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Acute administration of captopril lowers the natriuretic and diuretic response to a loop diuretic in patients with chronic cardiac failure.

Angiotensin-converting enzyme inhibitors suppress plasma concentrations of the sodium retaining hormones angiotensin II and aldosterone. This action should potentiate the natriuretic and diuretic effects of loop diuretics. Some studies indicate, however, that the introduction of angiotensin-converting enzyme inhibitors for the treatment of cardiac failure is associated with transient weight gain and the development of oedema. We have compared the natriuretic and diuretic response to intravenous frusemide 40 mg alone with the natriuretic and diuretic response to intravenous frusemide 40 mg following the administration of a single dose of captopril in 12 supine male patients with stable chronic cardiac failure. Captopril lowered the 4 h diuretic response to frusemide from 1160 (60) to 685 (77) ml (P less than 0.05) and the natriuretic response from 120 (9.6) to 68 (11.7) mmol (P less than 0.05). Creatinine clearance fell after captopril from 91 (7.2) to 57 (7.7) ml min-1 (P less than 0.05). Systolic and diastolic blood pressures were lower after the administration of captopril but these changes were not significant. Plasma renin activity rose from 3.8 (1.04) to 12.34 (2.94) ng ml h-1 (P less than 0.05) and plasma angiotensin II was reduced from 24.9 (5.05) to 8.14 (1.8) pg ml-1 (P less than 0.05). Plasma aldosterone concentrations were not significantly lower following captopril. Angiotensin-converting enzyme inhibitors cause an acute fall in creatinine clearance which may reduce the effects of loop diuretics and attention must be paid to diuretic dosage when initiating angiotensin-converting enzyme inhibitors for the treatment of cardiac failure.

Aged↗

Coupling of a loop diuretic-sensitive Na+ influx with the net loop diuretic-sensitive K+ efflux in mouse NIH 3T3 cells.

Mouse 3T3 fibroblasts have a loop diuretic sensitive Na+ transport system, responsible for more than 50% of the total Na+ influx. This transport system is dependent on the simultaneous presence of all three ions; Na+, K+, (Rb+) and Cl- in the extracellular medium. The same requirement for these three ions was also found for the loop diuretic-sensitive K+ efflux. In addition, the sensitivities of Na+ influx and Rb+ efflux for the two loop diuretics, furosemide and bumetanide were found to be similar. The similar ionic requirement and sensitivity towards loop diuretics of the two fluxes, support the hypothesis, that this loop diuretic-sensitive Na+ influx in mouse 3T3 cells, is accompanied by the net loop diuretic-sensitive K+ efflux.

Animals↗

Studies on uricosuric diuretics. 4. Three-dimensional structure-activity relationships and receptor mapping of (aryloxy)acetic acid diuretics.

Attempts to develop new (aryloxy)acetic acids with a better profile of diuretic and uricosuric activities as well as with fewer side effects have produced a series of compounds in which the ring system has been varied. Diuretic screening of these analogues in rats indicated that the great difference in the activity between these compounds might be ascribed to a difference in the ring system rather than that in the substituent effect and that the annulation hypothesis described before is not necessarily applicable to all of these compounds. This prompted us to study the relationship between the structure and the diuretic activity of the (aryloxy)acetic acids. An active model (receptor model) was created with the indanone moiety of R-(-)-3 and the dihydrobenzofuran-2-carboxylic acid moiety of S-(+)-4. The three-dimensional structure-activity study of known compounds 2-4, and 5a using the active model showed that the degree of fitting to the model is related to the diuretic activity of these compounds. This was also confirmed for compounds 6a, 6b, 9a, 10a, 11a, 12a, 13a, 14a, 15a, and 16a, and the relation between the structure and the diuretic activity was rationalized qualitatively. With these insights in mind, a modified receptor model was constructed. We believe that this model is useful for a prediction of the activity of compounds not yet synthesized as well as for designing new (aryloxy)acetic acid diuretics.

Acetates↗

Loop diuretics cause less postural hypotension than thiazide diuretics in the frail elderly.

Seventy frail elderly patients attending a day hospital were studied to investigate the incidence of postural hypotension in control patients on no diuretic treatment (n = 30), patients on loop diuretics (frusemide) for mild cardiac failure (n = 20) and patients on thiazide diuretics for mild cardiac failure (n = 20). The results showed that patients on thiazide diuretics had a higher incidence of postural hypotension (reduction in systolic blood pressure greater than 20 mmHg on standing after 2 minutes) than patients on loop diuretics (12 out of 20 vs 4 out of 20, p less than 0.05). Mean plasma potassium levels were lower in the thiazide group than in the frusemide group (p less than 0.05) and this correlated significantly with change in systolic blood pressure from supine to standing position (r = -0.56, p less than 0.01). These findings indicate that a loop diuretic (frusemide) is as safe if not safer than thiazides in older patients and the latter have an unjustified reputation of being safer first-line drugs for the treatment of cardiac failure.

Aged↗

Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1.

The renal tubular secretion of thiazides and loop diuretics via the organic anion transport system in renal tubules is required for them to reach their principal sites of action. Similarly, acetazolamide, a diuretic clinically administered for glaucoma, is excreted from the kidney by glomerular filtration and tubular secretion. In this study, we investigated the interaction and transport of these diuretics via the rat renal organic anion transporter rOAT1 by using Xenopus laevis oocyte expression system. p-[(14)C]Aminohippurate (PAH) uptake by rOAT1-expressing oocytes was inhibited in the presence of a thiazide (chlorothiazide, cyclothiazide, hydrochlorothiazide), a loop diuretic (bumetanide, ethacrynic acid, furosemide), or a carbonic anhydrase inhibitor (acetazolamide, ethoxzolamide, methazolamide). Dixon plot analysis demonstrated that the inhibition constant (K(i)) value was 1.1 mM for acetazolamide, 150 microM for hydrochlorothiazide, 9.5 microM for furosemide, and 5. 5 microM for bumetanide. Kinetic analysis revealed that acetazolamide inhibited rOAT1 competitively and that inhibition style of furosemide was a mixture of competitive and noncompetitive. [(14)C]PAH efflux was significantly enhanced when the rOAT1-expressing oocytes were incubated in the presence of unlabeled PAH, alpha-ketoglutarate, acetazolamide, chlorothiazide, or hydrochlorothiazide. rOAT1 stimulated acetazolamide uptake, which was inhibited by probenecid. Although the loop diuretics had little trans-stimulation effect on [(14)C]PAH efflux via rOAT1, the rOAT1-mediated furosemide uptake was observed. These findings suggest that rOAT1 contributes, at least in part, to the renal tubular secretion of acetazolamide, thiazides, and loop diuretics.

Acetazolamide↗

Diuretic profile of a novel loop diuretic torasemide in rats and dogs.

In the present study, the authors have examined the diuretic action of a novel loop diuretic torasemide and compared it to those of other diuretics, employing normal rats and dogs. Oral administration of torasemide elicited a dose-dependent increase in urine volume and electrolyte excretion, and elevated the urinary Na/K ratio in rats. These effects were more potent than those of the other diuretics furosemide, trichlormethiazide, indapamide and spironolactone. Moreover, torasemide exhibited a similar or higher urinary Na/K ratio than the combination of these diuretics and spironolactone. In a study employing anaesthetized dogs, i.v. injection of torasemide resulted in a higher urinary Na/K ratio in comparison to furosemide, in addition to potent and long-lasting diuretic activity.

Anesthesia↗

Influence of cardiac function on the diuretic and hemodynamic effects of the loop diuretic piretanide.

The influence of cardiac function on the diuretic and hemodynamic effects of the loop diuretic piretanide was investigated in nine patients with congestive heart failure. The diuretic response to piretanide correlated significantly with the pretreatment cardiac index (r = 0.90). Furthermore, a significant correlation was found between the pretreatment fractional sodium excretion and the cardiac index (r = 0.85). The fractional sodium excretion is reciprocal to the renal sodium and water reabsorption. No change in the hemodynamics was observed prior to the onset of diuresis. At 120 minutes after administration of piretanide, the reduction of mean pulmonary capillary wedge pressure (r = 0.88) and mean right atrial pressure (r = 0.80) was significantly related to the diuretic response. We conclude that the reduced diuretic response to piretanide in patients with low cardiac index is due to increased renal sodium and water reabsorption. The hemodynamic changes following the administration of piretanide are dependent on the diuresis.

Adult↗

Comparative natriuretic and diuretic efficacy of theophylline ethylenediamine and of bendroflumethiazide during long-term treatment with the potent diuretic bumetanide. Permutation trial tests in patients with congestive heart failure.

The additive natriuretic and diuretic effects of theophylline ethylenediamine and of bendroflumethiazide have been compared in permutation trial tests in patients with advanced congestive heart failure receiving long-term treatment with the highly potent diuretic, bumetanide. Statistical analysis of renal water and electrolyte excretion revealed that theophylline ethylenediamine, 400 mg orally, and bendroflumethiazide, 5 mg orally, had very similar effects, both quantitatively and qualitatively. The mechanism of action of the supplementary diuretics is discussed. It is concluded that theophylline ethylenediamine represents a useful alternative to thiazide diuretics when supplementary natriuretic treatment is considered in patients with congestive heart failure during long-term treatment with potent diuretics. The significance of maintaining the potassium balance during such a combined regimen is stressed.

Bendroflumethiazide↗

Balancing diuretic therapy in heart failure: loop diuretics, thiazides, and aldosterone antagonists.

In heart failure, sodium is retained by the kidneys despite increases in extracellular volume. There is activation of renin secretion, which culminates in the production of angiotensin II, causing vasoconstriction and aldosterone secretion. These synergistically produce an increase in tubular reabsorption of sodium and water. Diuretics are the mainstay of symptomatic treatment to remove excess extracellular fluid in heart failure. Diuretics that affect the ascending loop of Henle are most commonly used. Thiazide diuretics promote a much greater natriuretic effect when combined with a loop diuretic in patients with refractory edema. Recently, spironolactone, an aldosterone receptor blocking agent, has been recommended to attenuate some of the neurohormonal effects of heart failure. Regardless of the diuretic, patients need to be counseled on the importance of avoiding sodium in their diet

Benzothiadiazines↗

Diuretic and antihypertensive activity of ZENECA ZM224,832: a novel eukalemic diuretic with calcium channel blocking activity.

ZENECA ZM224,832 is a novel eukalemic diuretic from the aminomethylphenol pyrazine series which demonstrated a profile of calcium channel blockers. It produced diuretic and saluretic effects in animals but had only minimal alterations in kaliuresis after oral administration. In contrast to standard diuretics, the plasma K+ concentration was not altered in conscious dogs treated for 14 days with ZENECA ZM224,832 and the concurrent plasma renin activity was also minimally elevated. The isolated rat aorta evaluation indicated that ZENECA ZM224,832, like tiapamil and nifedipine, inhibited vascular smooth muscle tone by inhibiting voltage-dependent calcium channels. ZENECA ZM224,832 produced a dose-dependent decrease of blood pressure in spontaneously hypertensive rats (SHR) in which the antihypertensive activity was not noted with HCTZ. In addition, ZENECA ZM224,832, similar to diltiazem, produced an acute blood pressure lowering effect in nephrectomized SHR which was independent of its diuretic activity. It is concluded that ZENECA ZM224,832 is a potent eukalemic diuretic with calcium channel blocking properties.

Animals↗

[Studies on the diuretic effects of etozolin (Elkapin) in heart failure - a comparison with the loop diuretic agent furosemide (author's transl)].

UNLABELLED: In 115 randomized patients with left and/or right ventricular failure, the effect of the new diuretic Etozolin (800 mg p.o.) (n = 55) is compared with that of the loop diuretic Furosemide (80 mg p.o.) (n = 60). RESULTS: 1. The increased diuresis after Etozolin remains constant during the entire trial period. Furosemid initially induces a more intense diuresis. 2. Analysis of the action profile shows that the higher daily urinary output following Furosemide is due to a more intense diuresis in the first fractions of the day. The action of Etozolin is more constant and lasts into the evening. 3. Both substances reduce body weight to the same extent. 4. Heart rate and arterial blood pressure decline significantly during trial. 5. Etozolin induces lesser electrolyte elimination than Furosemide in the initial phase of the trial. Potassium elimination values, in particular, remain below Na+ and Cl- elimination values for both substances. 6. During the trial period both substances had no significant effect on blood and liver values, serum electrolytes, creatinine, urea and uric acid. Etozolin may be classified as a diuretic similar to a thiazide derivative in its 24-h profile but behaves like a loop diuretic in its diuretic effect.

Blood Cell Count↗

Failure of indomethacin to impair the diuretic and natriuretic effects of the loop diuretic torasemide in healthy volunteers.

The effects of torasemide, a new potent loop diuretic, on renin release, water and sodium excretion were investigated in young healthy volunteers before and after 3 days of treatment with indomethacin. Torasemide 20 mg i.v. induced a rapid and biphasic increase both in plasma renin activity and plasma angiotensin II levels, which was almost completely abolished by pretreatment with indomethacin. Torasemide also increased urine volume, sodium excretion and, during the first hour after dosing, the creatinine clearance. None of the latter effects was impaired by indomethacin pretreatment. It is concluded that, like other loop diuretics, torasemide stimulates renin release by increasing renal prostaglandin production. However, at variance with what is observed with other loop diuretics, the diuretic and natriuretic effects of torasemide as well as the change in creatinine clearance do not appear to be inhibited by indomethacin.

Adult↗

Loop diuretics alter the diurnal rhythm of endogenous parathyroid hormone secretion. A randomized-controlled study on the effects of loop- and thiazide-diuretics on the diurnal rhythms of calcitropic hormones and biochemical bone markers in postmenopausal women.

BACKGROUND: Thiazide diuretics (TD) reduce urinary calcium, bone loss and fracture risk. Loop diuretics (LD) may have opposite effects. These effects could depend on induced rhythmic changes in bone and calcium homeostasis. DESIGN: After a run-in period of 7 days, we studied (in a factorial design) the diurnal rhythms of plasma levels of calcium, phosphate, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D and osteocalcin, as well as renal excretions rates of calcium, phosphate, and cross-linked N-terminal telopeptide of type 1 collagen (NTx) in 50 postmenopausal women randomized to treatment with either a thiazide diuretic (TD; bendroflumethiazide, n = 14), a loop diuretic (LD; bumetanide, n = 13), LD plus TD (bendroflumethiazide plus bumetanide, n = 11), or placebo (n = 12). RESULTS: In all four groups, all measured quantities showed a diurnal variation. LD caused a steep increase, with a subsequent decrease, in urinary calcium and plasma PTH. The mean 24 h plasma PTH concentration was increased (8.5 +/- 0.9 mmol L-1) compared with placebo (4.4 +/- 0.4 mmol L-1), whereas net 24 h renal calcium excretion did not differ from that of the placebo group due to a rebound hypocalciuria. Compared with placebo, diurnal rhythms of plasma phosphate and osteocalcin were changed with an increase during daytime and a decrease during the night. TD did not alter the diurnal rhythm of any of the measured quantities. However, the 24-h renal calcium excretion decreased, whereas the mean 24-h plasma calcium concentration increased without PTH suppression. LD plus TD caused changes similar to those observed with LD alone. CONCLUSION: One daily dose of LD increases parathyroid activity with alterations in the diurnal pattern of osteocalcin. This could indicate a potential anabolic effect of LD.

Aged↗

Diuretic effect and diuretic efficiency after intravenous dosage of frusemide.

1. Frusemide was given intravenously at a dose of 5 mg kg-1 to five healthy volunteers and the diuresis was assessed by frequent spontaneous voiding over 5 h. Urinary volume and contents of sodium, chloride, potassium and frusemide were measured. 2. Diuretic response was evaluated using the sigmoid Emax model and non linear regression of diuresis vs frusemide excretion rate. The time courses of diuresis (pharmacological effect) and diuretic efficiency were constructed from the fitted parameters of the sigmoid Emax model. 3. The frusemide excretion rate associated with maximum efficiency was found, as predicted theoretically, to be less than the excretion rate associated with 50% of maximum effect in four of the five subjects in whom the slope factor was less than 2. 4. The effect over time is dependent both on the instantaneous drug effect but also on its pharmacokinetic properties and mode of administration. An intravenous bolus is the least efficient mode of administration while a controlled input producing a frusemide excretion at maximum efficiency should yield up to a 2.3 times higher diuretic response.

Adult↗

Bucolome, a potent binding inhibitor for furosemide, alters the pharmacokinetics and diuretic effect of furosemide: potential for use of bucolome to restore diuretic response in nephrotic syndrome.

To determine whether bucolome (5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhydropyrimidine), a nonsteroidal anti-inflammatory agent, can reverse diuretic resistance of furosemide in patients with nephrotic syndrome, we examined the inhibitory effect of bucolome on the protein binding of furosemide in serum and urine. Bucolome significantly inhibited the protein binding of furosemide not only in serum but also in urine of preparation albumin (UPA), which mimics urinary albumin concentration in patients with nephrotic syndrome by ultrafiltration method. The binding percentage of furosemide to albumin was approximately 70% in UPA. With coadministration of bucolome to healthy volunteers, renal clearance of furosemide was increased, reflecting the increase of the free fraction of furosemide in serum. Furthermore, coadministration of bucolome caused a significant increase of urine volume and sodium concentration in urine. Even at higher urine levels of furosemide, the inhibitory effect of bucolome on the protein binding of furosemide in UPA remains constant, and changes in pH at weakly acidic pH levels (pH 5.5-6.5) did not alter the inhibitory effect of bucolome. Interestingly, coadministration of bucolome with furosemide in doxorubicin (Adriamycin)-induced nephrotic syndrome model rats alleviated the diuretic resistance. These results suggest that bucolome has a potent inhibitory effect on the protein binding of furosemide in the urine and can partially restore the diuretic response of furosemide in patients with nephrotic syndrome by increasing the free fraction of furosemide at the site of action.

Adult↗

Use of piretanide, a new loop diuretic, in cirrhosis with ascites: relationship between the diuretic response and the plasma aldosterone level.

Twenty patients with cirrhosis and ascites but no renal failure were given piretanide, a new loop diuretic, in order to investigate its efficacy and to relate the diuretic response with the pretreatment plasma aldosterone concentration. Eleven patients responded to piretanide 12 mg/day (equivalent in potency to 80 mg furosemide); there was no response in nine patients. Both groups were similar with regard to liver function, plasma urea, serum creatinine, plasma electrolytes, urine volume, and urine potassium concentration. The basal urinary sodium excretion was significantly higher in those patients who responded (23.6 +/- 5.7 mmol/day vs. 4.3 +/- 1.42 mmol/day; P < 0.01) (M +/- SE). Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were normal or only slightly increased in patients who responded to piretanide (PRA = 1.22 +/- 0.20 ng/ml/h; PAC = 12.25 +/- 2.20 ng/100 ml) and very high in patients who did not respond (PRA = 8.71 +/- 1.18 ng/ml/h; PAC = 84.6 +/- 16.2 ng/100 ml) (P < 0.001). Patients unresponsive to piretanide 12 mg/day also failed to respond when the dose was increased to 24 mg/day. However, the addition of spironolactone, 150 mg/day, to piretanide was followed in these patients by a marked increase in diuresis and natriuresis. These results strongly suggest that the pre-treatment level of aldosterone is an important factor influencing the response to loop diuretics in patients with non-azotaemic cirrhosis and ascites.

Adult↗

Isolation and characterization of a diuretic peptide from Acheta domesticus. Evidence for a family of insect diuretic peptides.

A diuretic peptide (Acheta-DP) has been isolated from extracts of whole heads of the house cricket, Acheta domesticus. The native peptide increases both cyclic AMP production and the rate of fluid secretion by isolated Malpighian tubules in vitro to an extent comparable with those responses obtained with supra-maximal amounts of crude extracts of corpora cardiaca. The primary structure of Acheta-DP was established as a 46-residue amidated peptide: TGAQSLSIVAPLDVLRQRLMNELNRRRMRELQGSRIQQNRQLLTSI-NH2. Acheta-DP has 41% sequence identity with a diuretic peptide isolated from Manduca sexta, providing direct evidence for the presence of a family of diuretic peptides in insects.

Amino Acid Sequence↗