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PubMed2001

Nephron distribution of total low Km cyclic AMP phosphodiesterase in mouse, rat and rabbit kidney.

The activity of cAMP degradation enzyme, cAMP phosphodiesterase (cAMP PDE), in renal tubules is a critically important factor in determining cellular cAMP levels, particularly in response to hormones. In this study we examine the nephron distribution of cAMP PDE activity in the mouse, rat and rabbit kidney and important cellular regulators of cAMP PDE, namely calmodulin and adenosine triphosphate (ATP). We assayed total low Km cAMP PDE in microdissected tubule segments, using 10(-6) M (3H) cAMP as a substrate. Activities were expressed in fentomol cAMP hydrolyzed per minute per mm tubular length or per one glomerulus. The content of ATP was measured in outer medullary collecting duct and medullary thick ascending limb of Henle's loop with microbioluminescence assay using firefly luciferase. In mouse kidney, cAMP PDE was significantly higher in all tubular segments compared to glomerulus. Proximal convoluted tubule, proximal straight tubule, medullary thick ascending limb of Henle's loop (mTAL), and outer medullary collecting duct (OMCD) had intermediated activity. Greater cAMP PDE activity was detected in cortical ascending limb of Henle's loop (cTAL), cortical collecting duct and in distal convoluted tubule (DCT). The highest activity was found in connecting tubules. In rat, nephron distribution of cAMP PDE activities was similar to mouse, except that activity in glomeruli was higher than in mouse glomeruli. In rabbit, nephron distribution of cAMP PDE activities was different from those of mouse and rat. There was no single prominent segment with high cAMP PDE activity. DCT and cTAL showed low enzyme activity. Overall, the highest cAMP PDE activities were measured in the mouse and the lowest were measured in the rabbit nephrons, with those of rat nephron showing an intermediate activity. The maximum effective dose of the calmodulin antagonist, trifluoperazine (200 microM), inhibited cAMP PDE in all nephron segments from the rat kidney. However, there is no statistical significance of its inhibition among nephron segments. In OMCD and mTAL of the rat kidney, cAMP PDE activity was inhibited by ATP (5 mM to approximately 10 mM) which is far beyond the physiological concentartion of ATP in normal epithelial cell. Actual determinations of ATP in mTAL and OMCD were 0.1 mM and 0.17 mM, respectively. These observations show that distal segments of tubules have more active catabolism of cAMP than proximal segments. cAMP PDE in each nephron segment appear to be almost equally dependent on trifluoperazine-sensitive pathway that may reflect the Ca2+-calmodulin system. Cellular concentration of ATP might not be involved in the regulation of the total low Km cAMP PDE activity in rat mTAL and OMCD.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

The role of the IGF axis in IGFBP-1 and IGF-I induced renal enlargement in Snell dwarf mice.

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is generally believed to inhibit IGF action in the circulation. In contrast, IGFBP-1 has been reported to interact with cell surfaces and enhance IGF-I action locally in some tissues. Renal IGFBP-1 levels are found elevated in various conditions characterized by renal growth (e.g. diabetes mellitus, hypokalemia). To test whether IGFBP-1 is a renotropic factor, IGFBP-1 was administered alone or in combination with IGF-I to Snell dwarf mice, an in vivo model without compensatory feedback effects on growth hormone (GH) secretion. In three control groups of Snell dwarf mice, placebo, GH or IGF-I was administered. Compared with placebo, kidney weight increased in all treated groups, however, with different effects on kidney morphology. Administration of IGF-I, alone or in combination with IGFBP-1, tended to increase glomerular volume, while no changes were seen in the other groups. Administration of IGFBP-1 or IGFBP-1+IGF-I both caused dilatation of the thin limbs of Henle's loop, while GH or IGF-I administration had no visible effect. Furthermore, IGF-I administration resulted in an increased mean number of nuclei per cortical area and renal weight, whereas GH, IGF-I+IGFBP-1 or IGFBP-1 caused a decreased renal nuclei number. In situ hybridization and immunohistochemistry showed specific changes of the renal IGF system expression patterns in the different groups. Particularly, IGFBP-1 administration resulted in extensive changes in the mRNA expression of the renal IGF system, whereas the other administration regimen resulted in less prominent modifications. In contrast, administration of IGFBP-1 and IGFBP-1+IGF-I resulted in identical changes in the protein expression of the renal IGF system. Our results indicate that IGFBP-1, alone or in combination with IGF-I, demonstrated effects on the renal tubular system that differ from the effects of IGF-I.

Animals↗
PubMed1992

Three-dimensional visualization of renal cells by NaOH maceration.

The three-dimensional fine structure of cells composing the renal tissue was demonstrated by SEM after the removal of extracellular matrices by NaOH maceration. This paper focuses on glomerular mesangial cells, Goormaghtigh's cells (extraglomerular mesangial cells), and epithelial cells in the thin limbs of Henle's loop in the rat, rabbit and dog. Mesangial cells reveal rough surfaces covered with short microvilli. The cells extend long branching processes in close association with the glomerular capillary, suggesting a role for them of regulating the capillary caliber. The mesangial cells interdigitate with each other by their microvilli, forming an intercellular labyrinth. Goormaghtigh's cells at the glomerular hilus are also covered with microvilli, which form narrow labyrinthine spaces between the cells. The labyrinth among the mesangial cells and that among Goormaghtigh's cells connect with each other at the hilus, giving rise to a channel system leading from the periphery of the glomerulus through the hilus to the interstitial space outside the glomerulus. Renal tubule cells display complicated intra- and intercellular interdigitations on the basal aspect. The pattern of epithelial interdigitation is specific to each tubular segment. The descending and ascending thin limbs of the long loops demonstrate a striking contrast to each other. The former is characterized by moderate intercellular interdigitation and by numerous microvilli on the lateral and basal surfaces; the latter is marked by elaborate, pectineal interdigitations, and by smooth basolateral surfaces.

Animals↗
PubMed1991

Ammonium transport in the kidney: new physiological concepts and their clinical implications.

This article is based on a Basic Science Symposium presented at the 23rd Annual Meeting of the American Society of Nephrology. New information on the segmental transport of ammonium by the proximal tubule, the thick ascending limb of Henle's loop, and the collecting duct is integrated into a thesis that NH4+ excretion is controlled by the rate of production, by diffusion of NH3 along gradients established by proton secretion, and by active transport of NH4+. These new concepts are applied to a novel explanation of the pathogenesis of distal renal tubular acidosis.

Acidosis, Renal Tubular↗
PubMed1985

Diuretics. Clinical pharmacology and therapeutic use (Part I).

25 years have elapsed since the introduction of the first effective oral diuretic, chlorothiazide. Diuretics are now amongst the most widely prescribed drugs in clinical practice worldwide. Availability of these drugs has not only brought therapeutic benefit to countless numbers of patients but it has at the same time provided valuable research tools with which to investigate the functional behaviour of the kidney and other electrolyte-transporting tissues. Despite many remaining gaps in our knowledge of the biochemical processes involved in diuretic drug action, available compounds can be divided into 5 groups on the basis of their preferential effects on different segments of the nephron involved in tubular reabsorption of sodium chloride and water. Firstly, there is heterogeneous group of chemicals that share the common property of powerful, short-lived diuretic effects that are complete within 4 to 6 hours. These agents act on the thick ascending limb of Henle's loop and are known as 'high ceiling' or 'loop' diuretics. The second group are the benzothiadiazines and their many related heterocyclic variants, all of which localise their effects to the early portion of the distal tubule. The third group comprises the potassium-sparing diuretics which act exclusively on the Na+-K+/H+ exchange mechanisms in the late distal tubule and cortical collecting duct. The action of drugs in groups 2 and 3 is prolonged to between 12 and 24 hours. The fourth group consists of diuretics that are chemically related to ethacrynic acid but have the unusual property of combining within the same molecule the property of saluresis and uricosuria. These compounds have actions, to different individual extents, in the proximal tubule, thick ascending limb, and early distal tubule and are known as 'polyvalent' diuretics. Finally, there is a mixed group of weak or adjunctive diuretics which includes the vasodilator xanthines such as aminophylline, and the osmotically active compounds such as mannitol. Available evidence on the molecular mechanisms of action of diuretics in each group is reviewed. The haemodynamic, humoral and physical factors involved in control of electrolyte and fluid handling by the kidney in normal conditions and pathological states are discussed in relation to rational choices of different diuretics in the treatment of various oedematous and non-oedematous conditions.

Animals↗
PubMedDate not supplied

Regulation of renal Na-K-Cl cotransporter NKCC2 by humoral natriuretic factors: relevance in hypertension.

A furosemide-sensitive Na-K-Cl cotransporter (NKCC2 isoform) accounts for almost all luminal NaCl reabsorption in the thick ascending limb of Henle's loop (TALH). The activity of this transport protein is regulated by humoral factors (CIF: cotransport inhibitory factors). One family of CIF compounds is represented by the urinary phytoestrogens equol and genistein, which inhibit cotransport fluxes at similar concentrations as furosemide. Moreover, they possess similar salidiuretic potency as furosemide in the isolated perfused rat kidney, but are less potent than furosemide in vivo. Thus, dietary phytoestrogens can be responsible, at least in part, for the low blood pressure of vegetarians. A second type of CIF is represented by a circulating and urinary factor which is evoked by salt-loading. This, which is not a "ouabain-like" factor, appears to be a new retropituitary natriuretic compound. Endogenous CIF is increased in hypertensive Dahl salt-sensitive rats, probably as a compensatory mechanism against the enhanced NaCl reabsorption in the TALH, which characterizes this model of hypertension. Finally, chronic excess of circulating CIF inhibits and induces up-regulation of erythrocyte Na-K-Cl cotransporter NKCC1.

Animals↗
PubMed1975

Evidence against bicarbonate reabsorption in the ascending limb, particularly as disclosed by free-water clearance studies.

Bicarbonate reabsorption in the thick ascending limb of Henle's loop was examined by studies of free-water clearance (CH2O) and free-water reabsorption (TcH2O). During maximal water diuresis in the dog, CH2O/GFR was taken as an indes of sodium reabsorption in, and urine flow (V/GFR) as an index of delivery of filtrate to, this scarbonate, infusion of a nonreabsorbable solute (hypotonic mannitol) and administration of an inhibitor of bicarbonate reabsorption (acetaent, but less than that achieved with hypotonic saline infusion. This suggests that sodium that sodium bicarbonate is not reabsorbed in the ascending limb. Rather, it is the sodium chloride, swept out of the proximal tubule by osmotic diuresis due to nonreabsorbed mannitol or sodium bicarbonate, that is reabsorbed in the ascending limb thereby increasing CH2O, whereas the nonreabsorption of mannitol and sodium bicarbonate results in a depressed CH20 per unit V when compared with hypotonic saline. V/GFR is not a satisfactory index of delivery to the ascending limb during osmotic diuresis, since it includes water obligated by nonreabsorbable solutes. When a better index of delivery, the sum of the clearances of chloride (CC1) and free-water (CH2O) is used, hypotonic bicarbonate infusion, hypotonic mannitol infusion and acetazolamide administration increase CH2O/GFR per unit delivery to the same extent as odes hypotonic saline infusion. Studies in dogs and rats on TcH2O also indicate that sodium bicarbonate is an impermeant solute in the ascending limb. Osmotic diuresis due to sodium bicarbonate diuresis, produced either by inhibition of sodium bicarbonate reabsorption (acetazolamide, L-lysine mono-hydrochloride) or infusion of sodium bicarbonate, or mannitol diuresis both produced marked chloruresis and increased TcH2O to the same extent as did hypertonic saline infusion. If chloride excretion was almost eliminated by hemodialysis against a chloride-free dialysate (dogs) or prolonged feeding of a salt-free diet (rats), TcH2O formation was unimpaired if hypertonic saline was infused but virtually obliterated during mannitol or sodium bicarbonate diuresis. Sodium reabsorption in the ascending limb, therefore, appears to be dependent upon chloride as the accompanying anion. At any given rate of bicarbonate excretion, more cloride is delivered out of the proximal tubule (as estimated from CC1 + CH2O) with hypotonic sodium bicarbonate infusion than with acetazolamide administration. This suggests that magnitude of the chlorutesis accompanying bicarbonate diuresis depends, not only on osmotic diuresis due to nonreabsorbed sodium bicarbonate, but also on the extent to which concomitant changes in effective extracellular volume influence overall sodium chloride reabsorption.

Acetazolamide↗
PubMedDate not supplied

[Mechanism of the diuretic effect of eufillin].

In acute experiments on rats the xanthine diuretic euphylline did not block the short-circuited current in the proximal tubule, nor did it lower the transtubular potential and the transepithelial resistance of the nephron wall. The diuretic speeded up significantly the passage of the tubular fluid along the proximal region of the nephron and Henle's loop. The dihydroergotoxin and inderal blocking of adrenoreceptors did not produce any influence on the renal effects of the xanthine agent. Reserpine totally blocked the diuretic and saluretic effects of euphylline, whereas other sympatholytics, such as alpha-methyl-dofa, anthabus and hemedin, did not modify the action of the diuretic.

Aminophylline↗
PubMed2002

The eicosanoid factor: a determinant of individuality of nephron segments.

BACKGROUND: Nephron function is segmented, each segment has characteristic transport mechanisms and individual eicosanoid profiles. The transport function of the medullary thick ascending limb of Henle's loop (mTAL) establishes the osmolar gradient upon which extra cellular fluid volume (ECFV) conservation depends. The overriding importance of the mTAL to regulation of ECFV is evident in the diuretic-natriuretic potency of furosemide-like agents which target the mTAL. RESULTS: The mTAL has been shown to be heavily invested with cytochrome P450 monooxygenases (CYP), chiefly omega/omega-1 hydroxylase activity, that generate 19- and 20-hydroxyeicosatetraenoic acid (HETEs). However, displacement of omega hydroxylase by an inducible cyclooxygenase mechanism (COX-2) can be effected by several interventions: long-term infusion of angiotensin II (ANG II), adrenalectomy and elevated extracellular Ca2+ concentrations. This switching mechanism (CYP > COX-2) has been shown to be dependent on activation of tumor necrosis factor alpha (TNFalpha) by ANG II. It represents a long-term adaptive mechanism of the mTAL with production of PGE2 whereas in the short-term, ANG 11 increases 20-HETE synthesis by the mTAL. The effect of Ca2+ on mTAL eicosanoid-related mechanisms provides an explanation for the natriuretic response to hypercalcemia and diminished ability to concentrate urine. CONCLUSION: The expression of COX-2 in the TAL has been linked to activation of the renin-angiotensin system, glucocorticoid deficiency and hypercalcemia, all of which operate through a mechanism in which production of TNFalpha by the TAL is pivotal.

Animals↗
PubMedDate not supplied

[Molecular physiopathology of Bartter's syndrome].

Bartter's syndrome is an autosomic recessive disease characterized by hypokalemic metabolic alkalosis accompanied with hypercalciuria, polyuria and hypotension due to volume depletion. The pathophysiology of this hereditary disease was largely unknown until the last few years in which inactivating mutations in up to five different genes have been shown to produce or be associated with the development of this syndrome. All the involved proteins are expressed either in the apical or basolateral membrane of the thick ascending limb of Henle's loop. These clinical and molecular findings have increased our understanding of the Bartter's disease and also of the thick ascending limb physiology.

Bartter Syndrome↗
PubMed2004

Transport proteins in rats' renal corpuscle and tubules.

UNLABELLED: The localization of transepithelial transport proteins for glucose and water reabsorption in renal corpuscle and tubules epithelium was observed. MATERIAL AND METHODS: Immunohistochemistry of normal male Wistar rats' kidney has been performed. Facilitated diffusion glucose transporter GLUT4, Na(+)-dependent glucose co-transporter SGLT1, a cargo transporter TGN38, and water transporter aquaporin-2 (AQP2) were used. RESULTS: An intensive GLUT4 expression in renal proximal tubules and in convoluted segment of distal tubules has been observed. The intensive SGLT1 expression was marked in all renal tubules, and also in the glomerulus of the renal corpuscle. TGN38 was expressed mainly in the S1 of proximal tubules and a bit weaker in the distal tubules. The most intensive AQP2 expression in the proximal tubules and in the thin part of Henle's loop has been detected. In some cases AQP2 expression in the collecting tubules has been observed. The same tubules nephroni are marked heterogeneously. The distribution of transepithelial transport proteins in different parts of nephroni is also greatly heterogeneous because of weak determination of urinary system. CONCLUSION: The comparable transport-proteins distribution with technique of fluorescence immunohistochemistry in rats' renal corpuscle and tubules was elucidated. Data suggest that expression of glucose and water transepithelial transporter proteins is heterogeneous in all parts of nephron, and, probably, is in accordance with recycling of transport proteins.

Animals↗
PubMedDate not supplied

[Ultrastructural organization of the inner medullary zone of the kidney of the water vole Arvicola terrestris].

Papillary component ultrastructure and acid mucopolysaccharide distribution have been investigated in the kidney of the water vole A. terrestris. Structural differences between the descending and ascending parts of the Henle's loop are rather small, cell cytoplasm of these segments being poor in organells. Unusual ultrastructure of the collecting duct epithelium with high level of cytoplasmic organization (elongated thin mitochondria, fairly developed Golgi complex, numerous phagosomes and pinocytotic vesicles, long branching microvilli) was described. Apical membrane of the epithelium is covered by rich glycocalix layer. Heil-positive substrances are located intracellularly inside phagosomes and on vesicle membranes, as well as on the membranes of cisternae of endoplasmic reticulum. Interstitium is abundant, but no close contacts between papillary components were found. Acid mucopolysaccharide content of the interstitium is low, "gel" filter being not formed. The described peculiarities are discussed in relation to water and salt metabolism of the rodents investigated.

Animals↗
PubMed1991

Structural identification of cytochrome P450-dependent arachidonate metabolites formed by rabbit medullary thick ascending limb cells.

The medullary thick ascending limb of Henle's loop (mTALH) contributes importantly to the regulation of extracellular fluid volume and composition and metabolizes arachidonic acid (AA) chiefly by a cytochrome P450 monooxygenase pathway. Rabbit mTALH cells, when incubated with radiolabeled [14C]AA, form products that segregate into two peaks designated P1 and P2 based on their reverse-phase high pressure liquid chromatography retention times. We have now definitively identified their chemical structures. mTALH cells, isolated from the rabbit outer medulla, were homogenized and incubated with [14C]AA in the presence of NADPH. The AA metabolites in P1 and P2 were identified by gas chromatographic-mass spectrometric methods, including fast atom bombardment, negative ion electron capture, and electron ionization. All mass spectrometric data, the lack of UV chromophores, and comparisons with authentic standards were consistent with P1 containing two principal components: 19-hydroxy-5,8,11,14 eicosatetraenoic acid (19-HETE) and 20 - hydroxy - 5,8,11,14 - eicosatetraenoic acid (20-HETE), P2 contained primarily 1,20-eicosa-5,8,11,14-tetraenedioic acid (20-COOH-AA). The biological properties of P1 and P2 were compared with those of the authentic standards of 19- and 20-HETE and 20-COOH-AA. P1 dose dependently relaxed precontracted mesenteric arterial rings, as did authentic (19S)- and (19R)-HETE, whereas 20-HETE relaxed at lower and contracted at higher concentrations. As P1 contained a mixture of 19- and 20-HETE, each of these AA metabolites presumably contributed to the vascular relaxation produced by P1. Neither P2 nor 20-COOH-AA exhibited vasoactivity, but each demonstrated a similar potency in inhibiting rabbit medullary Na(+)-K(+)-ATPase activity. As previously reported, P2 was a more potent inhibitor of Na(+)-K(+)-ATPase than P1. The lesser inhibitory activity of P1 presumably reflects the presence of similar amounts of 19-HETE, the least active metabolite, and 20-HETE, which resembles 20-COOH-AA in its capacity to inhibit Na(+)-K(+)-ATPase. Thus, the biological activity of the less polar peak, P1, can be accounted for by 19- and 20-HETE, and that of P2, by 20-COOH-AA.

Animals↗
PubMed1990

Effects of acute cisplatin administration on renal ATPase activities and magnesium excretion of rats.

Male Wistar rats were killed 1, 2, or 4 days after a single intraperitoneal injection of cisplatin (5 mg/kg). Functional renal indices, enzymatic activities, and morphological variables were studied. One day after the injection, the treated group showed an increase in the magnesium and phosphate fractional urinary excretion (FE) vs the control group (FE Mg = 5.2 +/- SEM 0.5% vs 13.0 +/- 1.7%; P less than 0.01; and FE P = 4.7 +/- 0.7% vs 14.0 +/- 1.9%; P less than 0.01). Two days after cisplatin administration, a decrease in creatinine clearance of treated animals was found, to 0.33 +/- 0.03 vs 0.51 +/- 0.03 ml/min; P less than 0.05. Na-K-ATPase and ouabain-insensitive ATPase activities were studied in the proximal convoluted tubule, the medullary thick ascending limb of the Henle's loop (mTAL), and the distal convoluted tubule. Only in mTAL one day after the cisplatin injection was there a decrease in Na-K-ATPase activity in the treated group vs controls (1103 +/- 145 vs 1734 +/- 189 pmol Pi/mm.h; P less than 0.05). Morphological studies showed a decrease in mTAL diameters on day 1, and an increase in proximal convoluted tuble diameters at day 2 of treated rats vs controls, at 27.8 +/- 0.6 vs 31.4 +/- 0.7 microns; P less than 0.05, and 50.4 +/- 1.2 vs 47.4 +/- 0.2 microns; P less than 0.05 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed1990

Y-chromosomal influences on renal and adrenal measures in mice.

From a four-way cross between unrelated inbred strains of mice, a random-breeding line was developed that segregated at two coat-color loci and carried Y chromosomes from different sources. Adult males were used for measurements of body weight, kidney weight, renal papilla length, and adrenal gland weight. Clear evidence was obtained of Y-linked influences on papilla length and adrenal weight, whereas direct effects of Autosome 9 were indicated with regard to adrenal weight only. Epistatic interaction of the Y chromosome with Autosome 4 was found for kidney weight and a 4-9 interaction appeared for papilla length. The direct effects of Y-chromosomal variation are interpreted in terms of a functional relationship between adrenal action and the development of Henle's loops and, in connection with previous findings, discussed in terms of adrenal functioning in the regulation of hippocampally-mediated behaviors.

Adrenal Glands↗
PubMed1975

The separate modes and sites of action of furosemide and amiloride.

The effect of furosemide and amiloride on the transport of sodium, potassium, hydrogen and bicarbonate ions was studied in microperfusion experiments on the main excretory duct of the submaxillary gland of the rat. Furosemide did not impair transport of Na+, K+ and H+/HCO-3. Amiloride, however, completely abolished Na+ transport. Blockade of Na+ transport was accompanied by abolition of passive K+ secretion, whereas the active components of K+ and HCO-3 secretion were not affected. In urinary excretion studies, amiloride, which is known to block sodium transport selectively, was used in order to assess whether furosemide has a distinct effect that is independent of sodium transport. Oral administration of amiloride caused a selective excretion of Na+ in a more alkaline urine with an extremely low K+ concentration. The injection of furosemide caused a copious diuresis of an isotonic urine, in which excretion of Na+ and K+ was balanced by the excretion of Cl- ions. Combined administration of amiloride and furosemide produced summation of the individual effects of both diuretics, indicating that the two drugs had different sites and modes of action. In the presence of furosemide the kidney no longer responded to antidiuretic hormone, which suggested that the urine concentrating mechanism in Henle's loop was blocked by furosemide.

Amiloride↗
PubMed1989

Effect of synthetic atrial natriuretic factor on superficial and deep proximal tubule sodium reabsorption.

The effects of synthetic atrial natriuretic factor (ANF) on sodium reabsorption by deep and superficial proximal tubules were examined in the rat. In response to ANF infusion (4 micrograms/kg/hr), the urinary fractional excretion of sodium increased from 1.21% +/- 0.53% to 3.48% +/- 0.48%, p less than 0.05 (n = 12). Fractional delivery of sodium (FDNa) from the deep proximal tubule was 25.9% +/- 3.7% before and 33.7% +/- 3.4% after ANF infusion. In time control animals, FDNa from deep proximal tubules was 34.3% +/- 3.0% and 28.5% +/- 4.0% respectively (n = 12). The change in FDNa from deep proximal tubules during ANF infusion (increase of 7.8% +/- 3.9%) was significantly different from the change in control animals (decrease of 5.8% +/- 3.1%) (ANF infusion vs control, delta 13.7% +/- 4.9%, p less than 0.05). No significant change was observed in FDNa in the superficial proximal tubule either during ANF infusion or in control animals. In summary, ANF infusion increased urinary fractional sodium excretion; however, fractional sodium reabsorption by the proximal tubule of superficial nephrons was unchanged. In contrast, sodium delivery to the point of micropuncture in the descending limb of Henle's loop of deep nephrons was increased, as compared with controls, suggesting inhibition of sodium reabsorption by proximal tubules of deep nephrons.

Absorption↗
PubMed1988

Renal action of a novel uricosuric diuretic, S-8666. II. Effects on Cl- and urate transport in isolated perfused rabbit renal tubules.

We have studied the effect of the two enantiomeric forms of the diuretic agent, S-8666 [6,7-dichloro-5-(N,N-dimethylsulfamoyl)-2,3-dihydro-2-benzofuran carboxylic acid], on the Cl- transport across the cortical thick ascending limb of Henle's loop (CAL) and on urate transport across the proximal tubule, using the in vitro microperfusion technique of individual tubular segments isolated from the rabbit kidney. S-8666 in the lumen reduced significantly the lumen-positive voltage in CAL. The suppression of lumen-positive voltage was instantaneous, and the effects were reversible when the drug was eliminated from the perfusate. These effects were observed with the (S-)-enantiomer of S-8666 but not with the (R+)-enantiomer. S-8666 did not affect the lumen-positive voltage when it was added to the bathing fluid. The lumen to bath 36Cl flux in CAL also was reduced by addition of S-8666 to the perfusate. S-8666 in the lumen inhibited the lumen-to-bath [14C]urate flux in both proximal convoluted tubule and proximal straight tubule. It also reduced the bath-to-lumen urate flux when it was added to the bath. Enantioselectivity was not found for these inhibitory effects on urate transport of S-8666. We conclude: 1) the (S-)-enantiomer of S-8666, but not the (R+)-enantiomer, has a direct effect on the Cl- transport in the CAL, acting from the luminal side and 2) both enantiomers of S-8666 inhibit urate to transport in proximal tubules.

Animals↗