Localization of diuretic effects along the loop of Henle: an in vivo microperfusion study in rats.
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In order to clarify the effects on sodium reabsorption in the loop of Henle of methazolamide (a carbonic anhydrase inhibitor), chlorothiazide and the loop diuretics frusemide and bumetanide, superficial loops were perfused in vivo in anaesthetized rats and the individual diuretics were included in the perfusate. Differentiation between effects in the pars recta and in the thick ascending limb of Henle (TALH) was achieved by comparing responses to the diuretics when using a standard perfusate, designed to mimic native late proximal tubular fluid, and a low-sodium perfusate, designed to block net sodium reabsorption in the pars recta. With the standard perfusate, methazolamide caused decreases in sodium reabsorption (J(Na)) and water reabsorption (J(V)); with the low-sodium perfusate, a modest effect on J(Na) persisted, suggesting that carbonic anhydrase inhibition reduces sodium reabsorption in both the pars recta and the TALH. The effects of chlorothiazide were very similar to those of methazolamide with both the standard and low-sodium perfusates, suggesting that chlorothiazide also inhibits sodium reabsorption in the pars recta and TALH, perhaps through inhibition of carbonic anhydrase. With the standard perfusate, both frusemide and bumetanide produced the expected large decreases in J(Na), but J(V) was also lowered. With the low-sodium perfusate, the inhibitory effects of the loop diuretics, particularly those of frusemide, were substantially reduced, while net potassium secretion was found. These observations indicate that a significant component of the effect of frusemide (and possibly of bumetanide) on overall sodium reabsorption is located in the pars recta, and that loop diuretics induce potassium secretion in the TALH. (+info)
Relation between renal interstitial ATP concentrations and autoregulation-mediated changes in renal vascular resistance.
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The present study was performed to examine the hypothesis that autoregulation-related changes in renal vascular resistance (RVR) are mediated by extracellular ATP. By use of a microdialysis method, renal interstitial concentrations of ATP and adenosine were measured at different renal arterial pressures (RAPs) within the autoregulatory range in anesthetized dogs (n=12). RAP was reduced in steps from the ambient pressure (131+/-4 mm Hg) to 105+/-3 mm Hg (step 1) and 80+/-2 mm Hg (step 2). Renal blood flow and glomerular filtration rate exhibited efficient autoregulation in response to these changes in RAP. RVR decreased by 22+/-2% in step 1 (P<0.01) and 38+/-3% in step 2 (P<0.01). The control renal interstitial concentration of ATP was 6.51+/-0.71 nmol/L and decreased to 4. 51+/-0.55 nmol/L in step 1 (P<0.01) and 2.77+/-0.47 nmol/L in step 2 (P<0.01). In contrast, the adenosine concentrations (117+/-6 nmol/L) were not altered significantly. Changes in ATP levels were highly correlated with changes in RVR (r=0.88, P<0.0001). Further studies demonstrated that stimulation of the tubuloglomerular feedback (TGF) mechanism by increasing distal volume delivery elicited with acetazolamide also led to increases in renal interstitial ATP concentrations, whereas furosemide, which is known to block TGF responses, reduced renal interstitial fluid ATP concentrations. The data demonstrate a positive relation between renal interstitial fluid ATP concentrations and both autoregulation- and TGF-dependent changes in RVR and thus support the hypothesis that changes in extracellular ATP contribute to the RVR adjustments responsible for the mechanism of renal autoregulation. (+info)
Deactivation of TSH receptor signaling in filter-cultured pig thyroid epithelial cells.
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Thyrotropin [thyroid-stimulating hormone (TSH)] receptor on-off signaling was studied in polarized monolayers of pig thyrocytes cultured on permeable support. Transepithelial resistance (R) and potential difference (PD) were used as parameters to monitor the effect of altered TSH concentrations on vectorial electrolyte transport. TSH induced rapid but long-lasting changes in R (decrease) and PD (increase) that were cAMP-dependent and related to enhanced transcellular conductance of sodium and chloride. Withdrawal of TSH from cultures prestimulated with TSH (0.1 mU/ml) for 48 h resulted in restitution of R to control level within 30 min. Such deactivation was markedly accelerated by mild trypsinization, which degraded receptor-bound ligand without affecting TSH receptor responsiveness or ion transporting capacity. Small alterations in the TSH concentration (0.01-0.1 mU/ml) were followed almost instantaneously by adjustments of R. In contrast, the reversal of R after acute TSH stimulation (30 min) and subsequent TSH washout was delayed for several hours independently of cell surface trypsinization. The observations indicate that, during continuous exposure to physiological concentrations, TSH exerts a close minute-to-minute surveillance of thyroid function and the rate-limiting step of deactivation is the dissociation of ligand from the TSH receptor at the cell surface. TSH-deprived cells briefly exposed to TSH are refractory to rapid deactivation, probably because of altered metabolism downstream of TSH receptor signal transduction. (+info)
Effects of furosemide on medullary oxygenation in younger and older subjects.
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Renal medullary hypoxia is characteristic of mammalian kidneys and can be assessed noninvasively in animals and humans by blood oxygen level-dependent magnetic resonance imaging (BOLD MRI). Water diuresis has been shown to improve medullary oxygenation in young human subjects but not in elderly subjects, a difference attributed to a decline in renal prostaglandin production with age. Loop diuretics such as furosemide also increase medullary oxygenation in experimental animals, by inhibiting active transport and oxygen consumption in the medullary thick ascending limb. We examined, using BOLD MRI, this response to furosemide in eight younger (23 to 34 years) and eight elderly (64 to 81 years) healthy women. We also attempted to assess the role of prostaglandins in age-related differences, using ibuprofen to inhibit prostaglandin E2 synthesis. Renal medullary oxygenation, initially low, increased during furosemide diuresis in younger subjects. In the older population, however, furosemide usually elicited little or no change in oxygenation of the renal medulla, despite profuse diuresis. Ibuprofen did not inhibit the action of furosemide to improve medullary pO2 in younger subjects. CONCLUSIONS: The action of loop diuretics to improve medullary oxygenation, apparent in younger subjects, is blunted by normal aging. Inhibition of prostaglandin synthesis did not counteract the effect of furosemide in younger subjects, suggesting that a decline in prostaglandin E2 production with age is not the central cause of this age-related defect. (+info)
Murine colonic mucosa hyperproliferation. I. Elevated CFTR expression and enhanced cAMP-dependent Cl(-) secretion.
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Fluid transport in the large intestine is mediated by the cystic fibrosis gene product and cAMP-dependent anion channel cystic fibrosis transmembrane conductance regulator (CFTR). cAMP-mediated Cl(-) secretion by gastrointestinal cell lines in vitro has been positively correlated with the insertion of CFTR into the apical membrane of differentiated senescent colonocytes and negatively correlated with the failure of CFTR to insert into the plasma membrane of their undifferentiated proliferating counterparts. In native tissues, this relationship remains unresolved. We demonstrate, in a transmissible murine colonic hyperplasia (TMCH) model, that (8-fold) colonocyte proliferation was accompanied by increased cellular CFTR mRNA and protein expression (8.3- and 2.4-fold, respectively) and enhanced mucosal cAMP-dependent Cl(-) secretion (2. 3-fold). By immunofluorescence microscopy, cellular CFTR expression was restricted to the apical pole of cells at the base of the epithelial crypt. In contrast, increased cellular proliferation in vivo led to increases in both the cellular level and the total number of cells expressing this anion channel, with cellular CFTR staining extending into the crypt neck region. Hyperproliferating colonocytes accumulated large amounts of CFTR in apically oriented subcellular perinuclear compartments. This novel mode of CFTR regulation may explain why high endogenous levels of cellular CFTR mRNA and protein within the TMCH epithelium were not matched with larger increases in transmucosal CFTR Cl(-) current. (+info)
Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome.
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Response to loop diuretics in patients with nephrotic syndrome (NS) is subnormal. Studies in animal models of NS have suggested that binding of diuretic to urinary albumin is one of the mechanisms that may be operative in this diuretic resistance. To explore this hypothesis, 12 patients with NS were studied to determine whether displacement from urinary protein binding with sulfisoxazole would restore response to 120 mg of furosemide. The study was stopped after treating seven patients because it was clear that sulfizoxazole had no effect. Sodium excretion (mean +/- SD) from furosemide alone was 239 +/- 90 versus 240 +/- 115 mEq/8 h with sulfisoxazole. Sulfisoxazole had modest effects on serum pharmacokinetics of furosemide but had no effect on either the time course of furosemide urinary excretion or overall amount excreted: 49 +/- 15 mg versus 54 +/- 12 mg for furosemide alone and furosemide plus sulfisoxazole, respectively. It is concluded that urinary protein binding of loop diuretics is not a major mechanism for the diuretic resistance of NS. In turn, strategies aimed at displacing such binding are unlikely to be clinically helpful. (+info)
Diuretic renography with the addition of quantitative gravity-assisted drainage in infants and children.
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The aim of this study was to evaluate the use of quantitative gravity-assisted drainage (GAD) using >50% residual activity as an indicator to confirm obstruction in diuretic renography in the investigation of hydronephrosis and hydroureteronephrosis in infants and children. This was evaluated in 2 groups: furosemide clearance half-time (t 1/2) > 20 min (obstructed range) and t 1/2 = 10-20 min (indeterminate range). METHODS: Two hundred children (155 boys, 45 girls; age range, 2 d to 16 y; median age, 26 wk) were studied over a 2-y period. One hundred thirty-five F+20 (diuretic given 20 min after radiopharmaceutical) and 65 F+0 (simultaneous administration of diuretic and radiopharmaceutical) studies were performed with intravenous administration of 99mTc-mercaptoacetyltriglycine (MAG3) and furosemide. At the end of the 20-min diuretic phase, a 5-min post-GAD image was obtained, and the percentage of residual activity was calculated by comparison with the last 5 min of the diuretic phase. All patients were monitored for 6-12 mo, and the final diagnoses were based on either surgical findings or conservative management with follow-up sonography or 99mTc-MAG3 studies. Results of the diuretic renography using quantitative GAD were then compared with the final diagnoses. RESULTS: A renal unit was defined as a kidney and its ureter. In the 200 patients studied, 256 hydronephrotic renal units were analyzed: 10 units showed no function, 1 unit showed poor function, 131 units had t 1/2 < 10 min, 62 units had t 1/2 > 20 min, and 52 units had t 1/2 = 10-20 min. Of the 131 renal units with t 1/2 < 10 min, there was only 1 case of obstruction. Using GAD > 50% residual activity for the diagnosis of obstruction in 62 renal units with t 1/2 > 20 min, the sensitivity was 88.4%, the specificity was 73.7%, and the accuracy was 83.9%. Similarly, using GAD > 50% residual activity for the diagnosis of obstruction in 52 units with t 1/2 = 10-20 min, the sensitivity was 100%, the specificity was 79.5%, and the accuracy was 82.7%. CONCLUSION: The quantitation of GAD > 50% residual activity in diuretic renography can help to differentiate between obstruction and nonobstruction in renal units with t 1/2 > 20 min and t 1/2 = 10-20 min. The quantitation of GAD when t 1/2 < 10 min is not useful because obstruction has already been excluded. (+info)
Prevalence and characterization of renal tubular acidosis in patients with osteopenia and osteoporosis and in non-porotic controls.
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BACKGROUND: Chronic metabolic acidosis may increase alkali mobilization from the bone and thus promote the development of osteoporosis. The objective of the current study was to compare urinary acidification in patients with reduced bone mineral content with that in control subjects with normal bone density. METHODS: Forty-six subjects (41 females, 5 males) with osteopenia or osteoporosis were studied. In none of the subjects were overt metabolic acidosis, derangement of potassium homeostasis, or renal insufficiency present. Distal tubular acidification was studied by means of oral ammonium chloride loading test (0.1 g/kg body weight) and the oral frusemide test (40 mg). In addition the frusemide test was performed in 20 healthy age- and sex-matched controls (17 females, 3 males). RESULTS: In all control subjects a urinary pH <5. 5 was observed following the ingestion of 40 mg frusemide. In contrast, in patients with reduced bone mineral density incomplete renal tubular acidosis type I (RTA I) was diagnosed in 10 of 46 subjects (22%) by oral ammonium chloride loading test. Disorders possibly related to RTA I were detected in eight of these 10 patients. Thirty-six patients had a normal urinary pH response following oral ammonium chloride loading. Oral frusemide, 40 mg, failed to lower urinary pH <5.5 in sixteen patients (35%), these included 10 subjects with incomplete RTA I, and six subjects with a normal oral ammonium chloride loading test. An abnormal frusemide test was found in 35% of patients with reduced bone mass and in none of the normal controls (chi(2)=7.39; P<0.01). With the ammonium chloride test as the gold standard for diagnosis of distal RTA, the frusemide test showed a sensitivity of 1.0 (95% CI, 0.69-1.0) and a specificity of 0.89 (95% CI, 0.78-0.96) for the diagnosis of distal RTA. Patients with incomplete RTA I were younger than those without incomplete RTA I (42+/-16 vs 54+/-14 years; P=0.025; mean+/-SD). Basal serum bicarbonate concentrations and capillary pH did not differ between the groups. CONCLUSION: Incomplete RTA I may be prevalent in a significant proportion of patients suffering from osteopenia or osteoporosis. The outcome of the frusemide test suggests either a defect of the H(+)ATPase in the cortical collecting tubule (CCT) or a defective Na(+) reabsorption in the CCT. Prospective studies are needed to further elucidate the impact of incomplete RTA I on the development of reduced bone mineral content. (+info)