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PubMed2006

Characterization of the uptake mechanism for a novel loop diuretic, M17055, in Caco-2 cells: involvement of organic anion transporting polypeptide (OATP)-B.

PURPOSE: M17055 is under development as a novel loop diuretic for oral administration. To investigate the molecular mechanism of its gastrointestinal absorption, we initially aimed to clarify the mechanism of uptake of M17055 by Caco-2 cells, focusing on possible involvement of OATP-B (SLCO2B1), which is localized in the apical membranes of human intestinal epithelial cells. MATERIALS AND METHODS: The uptake of [14C]M17055 by Caco-2 cells cultured on multi-well dishes was measured after cultivation for 14 days. Uptake of [14C]M17055 by HEK293 cells stably expressing OATP-B (HEK293/OATP-B cells) was also examined. RESULTS: M17055 uptake by Caco-2 cells was saturable, and was inhibited by various organic anions, including other loop diuretics, and several bile acids. Uptake of M17055 by HEK293/OATP-B cells was much higher than that by mock cells. The inhibitory profiles of various organic anions and the estimated Km values for M17055 uptake were similar in Caco-2 and HEK293/OATP-B cells. Moreover, the values of inhibition constants of several inhibitors for M17055 uptake were comparable in the two cell lines. CONCLUSION: Our data suggest that OATP-B plays a major role in the uptake of the novel loop diuretic M17055 from apical membranes in Caco-2 cells.

Algorithms↗
PubMed2003

The rational use of diuretics in heart failure.

Congestive heart failure is a progressive hemodynamic disorder associated with significant morbidity and mortality. Concomitant renal dysfunction is frequently seen in patients with heart failure, and can compromise fluid regulation, leading to acute decompensation, and increased morbidity and mortality. Diuretic therapy has been the mainstay for treatment of congestive symptoms, despite documented mortality benefits. Misuse or overuse of diuretics can have negative consequences in heart failure, and optimizing diuretic efficiency may improve outcomes. In addition, new agents targeting elevated neuropeptides may prove to be beneficial in regulating fluid status and optimizing renal function.

Disease Progression↗
PubMed1999

Old antihypertensive agents-diuretics and beta-blockers: do we know how and in whom they lower blood pressure?

Morbidity and mortality data that increasingly favor the use of diuretics and beta-blockers continue to accumulate. Nonetheless, the use of these agents particularly diuretics is viewed as a dated practice. The issue of which antihypertensive drug to use will remain complex and confusing as the marketing juggernauts of the pharmaceutical industry vigorously promote drug classes such as angiotensin- converting enzyme inhibitors, angiotensin-receptor antagonists, and calcium-channel blockers. A pharmacologic middle ground will probably be reached in the form of fixed-dose combination therapy. Diuretics and b-blockers are mechanistically rational when combined with numerous other drugs; thus, the issue of which drug should be used to begin treatment will be settled by a truce, albeit an uneasy one, favoring the increased use of fixed-dose combination antihypertensive therapy.

Adrenergic beta-Antagonists↗
PubMed1975

Cardiac effect of diuretic drugs.

Triamterene, amiloride, ethacrynic acid, and furosemide were studied to determine whether they modified the digitalis-induced egress of myocardial potassium which is thought to facilitate the development of digitalis arrhythmias. In a control group of 15 dogs, potassium was measured in samples obtained simultaneously from the femoral artery (FA) and the coronary sinus (CS) in a control period and at intervals after the administration of 1 mg. of acetylstrophanthidin. Acetylstrophanthidin caused a significant increase in cardiac A-V difference in the potassium concentration (CS-FA) averaging 0.47 mEq. per liter. In a group of 10 dogs, when 175 mg. of triamterene was infused prior to the acetylstrophanthidin, the rise in A-V differnece was abolished and the arrhythmias often aborted. In contrast, the infusion of potent diuretics (40 mg. of furosemide in five dogs and 100 mg. of ethacrynic acid in another five dogs) prior to acetylstrophanthidin, caused a doubling of the maximal A-V potassium difference. This study suggests that the clinical administration of antikaliuretic drugs may prevent the arrhythmias of digitalis toxicity not only by reducing kaliuresis and subsequent hypokalemia, but by a myocardial effect which antagonized the digitalis-induced loss of myocardial potassium. Contrariwise, potent diuretics may facilitate digitalis arrhythmias through a myocardial action causing a greater egress of myocardial potassium, thus explaining the development of arrhythmias despite normal serum potassium levels. These potent diuretics should be used cautiously, especially when given intravenously to patients receiving digitalis.

Amiloride↗
PubMed1983

Preclinical studies of indapamide, a new 2-methylindoline antihypertensive diuretic.

Indapamide is a new indoline antihypertensive diuretic agent whose chemical structure differs substantially from those of the thiazides. The hydrophobic indoline moiety of indapamide confers a lipid solubility to the molecule that is 5 to 80 times greater than that of the thiazide diuretics. Thus indapamide accumulates in vascular smooth muscle at a concentration 10 times higher than that of protein-free perfusate. The affinity of indapamide for vascular smooth muscle manifests itself in vitro and in vivo as a decrease in reactivity following various pharmacologic interventions. Moreover, in vitro studies have demonstrated that indapamide decreases the inward calcium current and the transmembrane influx of calcium. The diuretic effect of indapamide is predominantly due to inhibition of sodium reabsorption at the cortical diluting segment of the distal convoluted tubule. In animal studies, intravenous indapamide has no effect on glomerular filtration rate or renal blood flow. Indapamide is well absorbed and extensively metabolized in animals and humans, with biliary excretion being the predominant route of elimination in animals. Most important, repeat administration of indapamide to dogs with both kidneys removed produces no accumulation of intact indapamide or its metabolites. Extensive drug safety studies in animals indicate that indapamide produces no overt toxicity and exhibits a good margin of safety.

Animals↗
PubMed1984

Veterans Administration cooperative study on nadolol as monotherapy and in combination with a diuretic.

A series of studies on various therapeutic aspects of beta-adrenergic-blocking drugs was carried out by the Veterans Administration Cooperative Study Group on Antihypertensive Agents. In one study the diastolic blood pressures of 49% of 132 men with mild to moderate hypertension were controlled (less than 90 mm Hg) with once-daily nadolol. In a similar group, 85% were controlled with nadolol plus bendroflumethiazide, both given once daily. Nadolol alone was as effective as diuretic alone, although in another study comparing propranolol and hydrochlorothiazide, the latter was somewhat more effective. In both trials black patients tended to respond better to the diuretic, whereas white patients responded better to the beta blocker. Although high-renin hypertensive patients tended to respond better to the beta blocker and low-renin patients to the diuretic, the relationships were not close enough to provide a dependable guide to treatment. Sixty percent of patients whose blood pressure was not controlled on the nadolol-containing regimens reached goal blood pressure (less than 90 mm Hg) with the addition of hydralazine, 25 to 100 mg twice daily.

Adolescent↗
PubMed1987

The influence of non-beta-blocking drugs on the lipid profile: are diuretics outclassed as initial therapy for hypertension?

Diuretic drugs, when used in the treatment of hypertension, raise the blood concentrations of total cholesterol and low-density or very low-density lipoprotein cholesterol. Triglycerides often increase as well. Thiazide, phthalimidine, loop, potassium-sparing, and methylindoline drugs produce a similar effect. Only indapamide, a methylindoline agent with vasodilator activity, has been free of adverse lipid effects. It remains unclear whether it is the low dose of indapamide or some other quality that frees it of this effect. In long-term diuretic therapy, total cholesterol returns to, or below, baseline values, suggesting that the lipid elevations are transitory. However, in studies with adequate control groups, total cholesterol declines below baseline valves in control subjects such that an adverse differential in lipid values persists in long-term treatment. Selective alpha-1-adrenoceptor-blocking drugs cause no change or favorable alterations in lipid concentrations in short-term and long-term (1 year) treatment. Among all antihypertensive drugs, this class of agents, and especially prazosin, has produced the most consistently salutary lipid and metabolic effects. Although less well examined, guanabenz, clonidine, guanfacine, and diltiazem have been associated with favorable lipid changes. Captopril and nifedipine have caused no change in lipid-lipoprotein values in limited investigations. These agents are preferable to diuretics and certain beta blockers with respect to short-term effects on lipids and lipoproteins. Their ultimate superiority as monotherapy depends on whether they lower blood pressure equally well. Lowering of the probability of coronary heart disease in hypertensive patients depends as much on blood pressure control as on lipid effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1984

Effects of diuretic therapy in low-, normal- and high-renin isolated systolic systemic hypertension.

In 30 patients with isolated systolic systemic hypertension, diuretic therapy decreased body weight from 71.33 +/- 2.67 to 70.37 +/- 2.65 kg (p less than 0.0005) and the systolic blood pressure from 174 +/- 3 to 156 +/- 3 mm Hg (p less than 0.0005). Diastolic blood pressure and heart rate did not change significantly. Plasma renin activity increased from 2.25 +/- 0.33 to 4.27 +/- 0.43 ng/ml/hour (p less than 0.0005) and urinary aldosterone from 9 +/- 1 to 16 +/- 2 micrograms/24 hours (p less than 0.005). The antihypertensive effect of diuretics was significantly related only to the pretreatment plasma renin activity (r = -0.50, n = 30, p less than 0.05), and therefore the greatest decrease in systolic blood pressure occurred in the low-renin group, whereas the smallest occurred in the high-renin group (-22 +/- 2 vs -3 +/- 9 mm Hg, p less than 0.005). The diastolic blood pressure was significantly decreased only in the low-renin group (-7 +/- 2 mm Hg, p less than 0.005). There were no significant changes in blood pressure in 11 untreated control patients. These results indicate that diuretics are effective antihypertensive agents in most patients with low- and normal-renin isolated systolic systemic hypertension.

Adult↗
PubMed1986

Diuretic-induced hypokalemia and cardiac arrhythmias.

Premature ventricular contractions have long been recognized as a complication of severe diuretic-induced hypokalemia. Likewise, diuretic-induced mild hypokalemia is known to have an arrhythmogenic potential in patients who are concurrently being treated with digitalis compounds. Recent studies using exercise and ambulatory monitoring of the electrocardiogram suggest that diuretic-induced premature ventricular contractions may be a more common phenomenon than was previously recognized. The risk of this form of ventricular ectopic activity is controversial. However, the available data are substantial enough to warrant some precautions on the part of the clinician.

Arrhythmias, Cardiac↗
PubMed1986

Role of diuretics in treatment of essential hypertension.

Oral diuretics have traditionally been first-line (step 1) agents for initiating antihypertensive therapy in the stepped-care approach to management. They have a generally favorable side effects profile as well as several other attributes that make them particularly useful in this role. They are effective as monotherapy in many patients, convenient, easy to titrate, comparatively inexpensive and are well tolerated by most patients. They do not cause salt and water retention, which can lead to pseudotolerance. Monotherapy with a diuretic adequately controls hypertension in many patients with mild hypertension (diastolic blood pressure between 90 and 104 mm Hg). When therapy is initiated with a nondiuretic agent and an additional drug is needed, a diuretic can be used to advantage as step 2 in many patients.

Clinical Trials as Topic↗
PubMed1986

Clinical pharmacologic implications in diuretic selection.

Logical and comprehensive diuretic therapy is based on a sound knowledge of renal physiologic principles. Knowledge of the sites within the nephron at which the currently available diuretics work and their modes of action provide the clinician with a basis upon which to arrive at therapeutic decisions. True diuretic resistance is uncommon, but when it occurs, sequential nephron blockade can frequently reverse the refractoriness initially exhibited by the patient.

Bicarbonates↗
PubMed1987

Efficacy and safety of sustained-release diltiazem as replacement therapy for beta blockers and diuretics for stable angina pectoris and coexisting essential hypertension: a multicenter trial.

To determine if a sustained-release form of the calcium entry blocker diltiazem would be a satisfactory substitute for the combination of beta-adrenergic blocking agent and thiazide diuretic in the treatment of systemic hypertension and angina pectoris, 38 patients were studied in a 4-center trial. Blood pressure and heart rate were measured in the supine position, immediately after and 5 minutes after standing. Modified Bruce protocol treadmill tests were performed to determine the time to onset of 1 mm ST-segment depression, time to onset of chest pain and time to termination of exercise. Diltiazem monotherapy resulted in equivalent blood pressure control in 28 of 38 patients (74%). In the remaining patients, blood pressure control was achieved with resumption of the diuretic. Blood pressure with beta blocker plus diuretic compared with diltiazem were, in the supine position 137 +/- 22/82 +/- 7 (+/- 1 standard deviation) versus 139 +/- 22/82 +/- 8 mm Hg, immediately after standing 131 +/- 20/84 +/- 9 versus 133 +/- 21/82 +/- 10 mm Hg and after standing for 5 minutes 134 +/- 19/85 +/- 8 versus 137 +/- 18/85 +/- 9 mm Hg (difference not significant for each). The heart rate with diltiazem was higher supine (67 +/- 11 versus 60 +/- 11 beats/min), standing (73 +/- 13 versus 64 +/- 14 beats/min) and 5 minutes after standing (73 +/- 14 versus 63 +/- 14 beats/min, p less than 0.01 for each).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1982

Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia.

The effect of combined hydrochlorothiazide and furosemide therapy was studied in eight hypertensive patients with renal insufficiency who had poor response to either furosemide or hydrochlorothiazide alone. The study was divided into two parts. In part A, five patients had an inadequate response to furosemide in doses of 160 to 240 mg/day followed a strict protocol in order to compare the effect of increased doses of furosemide with combined hydrochlorothiazide-furosemide administration. All had azotemia, presumable from nephrosclerosis, and had serum creatinine concentrations ranging from 2.3 to 4.9 mg/dl. Four of the five patients had inadequate arterial pressure control, and the remaining patients had fluid retention from the administration of minoxidil. In all five patients, plasma volume was either increased or normal, despite long-term treatment with furosemide. Increasing the dose of furosemide to between 320 and 480 mg/day had only a modest additional diuretic effect, and plasma volume and arterial pressure were not significantly changed. Adding hydrochlorothiazide, 25 to 50 mg twice a day, produced a marked diuresis, and a significant reduction in weight, plasma volume and mean arterial pressure (p less than 0.025 for all three patients). In part B, combined hydrochlorothiazide-furosemide therapy was used to treat three additional patients who had an inadequate response to either diuretic alone. The results indicate that combined hydrochlorothiazide-furosemide is a potent diuretic regimen and is effective in many patients wit chronic renal failure who have a poor response to furosemide alone.

Adult↗
PubMed1984

Comparison of the effects of diuretic therapy and low sodium intake in isolated systolic hypertension.

Of 103 patients with isolated systolic hypertension, 71 were treated with diuretics and another 32 with low-sodium diet. In the 71 who were treated with diuretics, body weight decreased from 69.48 +/- 1.47 to 68.60 +/- 1.45 kg (p less than 0.0005) and systolic blood pressure from 178 +/- to 152 +/- 2 mm Hg (p less than 0.0005). Plasma renin activity increased from 1.78 +/- 0.30 to 7.32 +/- 1.78 ng/ml per hour (p less than 0.005) and urinary aldosterone from 10 +/- 1 to 23 +/- 4 micrograms per 24 hours (p less than 0.005). The greatest decrease in systolic blood pressure occurred in patients in the low-renin group (-32 +/- 2 mm Hg), whereas it decreased by 24 +/- 2 mm Hg (p less than 0.04) in the normal-renin group; however, blood pressure did not change significantly in the high-renin group. In the 32 patients who were treated with low-sodium diet, the 24-hour urinary sodium excretion decreased from 143 +/- 10 to 48 +/- 5 meq (p less than 0.005), body weight decreased from 71.18 +/- 2.50 to 70.17 +/- 2.47 kg (p less than 0.005), systolic blood pressure decreased from 174 +/- 2 to 156 +/- 3 mm Hg (p less than 0.0005), and diastolic blood pressure decreased from 90 +/- 1 to 87 +/- 1 mm Hg (p less than 0.01). Plasma renin activity increased from 2.25 +/- 0.33 to 4.27 +/- 0.43 ng/ml per hour (p less than 0.005) and urinary aldosterone from 9 +/- 1 to 15 +/- 2 micrograms per 24 hours (p less than 0.005). The decrease in the systolic blood pressure was related to the pretreatment 24-hour urinary sodium excretion (r = 0.40, p less than 0.05). The smallest decrease in systolic blood pressure occurred in the patients with high renin values (-1 +/- 9 mm Hg, n = 5), whereas the decrease in systolic blood pressure in the low-renin (n = 12) and normal-renin groups (n = 15) was similar, -22 +/- 2 mm Hg and -21 +/- 3 mm Hg, respectively (p less than 0.005 compared with the high-renin group). These results indicate that both diuretic therapy and low-sodium diet are effective antihypertensive means in most patients with isolated systolic hypertension and low or normal plasma renin activity.

Adult↗
PubMed1987

Magnesium depletion, diuretics, and arrhythmias.

Increasing information on the potentially serious risks of potassium and magnesium depletion associated with diuretic therapy demands a clinical focus on understanding the factors involved and on methods for preventing these electrolyte deficiencies. Data suggest that serum potassium and magnesium levels may be normal in the presence of tissue depletion, but decreases in serum levels are almost always associated with tissue and whole-body depletion of these electrolytes in patients in whom such depletion cannot be risked. Ventricular ectopy has also been associated with depletion of potassium and magnesium, which may explain the increased risk of sudden unexpected death in hypertensive patients. Any clinician who treats hypertension or congestive heart failure must consider whether to replete potassium and magnesium in patients already receiving diuretic therapy, or, better still, consider how to prevent depletion of these electrolytes in patients in whom such depletion cannot be risked. If prevention is selected, the clinician must then evaluate the data on available diuretic combinations for efficacy in electrolyte conservation, bioavailability, and dosage convenience. The combination of triamterene and hydrochlorothiazide (Maxzide, 75 mg triamterene/50 mg hydrochlorothiazide) has demonstrated electrolyte conservation, with bioavailability and dosage convenience.

Arrhythmias, Cardiac↗
PubMed1987

Multicenter comparison of the nifedipine gastrointestinal therapeutic system and long-acting propranolol in patients with mild to moderate systemic hypertension receiving diuretics. A preliminary experience.

The efficacy and safety of nifedipine in a gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation was compared with long-acting propranolol in 49 patients with mild to moderate hypertension already receiving diuretics. Using a two-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 24) in doses of 30 mg, 60 mg, or 90 mg once daily; or long-acting propranolol (n = 25) in doses of 80, 160, or 240 mg once daily. Previous diuretic therapy was continued. Sitting and five-minute standing blood pressure and heart rate measurements were made 24 hours after dosing. At the endpoint of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p less than 0.001) in the sitting and standing positions. Nifedipine GITS was more effective in lowering standing systolic blood pressure than was propranolol (p less than 0.02). Propranolol caused a greater reduction in resting heart rate than did nifedipine GITS (p less than 0.003). Both drugs were well tolerated. Nifedipine GITS is an effective and safe once-daily drug for use in patients with hypertension who are already receiving diuretics, may be more effective than sustained-release propranolol, and may be better tolerated than conventional nifedipine capsules.

Adult↗
PubMed1984

Inhibition of soluble glutathione S-transferase by diuretic drugs.

Glutathione transferases are believed to play an important protective role in the various tissues of animals and man by catalysing the glutathione conjugation of electrophilic drugs and electrophilic drug metabolites. Many of these compounds have the potential to react with vital cellular macromolecules in the absence of this enzyme system. We have investigated the interaction of a number of high ceiling diuretics with the glutathione transferases contained in the cytosolic fraction of the rat liver. Of bumetanide, ethacrynic acid, furosemide, indacrynic acid and tienilic acid, only ethacrynic acid was conjugated with glutathione. Further experiments revealed that ethacrynic, indacrynic and tienilic acids are all potent inhibitors of glutathione S- aryltransferase . Glutathione S- alkyltransferase and glutathione S-epoxide transferase were also inhibited by the diuretics, but to a lesser extent than glutathione S- aryltransferase . The diuretics giving the greatest inhibition of these reactions were chemically related to ethacrynic acid. The concept where inhibition of glutathione-S-transferase by a drug may enhance its own toxicity is considered. This mechanism has also the potential of enhancing the toxicity of other concurrently administered drugs which normally require glutathione S-transferase for detoxication.

Animals↗
PubMed1985

Inhibition of purified rat liver glutathione S-transferase isozymes by diuretic drugs.

Seven soluble rat liver glutathione S-transferase isozymes were isolated and the inhibition of these isozymes by selected diuretics was investigated using 1-chloro-2,4-dinitrobenzene as substrate. All isozymes were inhibited to some extent under the experimental conditions used, but there was significant isozyme dependent selectivity of inhibition. The greatest inhibitory effect (over 80%) was found when the phenoxyacetic acid diuretics and indacrynic acid were incubated with glutathione S-transferase 3-3, 3-4 and 4-4. The sulphamoylbenzoic acid diuretics, furosemide and bumetanide, were found to have a lesser effect on the isozymes studies. As glutathione S-transferase are thought to play an important protective role in the various tissues of animals and man, by catalysing the glutathione conjugation of electrophilic drugs and drug metabolites, their inhibition may be toxicologically important.

Animals↗