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PubMed2006

Differential effects of cation-chloride co-transport-blocking diuretics in a rat hippocampal slice model of epilepsy.

The cation-Cl- co-transport-blocking loop diuretics have clinically known anticonvulsant activity, though they can also induce seizures. We explored the effects of ethacrynic acid (ETA), furosemide (FUR) and bumetanide (BUM), prototypical blockers of cation-Cl- co-transport, on the epileptiform field potentials induced in CA3 area of hippocampal slices from 5-weeks-old rats by a high K+-low Ca2+ perfusion fluid. That milieu induces frequent spontaneous field bursts, making single fimbrial stimuli to evoke several repetitive population spikes, of increased amplitude. ETA (0.25-1 mM) concentration-dependently reduced spontaneous field bursting, up to terminating it. FUR, 5 mM also inhibited spontaneous field bursting, while BUM (12.5-100 microM) only presented an inconsistent tendency. Both ETA and FUR showed a less marked ability to depress the evoked responses, but approximately mM concentrations significantly reduced the number of repetitive population spikes and their amplitude. BUM only modestly reduced population spike amplitude, without concentration-dependence. This study shows that K+-Cl- co-transport-blocking diuretics ETA and FUR inhibit high K+-induced epileptiform activity in hippocampal slices from (nearly) adult rats, while the Na+-K+-2Cl- co-transport-preferring diuretic BUM had only negligible activity. These results support that neuronal K+-Cl- co-transport-blockade provides antiepileptic effects.

Animals↗
PubMed2004

Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure.

OBJECTIVES: This individually randomized, open-label, parallel-group pilot study was designed to test the hypothesis that the ability of loop diuretics to interfere with cardiac fibrosis in chronic heart failure (CHF) may be different between compounds. BACKGROUND: The apparent mortality and cardiac benefits seen in studies comparing torasemide with furosemide in CHF suggest that torasemide may have beneficial effects beyond diuresis (e.g., on the process of cardiac fibrosis). METHODS: Patients with New York Heart Association functional class II to IV CHF received diuretic therapy with either 10 to 20 mg/day oral torasemide (n = 19) or 20 to 40 mg/day oral furosemide (n = 17), in addition to their existing standard CHF therapy for eight months. At baseline and after eight months, right septal endomyocardial biopsies were obtained to quantify collagen volume fraction (CVF) with an automated image analysis system. Serum carboxy-terminal peptide of procollagen type I (PIP) and serum carboxy-terminal telopeptide of collagen type I (CITP), indexes of collagen type I synthesis and degradation, respectively, were measured by specific radioimmunoassays. RESULTS: In torasemide-treated patients, CVF decreased from 7.96 +/- 0.54% to 4.48 +/- 0.26% (p < 0.01), and PIP decreased from 143 +/- 7 to 111 +/- 3 microg/l (p < 0.01). Neither CVF nor PIP changed significantly in furosemide-treated patients. In all patients, CVF was directly correlated with PIP (r = 0.88, p < 0.001) before and after treatment. No changes in CITP were observed with treatment in either group. CONCLUSIONS: These findings suggest that loop diuretics possess different abilities to reverse myocardial fibrosis and reduce collagen type I synthesis in patients with CHF.

Collagen Type I↗
PubMed2004

Diuretic and nephroprotective effect of Jawarish Zarooni Sada--a polyherbal unani formulation.

A number of drugs, both single and compound preparations are used widely in Tibb-e-Unani (Unani medicine) in the management of renal diseases. But such drugs mostly, have not been investigated for their described effects. Jawarish Zarooni Sada (JZS) is one such polyherbal preparation containing 15 ingredients, mainly described to be diuretic and nephroprotective. Therefore, in the present study ethanol and water extracts of JZS (300 mg each) were investigated for diuretic activity by measuring the total urine output over a period of 6h. Sodium and potassium level in urine sample was also estimated. Nephroprotective activity of JZS against gentamicin-induced nephrotoxicity was investigated by administering JZS along with high dose of gentamicin (40 mg/kg) and elevation of serum urea and serum creatinine was taken as the index of nephrotoxicity. JZS showed significant diuretic and nephroprotective effect.

Animals↗
PubMed2006

Structure-activity relationships for in vitro diuretic activity of CAP2b in the housefly.

A series of truncated and Ala-replacement analogs of the peptide Manse-CAP2b (pELYAFPRV-NH(2)) were assayed for diuretic activity on Malpighian tubules of the housefly Musca domestica (M. domestica). The C-terminal hexapeptide proved to be the active core, the minimum sequence required to retain significant diuretic activity. However, full activity required the C-terminal heptapeptide, which was equipotent with the most active of the native housefly CAP2b peptides. Replacement of Arg(7) and Val(8) with Ala led to inactivity and a large 70-fold drop in potency, respectively, indicating that these were critical residues. The Leu(2) was semicritical, where a six-fold loss in potency was observed. Conversely, the replacement of all other residues with Ala led to much smaller effects on potency and these positions were considered to be noncritical. This structure-activity relationship data can aid in the design of mimetic agonist/antagonist analogs of this diuretic peptide family with enhanced biostability and bioavailability, as tools for arthropod endocrinologists and as potential pest management agents capable of disrupting the water balance in pest flies.

Amino Acid Sequence↗
PubMed1997

Association between diuretic use, clinical response, and death in acute heart failure.

Because the impact of diuretic use on mortality in acute congestive heart failure (CHF) is not known, we examined the association between drug use, fluid balance, and death among 1,150 patients hospitalized for evaluation and treatment of CHF. After adjusting for other relevant intergroup differences, we observed that less net weight loss and a greater number of intravenous drug doses retained significant predictive value for death, suggesting that more frequent diuretic dosing or diuretic resistance may be related to mortality in acute CHF.

Acute Disease↗
PubMed2001

Influence of diuretics on the concentration of proteins and other components of pleural transudates in patients with heart failure.

PURPOSE: Diuretic therapy increases the total protein and lactate dehydrogenase concentrations in pleural fluid in patients with transudates due to heart failure, but the effect of diuresis on other substances in pleural fluid constituents is not known. SUBJECTS AND METHODS: Twenty-one patients with transudative pleural effusions due to congestive heart failure were prospectively studied. Repeated diagnostic thoracentesis (mean +/- SD = 3 +/- 1; range, 2 to 6) was performed until the effusions were radiographically unapparent (5 +/- 2 days). Thirty-one patients with congestive heart failure who underwent only a single thoracentesis after diuretic therapy served as controls. We measured the concentrations of various components of pleural effusions in the serum and in the pleural fluid, and determined the serum-pleural fluid gradient (serum concentration minus pleural fluid concentration) and ratio (serum concentration divided by pleural fluid concentration). RESULTS: The pleural concentrations of most components increased significantly (P <0.001) from the initial specimen to the final specimen: total protein, from 23 +/- 7 g/L to 33 +/- 9 g/L; albumin, from 13 +/- 4 g/L to 18 +/- 6 g/L; lactate dehydrogenase, from 177 +/- 62 U/L to 288 +/- 90 U/L; cholesterol, from 31 +/- 16 mg/dL to 52 +/- 22 mg/dL; and cholinesterase, from 1,304 +/- 616 U/L to 1,884 +/- 674 U/L. Expressed as percentage change, the increases in the serum-pleural fluid gradients for albumin (12% +/- 22%) and total protein (11% +/- 12%) were significantly less than the increases in their concentrations in pleural fluid (albumin, 47% +/- 49%; total protein, 48% +/- 40%) or in their pleural fluid/serum ratios (albumin, 27% +/- 29%; total protein, 38% +/- 34%). CONCLUSIONS: The concentrations of the biochemical components commonly measured in pleural fluid increase progressively during diuretic therapy. Calculation of the serum-pleural fluid gradients for protein and albumin may be the most useful way to distinguish transudates from exudates in patients with congestive heart failure who have undergone diuresis.

Aged↗
PubMed1984

Diuretic-induced hypokalemia.

Diuretic therapy is the most common cause of potassium deficiency. Although the extent of potassium deficiency usually does not exceed 200 or 300 mEq, under appropriate circumstances such modest deficiency may have important consequences. Factors that tend to increase the incidence or severity of potassium deficiency in patients who take diuretics include high salt diets, large urine volumes, metabolic alkalosis, increased aldosterone production, and the simultaneous use of two diuretics that act on different sites in the renal tubule. There are many serious complications of potassium deficiency, including cardiac arrhythmias, muscle weakness, rhabdomyolysis, glucose intolerance, and several complications that result directly from increased ammonia production, such as protein and nitrogen wasting and hepatic coma. Emphasized herein are those conditions that impose potential danger in patients with mild hypokalemia. Important factors that identify specific causes of potassium deficiency and its treatment are discussed briefly.

Animals↗
PubMed1996

Metabolic manifestations of low-dose diuretics.

Hypertension has been defined and treated as a disease of abnormal systolic and diastolic blood pressure. Recent data have, however, demonstrated that effective blood-pressure control has not resulted in the expected decrease in coronary artery disease. These findings are probably a result of hypertension being a complex inherited syndrome of cardiovascular risk factors, all of which are genetically linked and all of which contribute to the development of cardiovascular disease in these patients. Included in the hypertension syndrome are abnormalities of lipid profile, insulin resistance, changes in renal function, left ventricular hypertrophy and reduced arterial compliance. In many patients, high blood pressure is a late manifestation of this disease process. Since all cardiovascular risk factors contribute to heart disease in these patients, they should all be considered in the management of this disease process. Diuretics and beta blockers, when used at high doses, negatively impact lipid metabolism and insulin sensitivity, while angiotensin converting enzyme (ACE) inhibitors and calcium antagonists tend to have a neutral effect on these metabolic risk factors. These findings have resulted in decreased use of diuretics and beta blockers in favor of newer agents such as ACE inhibitors and calcium antagonists. However, recent data have demonstrated that when used at low doses (6.25 or 12.5 mg of hydrochlorothiazide), diuretics lack significant metabolic side effects while bringing about significant reductions in blood pressure. Thus, at these doses, hydrochlorothiazide is a useful drug in the treatment of hypertension, both as monotherapy and in combination therapy.

Antihypertensive Agents↗
PubMed1996

Vascular effects of loop diuretics.

Although it is generally believed that the beneficial effect of loop diuretics is the result of a rapid increase in diuresis, substantial evidence, from a large number of in vitro and in vivo experiments, has accumulated showing that administration of furosemide causes direct vascular effects, which probably contribute to its acute clinical effects. Several mechanisms are involved in the vascular response to loop diuretics. The role of the renin-angiotensin-adolsterone axis, prostaglandins and the direct vascular effects of loop diuretics on both the arterial and venous parts of the vasculature are discussed.

Animals↗
PubMed2004

Continued importance of diuretics and beta-adrenergic blockers in the management of hypertension.

The use of thiazide diuretics as one of the preferred antihypertensive medications has stood the test of time. Since the introduction of orally effective agents in 1957 to 1958, these drugs have continued to prove their usefulness. Numerous clinical trials have confirmed that these medications are as or more effective in reducing blood pressure and cardiovascular events than any of the other effective antihypertensive agents. Although some metabolic changes may occur with higher dosages of these medications, they seem to be of limited clinical significance. In addition to being well tolerated and effective. thiazide-type diuretics are less expensive than other agents. This should be considered in view of the fact that quality of care is not compromised when the less expensive medication is used. beta-Blockers should also be considered as a major drug class in the management of hypertensive patients. There are few studies directly comparing these drugs with other agents. Although some data suggest that they are less effective in reducing CHD events in the elderly, there are numerous situations where beta-blockers are clearly indicated. Combination therapy with a beta-blocker and diuretic has been shown to be highly effective in reducing cardiovascular events in both diabetic and nondiabetic patients.

Adrenergic beta-Antagonists↗
PubMed2000

Effects of hydrochlorothiazide and furosemide diuretics on human bone marrow stromal osteoprogenitor cells.

Thiazide diuretics have been shown to decrease bone loss and improve bone mineral density, while long-term furosemide therapy has been suggested to decrease bone mineral content. However, the direct effects of these diuretics on osteoblastic cells are not well established. Some investigators have reported direct effects of thiazides on osteoblastic cells but the results remain controversial, and there are few data about the direct effect of furosemide on osteoblastic cells. We investigated the effects of hydrochlorothiazide (HCTZ) and furosemide on proliferation, alkaline phosphatase activity, osteocalcin, and interleukin-6/interleukin-11 (IL-6/IL-11) secretion in cultured normal human bone marrow stromal osteoprogenitor cells (hBMSCs). Treatment with HCTZ or furosemide for 24 hours in the concentration range of 10(-6) to 10(-4) mol/L did not affect 3H-thymidine incorporation in hBMSCs. Cellular alkaline phosphatase activity and osteocalcin production were not changed significantly by treatment with HCTZ or furosemide (up to 10(-4) mol/L) during culture. There was also no significant difference in IL-6 and IL-11 production in hBMSCs. These results suggested that HCTZ or furosemide had no significant direct effect on proliferation, alkaline phosphatase activity, osteocalcin, and IL-6/IL-11 production in hBMSCs, and the effects of these diuretics on bone mass may be related to the indirect action on calcium balance.

Alkaline Phosphatase↗
PubMed1976

Deterioration of glucose tolerance in hypertensive patients on prolonged diuretic treatment.

Glucose tolerance was investigated in 51 hypertensive patients before and after 1 and 6 years of treatment with oral diuretics. Glucose tolerance was unchanged after 1 year but had deteriorated significantly after 6 years' therapy. In a comparable group of 16 patients tested at similar intervals in which diuretic therapy had been given only for 3 of the 6 years there was no change in glucose tolerance, suggesting that prolonged oral treatment with thiazide diuretics is diabetogenic.

Administration, Oral↗
PubMed1981

beta-blockers or diuretics in hypertension? A six year follow-up of blood pressure and metabolic side effects.

The antihypertensive effect and metabolic side effects of bendroflumethiazide have been compared with those of propranolol in two randomly selected groups, of 53 previously untreated middle-aged men during 6 years' treatment for mild to moderately severe essential hypertension. The blood pressure-reduction was the same in the two groups. During the follow-up 1 man in the bendroflumethiazide group and 3 in the propranolol group died while 2, 1 on each treatment, became diabetic. None had gout but serum urate increased in both groups. Glucose tolerance improved significantly in both groups during the first year and this improvement was sustained for the follow-up period. Serum potassium did not differ in the two groups during the first 5 years but during the sixth year it decreased in the diuretic group. Total potassium was, however, unchanged in both groups. These results indicate that the frequency of metabolic side effects during diuretic treatment of mild to moderately severe essential hypertension is low and has been grossly exaggerated. Since the antihypertensive effect and side effects were equal with both drugs, and since the diuretics are cheaper, they should be the drug of first choice in this type of hypertension.

Adrenergic beta-Antagonists↗
PubMed1983

Prior thiazide diuretic treatment increases adrenaline-induced hypokalaemia.

Hypokalaemia is a common finding in acutely ill patients and may be related in part to increased sympathoadrenal activity. In an investigation to determine whether pretreatment with thiazide diuretics causes the serum potassium to fall to an even lower level during increased sympathoadrenal activity, adrenaline was infused into healthy subjects after pretreatment for 7 days with either bendrofluazide (5 mg) or placebo. Thiazide diuretic pretreatment had no effect on the adrenaline-induced changes in blood pressure and heart rate. However, not only was the baseline serum potassium lower after bendrofluazide (3 . 40 mmol/l vs 3 . 83 mmol/l) but the serum potassium also fell to a significantly lower level during adrenaline infusion after bendrofluazide (2 . 73 mmol/l vs 3 . 08 mmol/l). Transient profound hypokalaemia may increase the risk of ventricular arrhythmias in patients on diuretics, and routine monitoring of the resting serum potassium may underestimate this risk.

Adult↗
PubMed1996

Pharmacokinetics and pharmacodynamics of torasemide and furosemide in patients with diuretic resistant ascites.

BACKGROUND/AIM: To evaluate the pharmacokinetics and pharmacodynamics of furosemide and torasemide in patients with cirrhosis and diuretic resistant ascites. METHODS: Eighteen patients were randomly allocated to receive intravenous torasemide (40 mg) or furosemide (80 mg). The renal response to these drugs was assessed in baseline conditions and in the 24 h following drug administration together with plasma and urinary concentrations of furosemide, torasemide and its metabolites. RESULTS: Torasemide induced significantly greater diuretic and natriuretic effects than furosemide in the first hour after drug administration. No other significant differences between the two drugs were observed with respect to the renal response to these drugs. Torasemide reached a lower maximum plasma concentration than furosemide, but the former drug had a longer apparent terminal half-life and lower renal and non-renal clearances. Comparing these results with those previously reported in healthy subjects, both drugs showed a reduced elimination rate through renal and non-renal routes, and a larger distribution to body fluids. As a consequence, the half-life of both drugs was longer than in healthy subjects. Urinary excretion of pharmacologically active species, however, was quantitatively unchanged after torasemide administration, whereas it was reduced after furosemide. Finally, the natriuretic potency of both drugs was markedly reduced in these patients. CONCLUSIONS: The pharmacokinetics and pharmacodynamics of torasemide and furosemide are markedly altered in patients with diuretic resistant ascites.

Adult↗
PubMed2000

High-performance liquid chromatographic separation of a complex mixture of diuretics using a micellar mobile phase of sodium dodecyl sulphate. Application to human urine samples.

A systematic optimization of the HPLC separation of a complex mixture containing 19 diuretics by micellar liquid chromatography using sodium dodecyl sulphate (SDS), a Hypersil (150 mmx3.0 mm I.D., 5 microm) C18 column, a flow-rate of 0.5 ml min(-1) and UV absorbance detection has been carried out. Several mobile phases consisting of SDS and organic modifiers such as acetonitrile, tetrahydrofuran, propanol, butanol or pentanol, and the pH adjusted to 3.2, were tested. The effect of the organic modifier and SDS concentration on the retention behavior and separation of the diuretics was investigated. A mobile phase containing 40 mM SDS and 4% tetrahydrofuran was finally selected. Under these conditions, 14 out of 19 diuretics were separated in about 31 min. A bivariant optimization method for the mobile phase SDS-tetrahydrofuran corroborated the above results. The effect of temperature on the retention was also studied, and 50 degrees C was selected. The optimized method was applied to human urine samples of subjects administered Diurex (tablets containing 20 mg of the active ingredient xipamide) without sample preparation.

Calibration↗
PubMed1996

Detection of diuretic agents in doping control.

Since the inclusion of diuretics in the list of banned substances in sports in 1988, a large number of screening and confirmation procedures to detect the presence of these substances in urine samples have been developed. In this paper, a review of the analytical methodology described to analyze diuretics is presented. The paper has been focused on the needs of doping control and mainly screening procedures including sample preparation and liquid or gas chromatographic separation have been considered. More relevant papers using capillary zone electrophoresis have been also considered. Mass spectrometry is mandatory in doping control for confirmation purposes, and finally, mass spectrometric techniques described for diuretics have been reviewed.

Chromatography, Gas↗
PubMed2001

Diuretic effects of selected Thai indigenous medicinal plants in rats.

Extracts of five indigenous Thai medicinal having ethnomedical application in the treatment of dysuria were investigated for their diuretic activity. Root extracts of Ananas comosus and Carica papaya, given orally to rats at a dose of 10 mg/kg, demonstrated significantly increased urine output (P < 0.01) which was 79 and 74%, respectively, of the effect of an equivalent dose of hydrochlorothiazide. Both plant extracts gave similar profiles of urinary electrolyte excretion to that of the hydrochlorothiazide. The analyses of the urinary osmolality and electrolyte excretion per unit time suggest the observed effect of A. comosus was intrinsic, whereas that of C. papaya may have resulted from a high salt content of this extract. However, our experimental evidence on the diuretic activities of the other three plants did not parallel their local utilization for dysuria. It was found that the rhizome of Imperata cylindrica apparently inhibited the urination of rats whereas the rhizome of Cyperus rotundus and the stem of Averrhoa carambola failed to demonstrate any diuretic activities. These results indicate that two of the plants investigated exert their action by causing diuresis. The other three plants need further investigation to determine their effectiveness in the treatment of dysuria.

Animals↗