound effects, loop diuretics also inhibit Ca2+ and Mg2+ reabsorption in the thick ascending limb in a manner which is still not clear. They also increase urinary K+ excretion by an increase in distal tubule NaCl and water delivery and probably also by the reduction of K+ reabsorption which goes on under in vivo conditions in the thick ascending limb segment. Finally, by the reduction of the transport work in the thick ascending limb, these compounds reduce dramatically the substrate and oxygen dependence of this nephron segment.

Animals↗
PubMed1987

Potassium-sparing diuretics.

Amiloride, triamterene, and the spirolactones are potassium-sparing diuretics which act on the distal parts of the nephron, from the late distal tubule to the collecting duct. In these segments, active sodium reabsorption occurs through the following mechanism: sodium ions enter the cell through specific channels present in the luminal membrane and are extruded out of the cell into the peritubular medium by a sodium-potassium exchange pump, the Na-K-ATPase. Amiloride in micromolar concentrations reduces the sodium transport by blocking the luminal membrane sodium channel. Triamterene has a similar effect, although with a lower affinity; the available studies do not allow to determine if an inhibitory effect of triamterene on the Na-K-ATPase plays an additional role in its diuretic action. The spirolactones are competitive inhibitors of aldosterone, the mineralocorticoid hormone which promotes sodium reabsorption by increasing both the number of active sodium channels in the luminal membrane and the number of active Na-K pumps in the peritubular membrane. By the inhibitory effect on the electrogenic sodium transport, amiloride, triamterene, and the spirolactones decrease the lumen-negative transepithelial potential difference. This reduces the driving force for potassium movement into the tubular lumen and thus decreases potassium excretion.

Aldosterone↗
PubMed1994

Efficacy and tolerance of low-dose loop diuretics in hypertension.

Prospective studies have emphasized the key role for diuretics in the treatment of high blood pressure. Short-acting loop diuretics have not achieved the same acceptance as the thiazides in treatment of hypertension. Newer long-acting compounds, however, such as torasemide, have now been found to be as efficacious as the thiazides, particularly as they can be given once daily and have a low side-effect profile. Adverse laboratory side-effects are rare in hypertensive patients treated with torasemide; carbohydrate intolerance, dyslipidaemia, or hypokalaemia have seldom been observed during its long-term administration. For these reasons, torasemide is therapeutically attractive due to its antihypertensive efficacy with once-daily administration, low incidence of adverse side-effects, and sustained improvement of the cardiovascular risk profile.

Blood Pressure↗
PubMed1994

Symptomatic achievements with diuretics in congestive heart failure.

The short-term clinical efficacies of furosemide, 25 mg/day, and torasemide, 10 mg/day, have been compared in 2 groups of 12 patients with severe heart failure. In each group there were similar numbers of patients in whom heart failure was due to coronary heart disease, high blood pressure, or idiopathic dilated cardiac myopathy. The design of the study was open and the diuretics were added to baseline treatment with digoxin. Treatment for 8 days with the 2 loop diuretics resulted in similar substantial and significant improvements in symptoms and exercise tolerance as judged by the increase in total body oxygen consumption, and reductions in radiographic evidence of pulmonary congestion and in right heart filling pressure as judged from the jugular venous pressure wave. The results of this short-term comparative study confirm that furosemide and torasemide are equally efficacious in inducing substantial improvements in the clinical status of patients in severe heart failure.

Diuretics↗
PubMed1979

Differential effects of diuretic agents on electrolyte excretion in the dog. Role of renal hemodynamics.

The sulfonamide derivative diuretics acetazolamide, metolazone and furosemide produce differing degrees of natriuresis and varying patterns of phosphate excretion. At least part of the explanation for these diverse actions could be related to divergent effects of the drugs on total renal blood flow (TRBF) and its intracortical distribution (IBFD). To test this hypothesis, and to determine if a consistent thesis regarding alterations in interenal blood flow could be developed, clearance studies were performed in chronically thyroparathyroidectomized dogs in which radioactive microsphere methodology was utilized to evaluate the distribution of blood flow within the renal cortex. These data were then compared with those available in the literature. The variations which the drugs induced in TRBF and IBFD did not help to explain the differences in their diuretic actions. However, a consistent hypothesis relating natriuresis, perfusion pressure, renal vascular resistance, TRBF and IBFD could be developed based on the data from this study and those available in the literature.

Acetazolamide↗
PubMed1979

Salt, diuretics and pregnancy.

This article reviews the homeostasis of water and salt in normal and pre-eclamptic pregnancy. During pre-eclampsia there is a decrease in circulating plasma volume, which the administration of diuretics reduces still further. There is no proof that diuretics have a beneficial effect on prevention or treatment of toxemia of pregnancy. They should thus be regarded as contraindicated, except in cases of cardiac insufficiency and certain renal diseases.

Aldosterone↗
PubMed1986

Pharmacodynamic determinants of furosemide diuretic effect in children.

The pharmacodynamics of 1 or 2 mg/kg of furosemide administered as a single dose orally or intravenously were studied in 34 hospitalized children (ranging in age from 9 days to 16.5 years) with normal renal function. These patients were divided into 3 groups: infants (furosemide 1 mg/kg, intravenously); children with steroid-responsive nephrotic syndrome (furosemide 2 mg/kg, orally and intravenously); patients with urinary tract infections and mild hypertension (furosemide 2 mg/kg, orally). A statistically significant positive linear relationship was found in these groups between the furosemide urinary excretion rate and urine flow rate, but log dose-response curves to furosemide were found to vary between the groups of patients studied. This variability reflects differences in the relationship between the amounts of furosemide reaching active sites and the pharmacodynamic effect of the drug. No sigmoid-shaped log dose-response curve (i.e., one approaching a zero response at very low furosemide urinary excretion rates, and a maximum response at very high excretion rates) was attained in this study. This suggests that the capacity of the kidney tubules to respond diuretically to the administered doses of furosemide was not exceeded in the studied patients. However, in the infants, a very steep log dose-response curve to a 1 mg/kg intravenous dose of furosemide suggests that higher doses may not result in a significant increase in diuretic response in infants with reasonably normal renal function. The lowest mean furosemide urinary excretion rate associated with significant diuresis was 0.58 +/- 0.33 micrograms/kg/min. Also, a significant correlation was found between the amount (in milligrams), of furosemide excreted in the urine during the first 6 h after administration and the urine volume collected during that time (r = 0.71; p less than 0.001; number of measurements = 43).

Administration, Oral↗
PubMed1978

Effect of digoxin and diuretics on high altitude left ventricular dysfunction.

Systolic time intervals, stroke volume, cardiac output and (dZ/dt)/RZ index were serially estimated in 51 normal healthy volunteers at sea level, for ten days after air induction to 3658 m altitude and on return to sea level. The subjects were divided into three groups and were administered a diuretic, beta methyldigoxin and placebo in a double blind protocol. The group on placebo showed an increase in heart rate, reduction in stroke index and cardiac index during high altitude exposure with normalization on return to sea level. A deterioration in left ventricular function as manifested by prolongation of pre-ejection period, increase in PEP/LVET ratio, reduction in (dZ/dt)/RZ index and left ventricular ejection time was also noted at high altitude. The subjects on digoxin maintained normal stroke/cardiac index and did not show any significant changes in the parameters of myocardial function. The diuretic group showed more deterioration in the parameters than the placebo group. No significant side effects were noted. Left ventricular dysfunction and reduction of stroke index at high altitudes may be causually related; digoxin administration may prevent them from occurring.

Adult↗
PubMed1993

Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Results of the flosequinan-ACE inhibitor trial (FACET).

BACKGROUND: Angiotensin converting enzyme inhibitors, diuretics, and digoxin are each effective in treating congestive heart failure, but many patients remain symptom-limited on all three medications. This trial was designed to determine whether the addition of oral flosequinan, a new direct-acting arterial and venous vasodilator with possible dose-dependent positive inotropic effects, improves exercise tolerance and quality of life in such patients. METHODS AND RESULTS: In a randomized, double-blind multicenter trial, 322 patients with predominantly New York Heart Association class II or III congestive heart failure and left ventricular ejection fractions of 35% or less, who were stabilized on a diuretic, angiotensin converting enzyme inhibitor, and digoxin, were treated with 100 mg flosequinan once daily, 75 mg flosequinan twice daily, or matching placebo. Efficacy was evaluated with serial measurements of treadmill exercise time, responses to the Minnesota Living With Heart Failure Questionnaire (LWHF), and clinical assessments during a baseline phase and a 16-week treatment period. After 16 weeks, 100 mg flosequinan once daily produced a significant increment in median exercise time (64 seconds at 16 weeks) compared with placebo (5 seconds), whereas the higher-dose flosequinan group did not show a statistically significant increase. Flosequinan (100 mg once daily) also improved the overall LWHF score significantly compared with placebo; both active therapies decreased the physical component, but 75 mg flosequinan twice daily was associated with a trend toward worsening of the emotional component. Most clinical assessments tended to improve on active therapy. CONCLUSIONS: These results indicate that additional symptomatic benefit can be attained by adding flosequinan to a therapeutic regimen already including a converting enzyme inhibitor. Because in the future most patients will fall into this category, flosequinan is a potential adjunctive agent in the management of severe congestive heart failure. However, because recent evidence indicates that the flosequinan dose studied in the present trial has an adverse effect on survival, the benefit-to-risk ratio must be assessed in individual patients.

Adult↗
PubMed2003

Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind, active, controlled clinical trial conducted to determine whether newer antihypertensive agents, including doxazosin, an alpha-blocker, differ from chlorthalidone, a diuretic, with respect to coronary heart disease (CHD) and other cardiovascular disease (CVD) events in hypertensive patients at high risk of CHD. In February 2000, the doxazosin treatment arm was discontinued, and findings through December 1999 were reported. This report includes an additional 9232 participant-years and 939 CVD events. At 623 clinical centers, patients (aged >or=55 years) with hypertension and at least 1 other CHD risk factor were randomly assigned to either chlorthalidone or doxazosin. The primary outcome measure was the combined occurrence of fatal CHD or nonfatal myocardial infarction (MI), analyzed by intent to treat; prespecified secondary outcome measures included all-cause mortality, stroke, combined CHD (fatal CHD, nonfatal MI, hospitalized angina, and coronary revascularization), and combined CVD (combined CHD, stroke, angina treated outside the hospital, heart failure, and peripheral arterial disease). Mean follow-up was 3.2 years. There was no difference in primary outcome between the arms (relative risk [RR], 1.02; 95% confidence interval [CI], 0.92 to 1.15). All-cause mortality also did not differ (RR, 1.03; 95% CI, 0.94 to 1.13). However, the doxazosin arm compared with the chlorthalidone arm had a higher risk of stroke (RR, 1.26; 95% CI, 1.10 to 1.46) and combined CVD (RR 1.20; 95% CI, 1.13 to 1.27). These findings confirm the superiority of diuretic-based over alpha-blocker-based antihypertensive treatment for the prevention of CVD.

Adrenergic alpha-Antagonists↗