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PubMed2004

Pharmacological characterization of N-tert-butyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a novel thromboxane A2 receptor antagonist and thromboxane synthase inhibitor in a rat model of arterial thrombosis and its effects on bleeding time.

The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea], an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor in rats, and to determine its effects on mice bleeding time. Intraperitoneal injection of a single dose of 5 mg/kg BM-573 to rats inhibited U-46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F(2))-induced washed platelet aggregation 30 min and 1, 2, and 4 h after drug administration with a maximum antiplatelet effect observed after 1 and 2 h. In a rat model of thrombosis induced by ferric chloride application on the abdominal aorta, BM-573 significantly reduced the thrombus weight by 92.53, 80.20, 64.75, and 18.21% at doses of 5, 2, 0.5, and 0.2 mg/kg, respectively. Time to occlusion of abdominal aorta in the BM-573-treated group (41.50 +/- 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 +/- 0.79 min). Like furegrelate, seratrodast, and acetylsalicylic acid, BM-573 did not affect the tail bleeding time induced by tail transection in mice compared with vehicle-treated mice. Moreover, BM-573, a close derivative of the loop diuretic torasemide, failed to induce a significant increase in diuresis in rat and did not produce a decrease in blood glucose concentration as observed with the sulfonylurea glibenclamide. In conclusion, we have demonstrated that the nitrobenzenic sulfonylurea BM-573, an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor, is a potent antithrombotic agent that does not affect bleeding time. Moreover, BM-573 lost the diuretic property of torasemide and has no impact on glycemia.

Animals↗

PubMed2001

Long-term efficacy of torsemide compared with frusemide in cirrhotic patients with ascites.

BACKGROUND: Torsemide is a new loop diuretic that has shown, in short-term studies, to induce a longer and higher diuretic and natriuretic action than frusemide. However, torsemide long-term effects and complications have not been sufficiently investigated. The aim was to compare the efficacy and safety of torsemide versus frusemide in cirrhotic patients with uncomplicated ascites. METHODS: Forty-six patients were randomized in two groups to receive torsemide 20 mg/day (n = 22) or frusemide 40 mg/day (n = 24). Both drugs were administered in association with spironolactone 200 mg/day. The initial doses of diuretics were increased every 3 days up to 60, 120 and 400 mg/day, respectively, if the body weight loss was less than 300 g/day or natriuresis was below 50 mEq/day. RESULTS: Torsemide induced a significantly greater diuretic response than frusemide at 24 h and the maximum diuresis while mean diuresis was similar in both groups. Natriuresis was also higher with torsemide but the difference was not significant. The body weight loss, the treatment period, the ascites resolution and complications were similar in both groups. Diuretic doses were increased in two patients treated with torsemide and in nine patients treated with frusemide (P < 0.05). CONCLUSIONS: These results show that torsemide is as effective and safe as frusemide for long-term treatment of cirrhotic patients with ascites.

Adult↗

PubMed1998

A novel therapy for nocturnal polyuria: a double-blind randomized trial of frusemide against placebo.

OBJECTIVE: To report a randomized, double-blind, placebo-controlled trial of an afternoon dose of the diuretic frusemide, used to establish an early evening diuresis and so diminish nocturnal voiding frequency and voided volume in elderly men presenting with lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: After a 2-week placebo run-in period, 49 men aged > 50 years were randomized to receive 40 mg of frusemide or placebo, taken 6 h before their usual bedtime. Day and night-time frequency and voided volume during the run-in and treatment periods were compared between the placebo and frusemide groups. RESULTS: In the 43 men completing the study, there was a significant reduction in night-time frequency (-0.5 and 0) and percentage night-time voided volume (-18% and 0%) in those taking frusemide compared with placebo. Of patients on active treatment, seven of 19 had a reduction in night-time frequency of > or = 1, compared with only one of 20 on placebo, and 14 of 21 felt that frusemide had helped their nocturia, compared with only five of 22 on placebo. CONCLUSION: Men with LUTS whose most prominent symptom is nocturia should complete a frequency-volume chart. In those with nocturnal polyuria, 40 mg of frusemide resulted in a significant reduction in night-time frequency and percentage voided volume.

Aged↗

PubMed1999

The distribution of a CRF-like diuretic peptide in the blood-feeding bug Rhodnius prolixus.

The blood-feeding bug Rhodnius prolixus ingests a large blood meal, and this is followed by a rapid diuresis to eliminate excess water and salt. Previous studies have demonstrated that serotonin and an unidentified peptide act as diuretic factors. In other insects, members of the corticotropin-releasing factor (CRF)-related peptide family have been shown to play a role in post-feeding diuresis. Using fluorescence immunohistochemistry and immunogold labelling with antibodies to the Locusta CRF-like diuretic hormone (Locusta-DH) and serotonin, we have mapped the distribution of neurones displaying these phenotypes in R. prolixus. Strong Locusta-DH-like immunoreactivity was found in numerous neurones of the central nervous system (CNS) and, in particular, in medial neurosecretory cells of the brain and in posterior lateral neurosecretory cells of the mesothoracic ganglionic mass (MTGM). Positively stained neurohaemal areas were found associated with the corpus cardiacum (CC) and on abdominal nerves 1 and 2. In addition, Locusta-DH-like immunoreactive nerve processes were found over the posterior midgut and hindgut. Double-labelling studies for Locusta-DH-like and serotonin-like immunoreactivity demonstrated some co-localisation in the CNS; however, no co-localisation was found in the medial neurosecretory cells of the brain, the posterior lateral neurosecretory cells of the MTGM or neurohaemal areas. To confirm the presence of a diuretic factor in the CC and abdominal nerves, extracts were tested in Malpighian tubule secretion assays and cyclic AMP assays. Extracts of the CC and abdominal nerves caused an increase in the rate of secretion and an increase in the level of cyclic AMP in the Malpighian tubules of fifth-instar R. prolixus. The presence of the peptide in neurohaemal terminals of the CC and abdominal nerves that are distinct from serotonin-containing terminals indicates that the peptide is capable of being released into the haemolymph and that this release can be independent of the release of serotonin.

Animals↗

PubMed1992

Mobilization of malignant ascites with diuretics is dependent on ascitic fluid characteristics.

Serial ascites and plasma volumes were measured during diuresis in nine patients with ascites caused by peritoneal carcinomatosis, four patients with chylous malignant ascites, and three patients with portal hypertension-related ascites caused by massive hepatic metastases. Oral diuretics were given to achieve an adequate natriuresis on a sodium-restricted diet. During the study period (7.8 +/- 3.2 days), patients with peritoneal carcinomatosis and chylous ascites lost 0.49 +/- 0.31 and 0.51 +/- 0.42 kg/day in weight, respectively, with negligible change in ascites volumes (-0.03 +/- 0.11 and 0.02 +/- 0.09 L/day). Patients with ascites caused by massive hepatic metastasis lost 1.06 +/- 0.15 kg/day in weight (P = 0.01 for massive hepatic metastasis vs. peritoneal carcinomatosis) and 0.23 +/- 0.13 L/day of ascites (P less than 0.05 vs. other groups). Plasma volume changes were not significantly different among the three groups. Patients with edema (9/16) had a greater natriuresis and daily weight loss. Three patients with peritoneal carcinomatosis and one with chylous ascites developed renal dysfunction or symptomatic hypotension. No patient with massive hepatic metastasis developed these complications. In patients with ascites caused by peritoneal carcinomatosis or chylous malignant ascites there is no mobilization of ascites, whereas in patients with massive hepatic metastasis, ascites may be mobilized with diuretics.

Adult↗

PubMed1990

[Mechanism of action of the diuretic effect of muzolimine].

Muzolimine is a diuretic which has been proposed in the treatment of hypertension. Muzolimine shared both the high ceiling effect of loop diuretics and the long duration of action of thiazides but has a chemical structure different from those of other loop diuretics. It may act as a prodrug and an active metabolite present in the urine may inhibit NaCl reabsorption in the Henle's loop. We studied the effect of urines of piretanide and muzolimine treated rats on Na+K+Cl- cotransport in renal cells in culture (MDCK). In the presence of ouabain (0.5 mM), the Na+K+Cl- cotransport measured by 86Rb influx, represented 92 p.100 of the total 86Rb influx (6.16 +/- 1.12 nmol 86Rb/min/mg prot, n = 10). Both diuretics were administered i.v. to rats where they induced marked diuresis. Excreted urine (dilution to 1/100) was tested for cotransport inhibition. After piretanide (27 mumol/kg) the urine inhibited the Na+K+Cl- cotransport in MDCK cells (72% and 41% inhibition at the 15th and 45th minutes after diuretic injection). After muzolimine (50 mumol/kg), urines also inhibited Na+K+Cl- cotransport but the effect was slower in onset and more prolonged (42% and 49% inhibition at the 15th and 60th min). Diuretic effects in vivo and Na+K+Cl- cotransport inhibition in vitro by the urine developed parallel for both diuretics. Probenecid (100 mumol/kg) suppressed simultaneously the diuretic effect of muzolimine and the Na+K+Cl- cotransport inhibition by the urine of muzolimine treated rats. Our results suggest that muzolimine acts as a prodrug. Its active metabolite is secreted into the tubular lumen through a probenecid sensitive pathway and inhibits, like other loop diuretics, Na+K+Cl- cotransport.

Animals↗

PubMed1989

Dissociation of natriuresis and diuresis and heterogeneity of the effector system of atrial natriuretic factor in rats.

The hypotensive, natriuretic, and diuretic actions of human atrial natriuretic factor-(99-126) (hANF) are accompanied by an elevation of cyclic guanosine monophosphate (cGMP) in plasma and urine. However, the oxidized hANF analogue, human [Met-O110]ANF-(99-126) (Met-O-ANF), has been reported to be unable to increase cGMP (Biochem. Biophys. Res. Commun. 128: 538-546). We employed this oxidized peptide to evaluate the relationship between its biological effects and cGMP generation, with cGMP serving as a marker of the recognized property of ANF to stimulate particulate guanylate cyclase. Met-O-ANF appeared to be a partial agonist, exhibiting a decreasing order of relative potency of hypotensive, vasorelaxant, diuretic, and natriuretic functions compared to hANF. A lower degree of cGMP increases was achieved by this analogue in cultured smooth muscle and endothelial cells. Met-O-ANF doses, which led to a significant increase in diuresis, were neither natriuretic nor accompanied by an increase of urinary cGMP. We were thus able to dissociate the diuretic and natriuretic effects of ANF. High doses of the oxidized analogue were required to elevate cGMP levels in plasma and urine. In isolated kidney fractions, Met-O-ANF's action on cGMP was significantly lower in glomeruli (fivefold less), virtually absent in the collecting duct, yet only slightly different (20% less) in thick ascending limb. Our results indicate that the diuretic and natriuretic effects are exerted at distinct sites, with only the natriuresis being related to an increase of extracellular cGMP. The variability of differential potency of biological and biochemical effects from tissue to tissue of these two forms of human ANF support the notion of the heterogeneity of the ANF effector system.

Animals↗

PubMed1980

Dopamine-induced diuresis in the cat without changes in renal hemodynamics.

The effects of intravenous (i.v.) and intraarterial (i.a.) injection and infusion of dopamine (DA) on renal hemodynamics, regional sympathetic activity and kidney function were investigated in anaesthetized cats. In response to the i.v. bolus injection of DA (25 microgram/kg), mean arterial blood pressure (MABP) was increased by 19.7%, renal blood flow (RBF) by 16.6%, and regional sympathetic discharges were inhibited. The principal effect of i.a. bolus injection of DA into the renal artery was vasoconstriction. Vasodilation was observed neither after lower doses of DA nor after pretreatment with phenoxybenzamine. During continuous i.v. infusion of 10 microgram DA kg-1 min-1 MABP, RBF, renal sympathetic discharges and glomerular filtration rate (GFR) did not change, whereas urine volume was increased by 120.5%, sodium excretion by 99.7%, chloride excretion by 143.2%, and potassium excretion by 31.9%. Urine osmolality was decreased and osmolal clearance increased. Raising the DA dose to 25 microgram kg-1 min-1 resulted in a fall of GFR, but the diuretic response was not significantly different from that of the low dose. Bulbocapnine (6 mg/kg i.v.) antagonized the DA-induced diuresis. In conclusion, the diuretic effect of DA in the cat is not dependent on a change in RBF, GFR or renal sympathetic activity. This suggests that a tubular site of action is primarily responsible for DA diuresis.

Animals↗

PubMed1986

Role of proximal convoluted tubule in pressure diuresis in the rat.

The role of different nephron segments in the diuretic response to acute arterial hypertension was studied with tubular microperfusion. Early proximal convolutes were perfused with synthetic glomerular ultrafiltrate; fluid was collected from the last visible loop of the same proximal or from the first loop of the distal tubule. In late proximal collections, an increase of arterial pressure of 24 +/- 2 mmHg reduced reabsorption of tubular fluid 44 +/- 4%. Perfusate chloride concentration fell, but only 2 meq/liter, so that chloride reabsorption was inhibited in proportion to the inhibition of fluid reabsorptions, with a corresponding increase in chloride delivery to the loop of Henle. In early distal collections, there was no significant difference of the early distal flow rate with hypertension, but early distal chloride concentration increased 31 +/- 8% and chloride load increased 45 +/- 12%. Qualitatively similar increases were obtained from paired collections made from free-flowing early distal tubules. Inhibition of proximal fluid reabsorption is a primary response to acute hypertension and may contribute to pressure diuresis. In addition, this inhibition increases the strength of the luminal signal to the macula densa, enhancing the autoregulatory response to hypertension.

Absorption↗

PubMed1979

Effect of furosemide on serum clearance and renal excretion of digoxin.

Serum turnover and urinary excretion of digoxin with or without oral furosemide were studied in six healthy subjects who received 0.006 mg/kg body weight digoxin intravenously. During furosemide treatment, the total amount of urinary digoxin did not change but the digoxin clearance during the diuretic phase and the digoxin excretion after the diuresis decreased significantly. The average serum half-life was prolonged from 37 hours in the control period to 86 hours in the furosemide period. Decreased glomerular filtration rate by volume depletion might have been responsible for the decreased excretion of digoxin, but there was no significant difference in urine volume after diuresis between the two periods, suggesting the possibility of inhibition of tubular secretion of digoxin by furosemide. It is also possible that serum digoxin concentration may be elevated if furosemide were given more frequently.

Adult↗

PubMed1994

Effect of crude extract of roots of Bredemeyera floribunda Willd. II. Effect on glomerular filtration rate and renal tubular function of rats.

The effect of crude extract of roots of Bredemeyera floribunda Willd., Polygalaceae used by Brazilian popular medicine as a potent diuretic, on renal function in antidiuresis or water diuresis in rats, was studied. During intravenous infusion of the extract (0.05 mg/min/100 g), mean arterial pressure did not change significantly but urine flow, glomerular filtration rate, fractional water and sodium excretion and solute clearance increased significantly, in both groups of animals. In antidiuresis rats the extract significantly increased reabsorption of water by the collecting duct and in water diuresis animals the extract significantly increased free water clearance. Our findings indicate a direct effect of extract on glomerular filtration rate, possibly by detergent like interactions with structural components of glomerular membranes and/or by decreasing renal perfusion pressure. The study on the concentrating and diluting mechanisms suggests preferential action of extract in the proximal tubular cells, possibly on the (Na(+)-K+)-ATPase countertransport system and/or on other proteins components of tubular cell membranes involved with salt transport mechanisms.

Animals↗

PubMed2003

Evaluation and management of hypo-osmolality in hospitalized patients.

Hyponatremia is the most common electrolyte disorder encountered in the clinical setting. Abnormalities of the mechanisms that maintain normal water and sodium metabolism are often present in hospitalized patients, including defects in renal water excretion. All of the current therapeutic approaches in patients with the syndrome of inappropriate antidiuretic hormone secretion and other forms of vasopressin-induced hyponatremia have significant limitations. Studies in animal models and humans have demonstrated that antagonists of the AVP V2 receptor in the kidney are effective in correcting hyponatremia. These new agents have been termed "aquaretics" because of their ability to induce a free water diuresis without the natriuresis or kaliuresis characteristic of diuretic drugs. When approved for clinical use, selective V2, and possibly also combined V1 + V2 receptor antagonists will be helpful in therapy.

Aged↗

PubMed2001

Intensive care unit management of the critically ill patient with fluid overload after open heart surgery.

Fluid overload is common before, during and after cardiac surgery. The fluid associated with cardiopulmonary bypass (CPB) and cardioplegia is a particularly important source of such fluid overload. In addition, renal dysfunction, which is common in these patients, participates in the pathogenesis of a positive sodium and water balance. Such fluid overload is physiologically undesirable and participates in the pathogenesis of several clinically important complications. Fluid overload can be partly prevented with the use of diuretics. However, in many patients, diuretics do not achieve sufficient sodium and water diuresis. In these patients, the application of hemofiltration (HF) during CPB and also immediately after CPB is an effective and safe approach to the maintenance of fluid homeostasis. If acute renal failure occurs, early intervention with HF may even improve survival.

Body Fluids↗

PubMed1978

Furosemide in hyaline membrane disease.

In a randomized clinical trial designed to evaluate the effect of diuresis on infants with hyaline membrane disease, seven infants were treated with furosemide (2 mg/kg intravenously) and five received 5% dextrose water in 0.225% sodium chloride (control group). Arterial blood gas analyses performed before and during the six hours after treatment showed no significant difference between control and treated infants. Urine output and urine sodium and calcium loss were significantly increased (P less than .05) in the infants receiving furosemide. The diuresis seemed to have no effect on left atrial size determined echocardiographically, whereas measurements of dynamic skinfold thickness suggested mobilization of subcutaneous water. One infant became seriously dehydrated and hypotensive secondary to a massive diuresis. We concluded that furosemide had a potent diuretic effect in infants with hyaline membrane disease but does not improve cardiorespiratory function acutely. This may be because of failure to mobilize pulmonary interstitial fluid in the time period tested. It may also be possible that the presence of pulmonary interstitial fluid does not play an important role in the impairment of gas exchange in the acute stage of hyaline membrane disease.

Carbon Dioxide↗

PubMed1985

[An old complication returns. Anuria caused by ureteral catheterization].

A case of secondary anuria following the insertion of a double pigtail stent to treat an anuria due to a tumoral obstruction of the ureter is presented. Washing of the stent through a second ureteral catheter parallel to it proved the patency of the stent. Diuresis ensued at last by the administration of diuretics and leaving both the stent and the ureteral catheter in place. The literature is reviewed and discussed.

Anuria↗

PubMed1987

Diminution by captopril of the diuretic, natriuretic and kallikrein stimulating action of furosemide by reduction in its renal secretion.

The effect of furosemide (40 mg iv) on diuresis, natriuresis and renal kallikrein and kinin excretion was investigated without and with pretreatment by captopril (100 mg po). Furosemide stimulated markedly diuresis and natriuresis as well as urinary kallikrein and kinin excretion. Pretreatment by captopril (C) reduced the diuretic and natriuretic effect of furosemide significantly (UNaV pre-C: +15, 1 +/- 2.1 ml/min vs. post-C: 7.0 +/- 0.3 ml/min; p less than 0.001). Similar changes in urinary kallikrein and kinin excretion were observed after captopril pretreatment, but because of the great coefficient of variation these changes did not reach statistical significance. The reason for the reduced activity of furosemide after captopril pretreatment was the diminished proximal-tubular secretion of furosemide, as it could be shown by direct measurement of the drug in urine. After furosemide injection changes in plasma aldosterone concentration paralleled changes in renal kallikrein and kinin excretion. However, after captopril there was a sharp dissociation between aldosterone, which was diminished by captopril continuously, and renal kallikrein and kinins, which were still stimulated by furosemide. These results suggest that renal kallikrein-kinin system is stimulated by furosemide directly and independently of aldosterone secretion.

Adult↗

PubMed1981

Diuresis in the ascitic patient: a randomized controlled trial of three regimens.

To compare the efficacy of three commonly used diuretic regimens in the treatment of ascites, we randomized 90 patients to three treatment groups: Sequential Spironolactone (spironolactone followed by furosemide if necessary), Combination (spironolactone and furosemide in combination), and Furosemide (furosemide given alone). Diuretics were begun at a low dose by mouth and the dosage increased until a 0.4-0.8 kg daily diuresis was achieved. The clinical and laboratory findings were comparable for the three experimental groups on admission to the study. All three regimens achieved a comparable rate of diuresis. To do so was far more difficult with furosemide alone, which required repetitious upward adjustments in dosage and massive KCl supplements. The incidence of encephalopathy, hepatorenal syndrome, and marked electrolyte abnormalities was similar for the three treatment groups except that severe hyperkalemia was more frequent on combination therapy. We conclude that diuresis should be initiated with one of the two spironolactone regimens and not with furosemide as the sole agent.

Ascites↗

PubMed1990

Diuretics after transurethral prostatectomy: a double-blind controlled trial comparing frusemide and mannitol.

Mannitol and frusemide were compared in a randomized, controlled, double-blind trial for their effects in promoting diuresis after prostatectomy and on indices of water intoxication. The drugs had comparable diuretic effects. Sodium loss was greater with frusemide, contributing to sodium depletion after operation. Administration of frusemide was associated with more frequent need for i.v. volume expansion after operation. Plasma osmolality was greater with mannitol (289 (SD 4.2 mosmol kg-1 at 1 h after operation and 285 (5.3) mosmol kg-1 at 4 h after operation) than with frusemide (282 (7.1) mosmol kg-1 and 279 (6.7) mosmol kg-1, respectively) (P less than 0.05). Plasma concentration of sodium was significantly greater with mannitol (136.9 (3.1) mmol litre-1) than with frusemide (134.4 (2.8) mmol litre-1) only on the morning after surgery (P less than 0.05). Mannitol is an effective alternative to frusemide in inducing diuresis after prostatectomy, and may protect against water intoxication.

Diuresis↗