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PubMed2002

Diuretic therapy, the alpha-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension.

CONTEXT: A genetic variant in alpha-adducin has been associated with renal sodium reabsorption and salt-sensitive hypertension. Whether this genetic variant modifies the effect of diuretic therapy on the incidence of myocardial infarction (MI) and stroke is unknown. OBJECTIVES: To estimate the interaction between alpha-adducin and diuretic therapy on the risk of MI or stroke. Specifically, we hypothesized that in participants with treated hypertension, the risk of MI or stroke associated with diuretic use would be lower in carriers of the adducin variant than in carriers of the adducin wild-type genotype. DESIGN, SETTING, AND PARTICIPANTS: Population-based case-control study of patients enrolled in a health maintenance organization, treated pharmacologically for hypertension, and genotyped as homozygous carriers of the adducin wild-type genotype or carriers of 1 or 2 copies of the Trp460 variant allele. Cases had a first nonfatal MI (n = 206) or stroke (n = 117) between January 1995 and December 1998. Controls (n = 715) were a stratified random sample of pharmacologically treated hypertensive patients who were matched to MI cases by age, sex, and calendar year. MAIN OUTCOME MEASURE: Risk of the combined outcome of first nonfatal MI or stroke. RESULTS: The adducin variant was present in more than one third of the participants. Among the 653 carriers of the adducin wild-type genotype, diuretic therapy was not associated with the risk of MI or stroke (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.78-1.52). Among the 385 carriers of the adducin variant allele, diuretic therapy was associated with a lower risk of the combined outcome of MI and stroke than other antihypertensive therapies (OR, 0.49; 95% CI, 0.32-0.77). The OR in carriers of the adducin variant was less than half of the OR in carriers of the wild-type genotype (P =.005). The case-control synergy index (SI) was 0.45 (95% CI, 0.26-0.79) for the combined outcome of MI and stroke. The point estimates of the diuretic-adducin interaction were similar in separate analyses of MI (SI, 0.41; 95% CI, 0.21-0.80) and stroke (SI, 0.53; 95% CI, 0.24-1.19). The diuretic-adducin interaction was not confounded by traditional cardiovascular risk factors, was specific to diuretic therapy but not present for other major antihypertensive drug classes, and did not differ substantially between subgroups defined by age, sex, race, diabetes, and history of cardiovascular disease. CONCLUSIONS: In carriers of the adducin variant, diuretic therapy was associated with a lower risk of combined MI or stroke than other antihypertensive therapies. If these findings are confirmed in other studies, this large subgroup of the hypertensive population may be especially likely to benefit from low-dose diuretic therapy.

Aged↗
PubMed1993

Increased risk of renal cell cancer among women using diuretics in the United States.

Use of prescription diuretics and incidence of renal cell cancer have increased in the United States in the past 25 years. Recent interview-based epidemiologic studies have reported an association between diuretic use and renal cell cancer risk. Our study evaluated this hypothesis using, for the first time, medical records as the source of the information on prescription diuretic use. Using medical records of women from a prepaid health plan, we identified 191 cases and 191 controls matched on age, membership duration, and membership at diagnosis. Diuretics use and history of potential confounding factors were ascertained by a standardized review of the medical records of each subject, without reference to case or control status. There was a strong and statistically significant association between renal cell cancer and prescription diuretics (odds ratio [OR] adjusted for hypertension, smoking, and obesity = 2.9, 95 percent confidence interval [CI] = 1.7-4.7). Risk tended to increase with dose, measured by number of prescriptions. Since renal cancer can induce hypertension, which is treated by diuretics, and thereby confound the association with diuretics, we examined diuretic use 10 or more years prior to diagnosis when secondary hypertension would be unlikely. The OR for prescriptions 10 or more years before diagnosis was 3.5 (CI = 1.7-7.4). Our results support earlier reports of an excess risk of renal cell cancer among users of prescription diuretics and indicate need for further study to evaluate this relationship, especially due to the extensive use of diuretics and the increasing incidence of this cancer.

Carcinoma, Renal Cell↗
PubMed1983

Insights into intrarenal sites and mechanisms of action of diuretic agents.

Effective diuresis requires both sufficient glomerular filtrate and adequate delivery of the diuretic drug to the lumen of the renal tubule. Diuretics will not "force open" the kidney. Diuretics that work primarily in the proximal tubule include osmotic diuretics (e.g., mannitol), diuretics that interfere with the adenyl cyclase system (e.g., xanthines), and those which inhibit carbonic anhydrase (e.g., acetazolamide). Some thiazide and thiazide-like diuretics have a secondary site of action in the proximal tubule based on either carbonic anhydrase inhibition or other mechanisms, such as inhibition of sodium phosphate reabsorption. The diuretics that work primarily in the medullary diluting segment of the loop of Henle, furosemide and ethacrynic acid, block the active reabsorption of chloride and interfere with the tubular reabsorption of free water. The exact mechanism remains unknown. These diuretics tend to have a "high ceiling," to be potent and rapidly acting, and to have a short duration of effect. They are excellent for the treatment of severe fluid overload or pulmonary edema but are not ideal for the treatment of uncomplicated hypertension. Furosemide is a sulfonamide derivative; ethacrynic acid can be used in patients who are allergic to sulfa drugs. Diuretics that work primarily in the cortical diluting segment include the thiazides and thiazide-like drugs. They inhibit sodium transport by an undetermined mechanism. Most of them seem to reach a dose-response plateau beyond which little additional effect is gained by increasing the dose. Most of them appear to lose efficacy as the glomerular filtration rate decreases, except for metolazone and indapamide. The thiazides are most commonly used to treat hypertension. Diuretics that work primarily in the distal tubule and collecting tubule include the aldosterone inhibitor spironolactone and two drugs that impair tubular reabsorption of sodium by direct action, triamterene and amiloride. These drugs are primarily used for their potassium-sparing effect.

Animals↗
PubMed1998

Use of diuretics and opportunities for withdrawal in a Dutch nursing home population.

BACKGROUND: Diuretics are frequently used by elderly patients and overprescription has been suggested. However, the present withdrawal patterns of these medications in clinical practice elderly patients are unclear. METHODS: Retrospective medical record analysis of all 584 patients aged 75 years or older admitted to a 240-bed nursing home facility in the years 1990-1994. One-year follow-up by record review and collection of updated information from nursing home physicians. RESULTS: Two hundred and twenty patients (37.7%) used diuretics, and use increased with age (p < 0.05). Reported indications for prescription were heart failure (n = 77), hypertension (n = 38), ankle edema without heart failure (n = 21), or not reported (n = 84). Diuretics were withdrawn in 82 of 220 patients (37.3%), but a doubtful actual indication for diuretic use was found in 72 of the remaining 138 patients (52.2%). After withdrawal, the probability of remaining free from diuretics for at least one year was 0.47. There were no reports of life-threatening or fatal incidents after withdrawal. Mortality rates for the patients whose diuretics were withdrawn did not differ from patients continuing on diuretics. CONCLUSIONS: Withdrawal of diuretics was frequently performed and often successful. In addition, doubtful indications for diuretics were found in half of the patients continuing on these medications, suggesting additional opportunities for diuretic withdrawal.

Aged↗
PubMed2000

[Pharmacologic action of diuretics in the kidney].

The currently available diuretics increase the urinary excretion of sodium chloride by selective inhibition of specific sodium transporters in the loop of Henle and distal nephron. In recent years, the molecular cloning of the distal diuretic-sensitive sodium transporters has improved our understanding of the cellular mechanisms of action of each class of diuretics. The identification of mutations in the genes encoding these transporters in inherited disorders characterized by altered salt balance has provided unequivocal evidence for the roles of the cloned diuretic-sensitive transporters in sodium homeostasis. The biochemical abnormalities observed in these disorders are identical to those induced by the specific diuretic. In the Guibaud-Vainsel syndrome (renal-tubular acidosis with osteopetrosis) the renal disturbances are comparable to the effects of a therapy with acetazolamide. Mutations in the proximal tubular carbonic anhydrase type II are the cause of this rare disorder. Bartter syndrome shows identical biochemical abnormalities as those found with chronic furosemide therapy. This syndrome is caused by mutations in the furosemide-sensitive Na-K-2Cl cotransporter in the thick ascending loop of Henle. In Gitelman syndrome the characteristic electrolyte and hormonal changes in blood and urine are comparable to those observed in patients treated with thiazide diuretics. This disorder results from mutations in the distal-tubular thiazide-sensitive Na-Cl cotransporter. The two forms of pseudhypoaldosteronism are distinguished by the characteristic metabolic changes encountered with a therapy with potassium-sparing diuretics. The genetic disturbance resides either in the amiloride-sensitive epithelial sodium channel (autosomal-dominant form) or in the spironolactone-sensitive mineralocorticoid receptor (autosomal-recessive form) in the distal tubule and cortical collecting duct. Current research concentrates on defining the structural sites for electrolyte transport and diuretic binding, as well as the molecular mechanisms of transport regulation. This information may allow a more appropriate use of diuretics and the design of new substances with diuretic action.

Benzothiadiazines↗
PubMed1998

Prescription patterns of diuretics in Dutch community-dwelling elderly patients.

AIMS: To describe age- and gender-related prescription patterns of diuretics in community-dwelling elderly, and to compare diuretics to other cardiovascular (CV) medications. METHODS: Cross-sectional study of patient-specific prescription data derived from a panel of 10 Dutch community pharmacies. Determination of proportional prescription rates and prescribed daily dose (PDD) of diuretics, cardiac glycosides, nitrates, angiotensin converting enzyme (ACE) inhibitors, beta-adrenoceptor blockers, and calcium channel blockers in all 5326 patients aged 65 years or older dispensed CV medications between August 1st, 1995 and February 1st, 1996. RESULTS: Diuretics were prescribed to 2677 of 5326 patients (50.3%), 1325 patients (24.9%) using thiazides and 1198 patients (22.5%) using loop diuretics. Prescription rates of loop diuretics increased from 15.1% in patients aged 65-74 years to 37.2% in patients aged 85 years or older. Rates also increased for digoxin and nitrates. Rates for thiazide diuretics remained unchanged with age; rates for beta-adrenoceptor blockers, ACE inhibitors and calcium channel blockers declined with age. Thiazides were prescribed to 30.1% of women compared with 16% of men (P < 0.001). Average PDD was 135 +/- 117% of defined daily dose (DDD) for loop diuretics, and highest for bumetanide (245 +/- 2.01% of DDD, equivalent to 2.5 +/- 2.0 mg). Average PDD was 74 +/- 40% of DDD for thiazides, and highest for chlorthalidone (100 +/- 49% of DDD, equivalent to 25 +/- 12 mg). CONCLUSIONS: Important characteristics of diuretic usage patterns in this elderly population were a steep increase in loop diuretic use in the oldest old, a large gender difference for thiazide use, and high prescribed doses for thiazides.

Age Factors↗
PubMed2003

Prescription patterns of diuretics in chronic heart failure: a contemporary background as a clue to their role in treatment.

BACKGROUND: Diuretics are the cornerstone of treatment for the congestive symptoms of heart failure (HF). Despite their widespread use, diuretic prescription data in clinical practice are scarce. In this study we evaluated the prescription pattern of diuretics in a large population of HF outpatients, enrolled by a national network of hospital-based cardiologists. METHODS AND RESULTS: Among 11070 HF outpatients (mean age 64 +/- 12 years, 72.9% men, 29.8% New York Heart Association [NYHA] class III-IV, mean left ventricular ejection fraction [LVEF] 35+/-12%), 9247 took a diuretic, the most frequently prescribed therapeutic agent (83.5%). Loop diuretics were prescribed alone (65.5%) or combined with other diuretics in 91.6% of patients. By multivariate analysis, the strongest independent predictors of diuretic use were a previous hospital admission for HF (odds ratio [OR] 2.55, 95% confidence interval [CI] 2.28-2.86), NYHA class III-IV (OR 2.52, 95% CI 2.14-2.96), LVEF < 30% (OR 1.87, 95% CI 1.57-2.24). Aldosterone antagonists were prescribed to 2142 patients (23.1%); independent predictors of their use overlapped with those of diuretics and moreover included treatment with loop diuretics (OR 3.52, 95% CI 2.66-4.66) and digoxin (OR 1.45, 95% CI 1.29-1.64). CONCLUSIONS: In this wide series of stable HF outpatients, cardiologists prescribed diuretics in accordance with published guidelines. Evolving prescription patterns of aldosterone-receptor blockers need to be further evaluated.

Diuretics↗
PubMed1998

Predictive factors influencing the therapeutic response to diuretic treatment of ascites in nonazotemic cirrhotic patients.

BACKGROUND: A low-sodium diet and diuretics, although widely used, are not always the most satisfactory therapy for treatment of ascites in nonazotemic patients with liver cirrhosis. The objective of this investigation was to analyze various predictive factors influencing the therapeutic response to diuretic treatment of ascites in these patients. METHODS: Twenty-seven patients with nonazotemic liver cirrhosis and ascites were initially treated with spironolactone, 200 mg/day. If no response was observed, furosemide was added at 40-120 mg/day. Before and during the diuretic therapy 30 clinical and laboratory variables were investigated as possible predictive factors influencing the therapeutic response to diuretics. The renal arterial resistive index (RI) (reflecting renal vascular resistance) was estimated with duplex Doppler ultrasonography. RESULTS: Sixteen of the 27 patients (59%) responded to spironolactone alone, whereas 6 patients (22%) responded to combined diuretic therapy with spironolactone and furosemide. Five patients (19%) did not respond to diuretic treatment. Eight of the 30 variables analyzed were statistically significant as possible predictive factors influencing the diuretic response: previous episodes of ascites and gastrointestinal hemorrhage, the presence of peripheral edema, the amount of ascites, plasma renin activity, plasma aldosterone concentrations, urinary sodium excretion, and renal interlobar arterial RI. In all patients who had diuretic-resistant ascites, renal interlobar arterial RI was greater than 0.70. Only 9% of patients who responded satisfactorily to diuretic therapy had interlobar arterial RI greater than 0.70. CONCLUSIONS: According to our results, consideration for combining the clinical findings with noninvasively measured renal arterial RI using duplex Doppler ultrasonography would be mandatory in identifying a subgroup of cirrhotic patients with ascites who are at high risk for diuretic unresponsiveness.

Ascites↗
PubMed1989

Captopril and the diuretic requirements in moderate and severe chronic heart failure.

The effect of captopril on diuretic requirements was assessed in 16 patients with moderate (13 NYHA Class III, 1 NYHA Class II) or severe (3 NYHA Class IV) stable non-oedematous chronic heart failure. The dose of diuretics was halved before captopril was started and follow-up was continued for two months. In all three patients in NYHA Class IV the diuretic dosage had to be increased to a dose close to, or the same as, the original dose of diuretics in order to keep them from congestive heart failure. One patient improved on the new regime but gained 3.5 kg in weight during follow-up. Of the 13 patients with moderate heart failure, seven showed an improvement in symptoms and exercise duration on the combination of captopril and the lower dose of diuretics (mean 6.9 to 12.5 min, P less than 0.001); two patients did not improve and gained 1.7 kg and 2.3 kg in weight, respectively; three patients required the original dose of diuretics to keep them from congestive heart failure and one patient lost weight on the reduced dose of diuretics but showed no improvement clinically or on treadmill exercise testing. Thus captopril does not have a diuretic sparing effect in patients with severe chronic heart failure. Those treated need the original dose of diuretics for maximal symptomatic benefit. Captopril does have a diuretic sparing effect in some patients with moderate chronic heart failure.

Adult↗
PubMed2000

Pharmacology of diuretics.

The diuretics in our therapeutic armamentarium have predictable effects based on their nephron sites of action. All but spironolactone must reach the lumen or urinary side of the nephron to exert their effects. Thus, in settings of decreased renal function, doses must be increased to deliver more diuretic into the urine. In other edematous disorders, such as congestive heart failure (CHF) and cirrhosis, adequate amounts of diuretic reach the site of action if renal function is satisfactory. Diminished response in these conditions is caused by a decrease in the sensitivity of the nephron to the diuretic, the mechanism of which is unknown. Rather than using large single doses of diuretic in CHF and cirrhosis, multiple doses and/or combinations of diuretics should be used. Therefore, thiazide diuretics coupled with loop diuretics are most logical because they affect different nephron sites and the thiazide counteracts distal nephron hypertrophy that may occur with loop diuretics alone. Ample studies have shown that such combinations can result in a truly synergistic response. Using pharmacokinetics and pharmacodynamics of diuretics, we can design therapeutic regimens in which satisfactory control of fluid and electrolyte homeostasis can be achieved in the vast majority of patients.

Benzothiadiazines↗
PubMed1982

Female preponderance in diuretic-associated hypokalemia: a retrospective study in seven long-term care facilities.

A retrospective review of the medical records of 161 geriatric nursing-home patients receiving diuretics alone or in combination with potassium supplements or potassium sparing-diuretics revealed a 13.7 per cent overall prevalence of hypokalemia. The prevalence of hypokalemia in patients receiving diuretics alone, diuretics with potassium supplements, and potassium-sparing diuretics with kaliuretic diuretics were similar. However, there was a significantly higher prevalence of hypokalemia in women (16.4 per cent) compared with men (3.0 per cent), P less than 0.05. In patients taking non-chloride salts of potassium, there was a significantly higher prevalence of hypokalemia than in those taking the chloride salt (3.6 per cent vs. 8 per cent, P less than 0.025). Seven per cent of patients taking diuretics with potassium supplements and 11.5 per cent of patients taking potassium-sparing diuretics had hyperkalemia. Thus, although many elderly women taking diuretics may have hypokalemia routine potassium supplementation for all non-digitalized geriatric patients receiving diuretics does not seem to be indicated.

Aged↗
PubMed1998

Beta adrenergic blockers lower renin in patients treated with ACE inhibitors and diuretics.

OBJECTIVE: To examine the effect of concomitant intake of beta blockers with angiotensin converting enzyme (ACE) inhibitors, diuretics, or both on plasma renin concentrations in a population based sample (MONICA survey, Augsburg, Germany). SUBJECT AND METHODS: 728 individuals were studied, of whom 171 were treated using monotherapy (ACE inhibitor (n = 21), diuretic (n = 10), or beta blocker (n = 72)), or combination treatment (ACE inhibitor + diuretic (n = 32), ACE inhibitor + beta blocker (n = 7), diuretic + beta blocker (n = 22), ACE inhibitor + diuretic + beta blocker (n = 7)). The remaining 557 individuals were untreated. Indications for treatment were hypertension (75%), coronary artery disease with (12%) or without (3%) hypertension, or unknown (10%). RESULTS: Mean (SEM) renin concentrations in individuals treated with an ACE inhibitor (41 (8) mU/l), a diuretic (41 (10) mU/l), or the combination of an ACE inhibitor and a diuretic (54 (10) mU/l) were raised compared with untreated individuals (17 (1) mU/l; p < 0.05 each). Monotherapy with a beta blocker, however, decreased mean renin concentrations (12 (1) mU/l; p < 0.01 v untreated). Renin concentrations in individuals taking a beta blocker with either an ACE inhibitor (21 (8) mU/l), or a diuretic (22 (4) mU/l), or with both an ACE inhibitor and a diuretic (21 (7) mU/L), were significantly lower compared with renin concentrations in groups not receiving beta blocker treatment (p < 0.05 each). CONCLUSION: These data suggest that the upregulation of renin by treatment with ACE inhibitors, diuretics, or both can be largely prevented by concomitant beta blocker treatment.

Adrenergic beta-Antagonists↗
PubMed2003

Mechanisms and management of diuretic resistance in congestive heart failure.

Diuretic drugs are used almost universally in patients with congestive heart failure, most frequently the potent loop diuretics. Despite their unproven effect on survival, their indisputable efficacy in relieving congestive symptoms makes them first line therapy for most patients. In the treatment of more advanced stages of heart failure diuretics may fail to control salt and water retention despite the use of appropriate doses. Diuretic resistance may be caused by decreased renal function and reduced and delayed peak concentrations of loop diuretics in the tubular fluid, but it can also be observed in the absence of these pharmacokinetic abnormalities. When the effect of a short acting diuretic has worn off, postdiuretic salt retention will occur during the rest of the day. Chronic treatment with a loop diuretic results in compensatory hypertrophy of epithelial cells downstream from the thick ascending limb and consequently its diuretic effect will be blunted. Strategies to overcome diuretic resistance include restriction of sodium intake, changes in dose, changes in timing, and combination diuretic therapy.

Diuretics↗
PubMed1998

Extreme diuretic dependence in idiopathic edema: mechanisms, prevention and therapy.

Idiopathic edema patients abusing diuretics are occasionally becoming dependent to such a degree on increasing doses of diuretics that their withdrawal results in severe cardiorespiratory failure, occasionally even pulmonary edema. Two such patients are described and 1 is investigated in depth as to the mechanism of the diuretic abuse-induced excessive tubular avidity for sodium. An extreme diuretic-induced secondary hyperaldosteronism and atrial natriuretic factor suppression, although tapering off when diuretics are stopped, results in a continuous tubular sodium hyper-reabsorption. Since the most affected patient was deprived of the benefits of converting enzyme inhibitors because of their side effects, the only way to partially overcome this condition was a generous combination of several diuretics acting at several segments of the nephron. This contrasted with a similar patient who was relatively well controlled by a converting enzyme inhibitor combined with lower dose diuretics. Diuretic abuse-induced secondary hyperaldosteronism and diuretic resistance are apparently best prevented by converting enzyme inhibitors. When nonpharmacological preventive measures fail, converting enzyme inhibitors are preferable to diuretics as the first-choice treatment of idiopathic edema patients.

Adult↗
PubMedDate not supplied

Diuretics versus angiotensin-converting enzyme inhibitors in autosomal dominant polycystic kidney disease.

Hypertension, which occurs commonly and early in autosomal dominant polycystic kidney disease (ADPKD), affects both renal and patient outcome. However, there is no consensus about the type of antihypertensive therapy that is most appropriate for patients with ADPKD. This historical prospective, nonrandomized study was designed to investigate the effect on renal function of diuretics versus angiotensin-converting enzyme (ACE) inhibitors in hypertensive patients with ADPKD who entered the study with comparable renal function. Among hypertensive ADPKD patients followed in our center, patients taking diuretics without any ACE inhibitors were included in the diuretic group (n = 14, male/female ratio 5/9, mean age 47 years), whereas patients taking ACE inhibitors but no diuretics were included in the ACE inhibitor (ACEI) group (n = 19, male/female ratio 11/8, mean age 41 years). For comparable blood pressure control, 21% of the ACEI group and 64% of the diuretic group (p < 0.05) needed additional antihypertensive medications. After an average follow-up period of 5.2 years, the creatinine clearance decreased significantly in the diuretic group (74 vs. 46 ml/min/1.73 m2, p < 0.0001) and in the ACEI group (83 vs. 71 ml/min/1.73 m2, p = 0.0005). The decrement in creatinine clearance was significantly larger in the diuretic group than the ACEI group (p < 0.05). The annual decrease in creatinine clearance was 5.3 ml/min/1.73 m2 in the diuretic group and 2.7 ml/min/1.73 m2 in the ACEI group (p < 0.05). A significant increase in urinary protein excretion occurred in the diuretic but not in the ACEI group. Hypertensive ADPKD patients treated with diuretics had a faster loss of renal function as compared with patients treated with ACE inhibitors, despite similar blood pressure control. This result will need to be further examined in a randomized study.

Adult↗
PubMedDate not supplied

Diuretics in renal failure.

Fluid retention following reduction in the glomerular filtration rate causes extracellular fluid volume expansion that reduces tubular reabsorption by residual nephrons, thereby maintaining the external sodium balance. The price paid for this is salt-dependent hypertension. Thus, loop diuretics are the best treatment for uremic hypertension. Diuretics are also used in chronic renal failure to treat edema due to nephrotic syndrome and congestive heart failure (CHF). In nephrotics, edema is often refractory to diuretics because of low plasma protein, depletion of the intravascular compartment, decrease in the protein-bound fraction of the diuretic in peritubular blood, and increase in tubular fluid. Thus, higher doses are needed. In uremics with CHF the efficacy of diuretics may be hampered because of the reduced renal blood flow. The association of dopamine (1-1.5 microg/kg body weight/min) may overcome this resistance; improvement in cardiac function by dialysis ultrafiltration may also help. Diuretic resistance is sometimes observed; it may be overcome by the following procedures: in CHF by the use of digitalis and/or angiotensin-converting enzyme inhibitors; by substitution of an ineffective loop diuretic for another one; by using larger doses of diuretic; by intravenous infusion rather than bolus therapy, and by a combination of diuretics acting in different segments of the tubule: loop diuretic+thiazide+amiloride. Intravenous infusion of 20% albumin has also been suggested.

Chronic Disease↗
PubMed2004

Long-term adaptation of renal ion transporters to chronic diuretic treatment.

Loop and thiazide diuretics are clinically useful to induce negative sodium balance. However, with chronic treatment, their effects tend to be blunted since the kidney adapts to diuretics. Molecular identification of the renal ion transporters has provided us with a new understanding of the mechanisms of intrarenal adaptation to diuretics at molecular levels. In the kidney, loop and thiazide diuretics are secreted from the proximal tubule via the organic anion transporter-1 (OAT1) and exert their diuretic action by binding to the Na-K-2Cl cotransporter type 2 (NKCC2) in the thick ascending limb and the Na-Cl cotransporter (NCC) in the distal convoluted tubule, respectively. Recent studies in animal models suggest that abundance of these ion transporters is affected by long-term diuretic administration. Downstream from the primary site of diuretic action, an increase in epithelial Na+ channel (ENaC) abundance is induced by chronic furosemide or hydrochlorothiazide treatment. This adaptation is consistent with previous reports showing cellular hypertrophy and increased Na+ absorption in distal tubular segments. The abundance of NKCC2 and NCC is increased by furosemide and hydrochlorothiazide, respectively. This compensatory upregulation suggests that either diuretic may activate the ion transporter within the primary site of action. In the proximal tubule, the abundance of OAT1 is increased by chronic treatment with furosemide or hydrochlorothiazide. This upregulation of OAT1 seems to be induced by substrate stimulation, lessening diuretic tolerance associated with long-term diuretic use.

Adaptation, Physiological↗
PubMed2004

Thiazide-like diuretics attenuate agonist-induced vasoconstriction by calcium desensitization linked to Rho kinase.

Lowering blood pressure using thiazide-like diuretics, including chlorthalidone and hydrochlorothiazide, has been proven to be effective in clinical studies. However, the mechanisms by which thiazide-like diuretics lower blood pressure are still poorly understood. To evaluate whether thiazide-like diuretics cause calcium desensitization in smooth muscle cells, we measured their effects on agonist-induced increase of blood pressure in Wistar rats in vivo and on agonist-induced vasoconstriction of aortic rings, DNA synthesis, and protein synthesis, RhoA, Rho kinase, and intracellular calcium in vascular smooth muscle cells in vitro. Thiazide-like diuretics significantly attenuated angiotensin II-induced or norepinephrine-induced increase of systolic blood pressure in rats. Thiazide-like diuretics inhibited agonist-induced vasoconstriction of aortic rings in a concentration-dependent manner in the presence and absence of endothelium. The inhibitory effects of thiazide-like diuretics were similar to that of the specific Rho kinase inhibitor Y27632. RT-PCR and immunoblotting showed that RhoA and Rho kinase were significantly reduced in vascular smooth muscle cells after administration of thiazide-like diuretics. In contrast, thiazide-like diuretics did not affect protein tyrosine phosphatase-2 (SHP-2) expression. Agonist-induced changes of intracellular calcium were not affected by thiazide-like diuretics. The study indicates that thiazide-like diuretics inhibit agonist-induced vasoconstriction by calcium desensitization in smooth muscle cells linked to the Rho-Rho kinase pathway.

Acute-Phase Proteins↗