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At least 1,261 records · Page 70Linked to original sources
PubMed1990

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

New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidines 1 and 6,10-dihydro-5H-pyrido[3',2':5,6]pyrimido[2,1-c] [1,2,4]triazines 4 with 5-one, 5-thione or 5-hydrazono substituents and in some cases 1,2,3,4 or 8,9 hydrogenated are synthetized. The diuretic, natriuretic and kaliuretic activities of these compounds in Wistar rats at a dose of 24 mg/kg were estimated. A series of 24 possible derivatives of 1 and 4 possessing diuretic and saliuretic activities are investigated for structure-activity relationships in light of Fujita-Ban model. The Fujita-Ban group contributions have been calculated for different structural variations on the parent ring 1a. It is observed that the hydrogenation of pyridine, [1,3]thiazole or [1,2,4]triazine rings on 1 or 4 decrease the diuretic and saliuretic activities.

Animals↗
PubMedDate not supplied

[Mechanism of the diuretic action of epiphyseal extracts].

Experiments on dogs demonstrated that intravenous administration of the epiphysis extracts prevented the antidiuretic action of both the endogenous (traumatic stress) and exogenous (pituitrin) antidiuretic hormone (ADH). Injection of the extract into the renal artery gave a unilateral diuretic effect. The diuretic action of the preparation was eliminated by the block of the alpha-adrenergic receptors, whereas beta-adrenoblockers were ineffective. A conclusion was drawn that the mechanism of the diuretic action of the epiphysis extracts consisted in the competitive suppression of the ADH action at the renal tubules level on account of excitation of the alpha-adrenoceptors and inhibition of the adenylcyclase activity.

Animals↗
PubMed1990

First-dose effects of enalapril and atenolol upon blood pressure and cerebral blood flow in patients with mild hypertension on diuretic therapy.

The present single-blind, randomised, cross-over, placebo-controlled study was set up to compare the first-dose effects upon blood pressure (BP) and cerebral blood flow (CBF, measured by Xenon inhalation) of a single oral dose of atenolol 50 mg and enalapril 5 mg in ten hypertensive patients receiving a thiazide diuretic. It was found that a) the timing and degree of fall in BP after the first dose of atenolol and enalapril on a diuretic background were similar and generally not associated with symptoms or a fall in CBF, and b) dizziness, which is sometimes associated with the first-dose effect of ACE inhibitors in hypertensives on diuretics, can occasionally occur accompanied by a substantial fall (43%) in CBF in the absence of marked falls in systolic blood pressure. It is suggested that the latter event may be linked to a disturbance of cerebral autoregulation in part dependent on localised renin-angiotensin systems.

Aged↗
PubMedDate not supplied

Antihypertensive and diuretic effects of NZ-105, a novel dihydropyridine derivative.

Studies on the antihypertensive and diuretic actions of NZ-105, a new dihydropyridine derivative, were performed in comparison with nicardipine. NZ-105 and nicardipine (5, 10 and 20 mg/kg, p.o.) dose-dependently decreased systolic blood pressure in three types of experimentally hypertensive rats, including spontaneously hypertensive rats, renal hypertensive rats and deoxycorticosterone acetate-salt hypertensive rats and normotensive Wistar-strain rats. The hypotensive effects were larger in hypertensive rats than in normotensive Wistar rats. The hypotensive actions of NZ-105 were very slow in onset and long-lasting in all models, e.g., the hypotension by NZ-105 (10 mg/kg, p.o.) reached a peak (-52 mmHg) at 3 hr and lasted for more than 9 hr in spontaneously hypertensive rats. The hypotensive action in spontaneously hypertensive rats was reproducible after repeated dosing twice a day for 29 days. The hypotensive action after i.v. injection of NZ-105 (0.1 mg/kg) in spontaneously hypertensive rats was also slow in onset (peak time: 10 min) and long-lasting (more than 120 min). The hypotensive potency of NZ-105 was about the same as that of nicardipine, but the increment in heart rate was smaller than in the case of nicardipine. Both NZ-105 and nicardipine showed diuretic and natriuretic actions in spontaneously hypertensive rats. After repeated administration, these actions of NZ-105 were unchanged, whereas those of nicardipine were reduced. These results suggest that NZ-105 is a useful antihypertensive drug with concomitant diuretic effects.

Animals↗
PubMed1990

Changes in rat and mouse salivary glands and pancreas after chronic treatment with diuretics: a potential animal model for cystic fibrosis.

Defective transepithelial chloride and water transport is thought to be the cellular basis of the disease cystic fibrosis (CF). Therefore, it was attempted to develop an animal model for this disease by chronically inhibiting transepithelial chloride transport in experimental animals by long term treatment with high doses of diuretics. In the present study, changes in the salivary glands and pancreas after such treatment were investigated by X-ray microanalysis and electron microscopy. Treatment of rats for one month with diuretics caused a significant decrease in chloride and an increase in calcium in the acinar cells of the submandibular gland. This increase was due to accumulation of mucus in the cells. The strongest effect was obtained after combined treatment with furosemide and acetazolamide. Only minor changes were noted in the parotid gland and the pancreas. Treatment of mice for three months with diuretics caused similar changes in the submandibular glands. In addition, marked changes in the pancreas were observed. The chloride content of the pancreatic acinar cells was decreased. In many acinar cells, only very few zymogen granules were present. The morphological and microanalytical results point to severe dysfunction of the exocrine pancreas. These changes parallel those found in patients with CF, and the chronically furosemide-treated mouse thus could serve as an animal model for this disease.

Acetazolamide↗
PubMed1987

A double-blind, placebo-controlled, crossover trial to investigate the additive hypotensive effect of a diuretic (mefruside) to that produced by nifedipine.

Several reports suggest that when diuretics are added to nifedipine (N), they do not exert any additional hypotensive effect to that produced by N alone. We present the first double-blind, crossover trial to investigate this interaction. Twenty-four black patients with moderate to severe essential hypertension entered the trial. After an initial "open" 4 weeks of therapy with N slow release (SR) 20 mg. b.i.d., those 17 patients whose blood pressures (BP) were not controlled (greater than 160 mm Hg systolic and/or greater than 90 mm Hg diastolic) were randomly allocated (double-blind) to 4 weeks treatment with N SR 20 mg. b.i.d., plus either mefruside 1 q.d. (a thiazide-like diuretic) or matching placebo. Patients then crossed over for a second 4 week treatment period. Blood pressures were measured at 2 weekly intervals under the same conditions using Hawksley random zero sphgymomanometers by one of two standardized observers after patients had been lying for 5 min and standing for 2 min. Analysis (taking account of period effect) of the mean results for the 16 patients completing the trial confirms that, contrary to what previous uncontrolled data suggest, lying and standing systolic and diastolic BPs are significantly lower (8.5/4.5 mm Hg: 2p less than 0.01 and 7.9/5.0 mm Hg: 2p less than 0.05, respectively) with nifedipine plus diuretic than with nifedipine plus placebo.

Adult↗
PubMed1988

Diuretic responsiveness of blood pressure in the elderly.

The problem of elevated blood pressure in the elderly is a common and potentially devastating one. Reduction of elevated blood pressure, whether systolic, diastolic, or both, is particularly beneficial in older hypertensive subjects in reducing morbidity and mortality. The older individual presents a unique pathophysiologic situation, one in which a variety of considerations must be given to the safest choice of antihypertensive agents. A consistent response of blood pressure in the elderly is not observed with different antihypertensive agents, and the problems of side effects and as well as life-threatening effects of antihypertensive drugs are of particular concern among older hypertensive subjects. While diuretics, on balance, appear to be more effective in lowering blood pressure in older hypertensive patients than in young individuals, the disadvantages and risks of diuretic therapy make them less than ideal agents. Calcium channel blockers and serotonin antagonists have proven, in preliminary studies, to be useful, effective, and safe alternatives to diuretic therapy in older hypertensive patients.

Aged↗
PubMed1989

AY-31,906, a novel high ceiling diuretic: characterization of its relative potassium-sparing actions in rats and dogs.

AY-31,906, exo-2-amino-4-[(bicyclo[2.2.1]hept-2-yl)amino-N-[[1- methylethyl)amino]carbonyl]-5-pyrimidinesulfonamide, exhibited potent diuretic and natriuretic activity in rats and dogs. After p.o. administration, AY-31,906 was 1.5- and 12.3-times more potent as a natriuretic than furosemide in rats and dogs, respectively, whereas it was 0.5- and 6.1-times as potent after i.v. administration. The maximum natriuretic effect of AY-31,906 in both species was similar to that observed with furosemide. At equiactive natriuretic p.o. doses in both species, AY-31,906 produced a greater increase in the urinary ratio of Na/K than furosemide, indicating a relative potassium-sparing effect. AY-31,906 produced significant increases in the fractional excretion of sodium and chloride in dogs at a dose that produced no statistically significant changes in the fractional excretion of potassium, glomerular filtration rate or renal plasma flow. After p.o. administration, the onset of activity of AY-31,906 occurred within the 1st hr in both rats and dogs and preliminary data demonstrated that the activity lasted for approximately 2 hr in rats and 4 hr in dogs. Clearance studies in conscious dogs suggest that AY-31,906 inhibited electrolyte reabsorption in the ascending limb of the loop of Henle and, unlike furosemide, AY-31,906 had no activity at the proximal tubule. These results indicate that AY-31,906 is a potent, high ceiling diuretic with relative potassium-sparing properties. The compound is well absorbed after p.o. administration with diuretic activity occurring in the 1st hr.

Animals↗
PubMed1989

Diuretics in congestive heart failure.

Congestive heart failure (CHF) is a condition characterized by a number of hormonal and renal adaptations which together conspire to salt and water retention. Diuretic therapy has been, and continues to be, a cornerstone to therapy for CHF. The rational use of diuretics, or diuretic combination such as metolazone-furosemide, can both effectively administer to the congestive symptoms seen in heart failure as well as temper many of the complications of this therapeutic modality.

Diuresis↗
PubMed1989

Thiazide diuretic receptors: autoradiographic localization in rat kidney with [3H]metolazone.

The localization of binding sites for [3H]metolazone, a quinazolinesulfonamide diuretic with thiazide-like actions, was determined by in vitro autoradiography. [3H]Metolazone bound saturably to rat kidney sections incubated in vitro with a dissociation constant (Kd) = 3.4 nM and binding site density = 0.14 pmol/mg of protein. Incubation conditions were used that excluded binding to low affinity sites and carbonic anhydrase. Pharmacological specificity of binding was consistent with labeling of physiologically relevant thiazide diuretic receptors, as identified in previous studies of [3H]metolazone binding to renal membranes. Autoradiographs obtained with tritium-sensitive film demonstrated that binding sites were limited to the renal cortex and were relatively sparsely distributed. Higher resolution autoradiography indicated that [3H] metolazone binding sites were localized in a highly specific manner over short lengths of tubular segments, which by their morphology and distribution most likely represented distal convoluted tubules. In the short sections of tubule that contained receptors, labeling was very dense and appeared to be more prevalent over luminal than peritubular surfaces. The intrarenal distribution of [3H]metolazone binding sites provides further evidence for their identity as thiazide diuretic receptors. These results are consistent with physiological studies demonstrating that the early distal tubule is the location of thiazide-sensitive sodium chloride cotransport.

Animals↗
PubMed1988

The diuretic effect of metipamide and its relationship to body weights in rats.

Metipamide [M], a new Czechosclovak diuretic with a hypotensive effect, was administered in a dose of 20 mg/kg (about 500-fold the therapeutic dose) I. for three weeks to rats of both sexes kept under normal conditions in groups of five, and II, for eight days to single male rats in metabolic cages. The animals' body weight and food and water consumption were studied and in the second series their daily faeces, urine and urinary sodium and potassium excretion were measured. Rats kept in individual cages were also given indapamide (I), the first diuretic with a separate hypotensive effect used in other countries, in a dose of 20 mg/kg. The experimental animals' body weight was significantly lower than that of controls with the same food consumption and their water intake and urine flow were much higher, especially after M. Sodium (and to a lesser extent potassium) excretion was raised at the outset of administration of both the test substances and again after the 5th to 8th dose, but only after M. After three weeks' administration of M. SNa, SK and S(osm) values were within normal limits. but after eight days the serum electrolytes and the osmolality of the serum were markedly reduced. After I. these values were normal. We conclude that the strong diuretic effect of M is not the only cause of lower body weight in rats.

Animals↗
PubMed1985

Influence of digoxin and diuretic therapy on sweat fluid composition.

The effect of digitalis and diuretic therapy on sweat fluid composition was investigated. Patients treated for congestive heart failure with a combination of digoxin and diuretics demonstrated a higher concentration of sodium and chloride in their sweat fluid when compared to age-matched controls. The administration of diuretics alone did not affect sweat fluid composition. The digoxin-induced increase in sodium concentration was significantly higher than that observed for chloride. These data suggest that digoxin markedly inhibits sodium reabsorption along the sweat gland tubule, whereas chloride transport is affected to a lesser degree. A significant correlation between sweat fluid sodium and serum digoxin concentrations was observed. We conclude that the increased digoxin-induced sweat sodium and chloride losses may affect sodium homeostasis in patients with congestive heart failure.

Aged↗
PubMed1988

Mechanisms of reduced effects of loop diuretics in healthy volunteers and in patients with renal disease.

Although most patients respond well to loop diuretics, poor response is sometimes a problem and some underlying mechanisms were addressed in this study. The renal response to continuous infusion of furosemide was investigated in eight healthy volunteers during controlled isotonic dehydration and after full restoration of volume losses. A rapidly reversible acute tolerance developed in parallel with dehydration and activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS). Dehydration also reduced the renal clearance of furosemide substantially, but only decreased the urinary delivery rate of the drug (the principal determinant of the diuretic effect) to a minimal extent. Delayed tolerance to an i.v. bolus dose of furosemide was found in 12 healthy volunteers after 1 week of oral furosemide treatment with and without angiotensin converting enzyme inhibition. No pharmacokinetic changes were seen. This type of tolerance was not related to dehydration or activation of RAAS. Thus, the induced decrease in renal sensitivity to furosemide was probably due to an intrarenal (structural?) adaptation. The pharmacokinetics and pharmacodynamics of piretanide were studied in six healthy volunteers and 22 patients with chronic renal failure (glomerular filtration rate 1-28 ml/min). Poor response to the diuretic action of the drug was found in the patients. This was entirely due to a decrease in the fraction of piretanide excreted unchanged in the urine, and the renal sensitivity to the drug was normal. Multiple daily doses of piretanide of maximally 24 mg are recommended for optimal efficiency in renal failure. Substantial changes in pharmacokinetics of furosemide were found after manipulation of plasma albumin in five patients with nephrosis, while the urinary delivery of the drug scarcely changed. Neither the induced alterations in proteinuria nor those in plasma volume influenced the renal sensitivity to furosemide significantly. Some methodological observations proved to be of significance. Creatinine was found to be an unreliable marker of GFR because of its substantial tubular secretion and reabsorption, both of which were related to the degree of hydration. Likewise, lithium was considered an unreliable marker of proximal tubular reabsorption, since there were reasons to suspect furosemide-sensitive distal lithium reabsorption.

Adult↗
PubMed1988

Diuretics--a risk in the long-term treatment of hypertensive patients?

The trial of the European Working Party on High blood pressure in the Elderly (EWPHE) revealed an overall decrease in cardiovascular mortality and morbidity in the actively treated patients. They received as first-line drugs a combination of hydrochlorothiazide and triamterene; methyldopa was added as necessary. The present post hoc analysis examined the effect of the diuretic treatment on cardiovascular events, both when given alone and in conjunction with methyldopa, by calculating the relative hazard rates (RHR) for cardiovascular mortality and morbidity. Using the Cox proportional hazard model, compared with placebo, a 34% reduction in cardiovascular mortality in the intention-to-treat analysis was demonstrated in the diuretic (hydrochlorothiazide and triamterene) group with an RHR of 0.66 and a 95% confidence interval (CI) of 0.44-0.97; the 16% decrease in the group treated with diuretics and methyldopa was not significant (RHR, 0.84; 95% CI, 0.56-1.25). The effect of treatment in the latter combined group became significant (RHR, 0.62; 95% CI, 0.40-0.95) when all cardiovascular study terminating events were considered; they were reduced by 38%. No effect of treatment on mortality from all causes was detected.

Aged↗
PubMed1988

Excretory function after renal denervation and administration of diuretics to unanesthetized dogs.

Diuretics were administered intravenously to unanesthetized dogs with exteriorized ureters for separate urine collection from both kidneys: furosemide (0.2 mg/kg), ethacrynic acid (0.22 mg/kg), acetazolamide (3.0 mg/kg), amiloride (1.0 mg/kg b.w.). Diuresis, urine and plasma osmolality, excretion, clearances and excretion fractions of sodium, potassium, chloride and magnesium were determined. After left-side kidney denervation not later than 50 days after operation, the above mentioned diuretics were administered to the same animals. The responses of the denervated and intact kidneys were compared. During some of the experiments after furosemide administration isotonic solution of sodium chloride in a volume, adequate to the volume of the collected urine, was infused. Furosemide or ethacrynic acid administration leads to a higher increase of both diuresis and chloride excretion from denervated kidney as compared to the intact one. After ethacrynic acid administration magnesium excretion from the denervated kidney was registered to be higher than that from the intact one. After chronic renal denervation of unanesthetized dogs, chloride and magnesium reabsorption in the ascending limb of Henle's loop was greater in the denervated than in the intact kidney. Amiloride suppression of potassium secretion in the distal part of the nephron did not lead to differences between the denervated and intact kidneys. The decreased volume of extracellular liquid, resulting from diuretic action, did not change the response of the denervated kidney to furosemide or to ethacrynic acid.

Acetazolamide↗
PubMed1988

Calcium antagonists: use in hypertension evaluation of calcium antagonists in combination with diuretics.

Hypertensive patients whose elevated blood pressure was not controlled with diuretics alone have received calcium antagonists in addition in several studies reported in the literature. These studies are summarized in this report. The combination was found to be effective in lowering blood pressure to desirable levels with minimal side effects. In the present era lowered doses of antihypertensive agents, particularly diuretics, are advised. The combination of low dose diuretic and calcium blocker is an attractive alternative for those patients for whom a beta-blocker is contraindicated.

Bendroflumethiazide↗
PubMed1988

Comparison of diuretic effects and pharmacokinetics of torasemide and furosemide after a single oral dose in patients with hydropically decompensated cirrhosis of the liver.

In a controlled double-blind randomized clinical trial, the pharmacodynamics and pharmacokinetics of 20 mg torasemide (1-isopropyl-3-([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea) (n = 10) and 40 mg furosemide (n = 9) were compared over 24 h after single oral administration to patients with ascites due to cirrhosis of the liver. The overall 24-h excretion of volume and sodium was not significantly different between patients receiving torasemide or furosemide. The diuretic effect of torasemide, however, was longer in duration than that of furosemide. This was in accordance with the pharmacokinetic behaviour of torasemide and furosemide. The serum elimination half-life of torasemide was longer (4.8 h) than that of furosemide (2.2 h) in these patients and also longer than that in healthy volunteers (3 h). The areas under the serum concentration-time curves for torasemide were higher than in healthy subjects by a factor of 2.5. In parallel with the considerably delayed formation of the diuretically inactive metabolite M5, which is formed via the diuretically active metabolite M1, the serum concentration of M1 was increased in these patients. However, the overall excretion of torasemide and the different metabolites was similar compared to healthy volunteers. These results indicate that the pharmacokinetics and metabolism of torasemide depend on liver function. No adverse reaction were experienced in either group.

Administration, Oral↗
PubMed1987

The pharmacologic basis of diuretic therapy in the newborn.

Effective use of diuretics in critically ill newborns requires an understanding of the ontogeny of renal function, a knowledge of the pathophysiology of the patient's disease, an expectation of the pharmacodynamics of the several classes of diuretics, and an appreciation of the kinetics and toxicities of the selected agents. Unfortunately, the number and scope of clinical pharmacologic studies of diuretics in critically ill newborns are inadequate for optimal therapy with most of these drugs.

Acute Kidney Injury↗