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Effect of cyclosporine A on renal electrolyte transport: whole kidney and Henle loop study.

We investigated whole kidney function and electrolyte transport in the loop of Henle of surface nephrons using micropuncture in rats pretreated for 5-7 days with cyclosporine A (CSA, 15 mg/kg). We also studied whether the kidney was able to increase K+ excretion acutely after a period of acute i.v. KCl loading (37 mumol/min.kg body weight). For Henle loop studies we microperfused the late proximal tubule downstream from an immobile wax block at two perfusion rates (15 and 40 nl/min). The fluid at the beginning distal tubule was collected and analyzed for inulin, Na+, K+, Cl-, Ca++, and Mg++. Plasma levels of CSA in our model ranged from 254 and 971 ng/ml and showed no relation to the obtained measurements. The pretreatment with CSA did not significantly change whole kidney or Henle loop electrolyte transport compared to drug free controls. Also, the CSA-pretreated rats were able to excrete an acute KCl load although this was at the expense of a marginally higher plasma K+ concentration and also a smaller urine flow increase during KCl loading. Thus CSA-pretreated rats showed only a mildly impaired response to KCl challenge in the absence of GFR impairment.

Animals↗

Henle loop basement membrane as initial site for Randall plaque formation.

Since the early description of Randall plaques in 1937, studies of the pathogenesis of stone formation mainly focused on the chemistry involving salt precipitation and crystallization, rather than tubular and interstitial medullar mechanisms of calcium concentration and supersaturation. In 2003, Bushinsky published a suggestive and inspiring sequence of events aimed to show that the basement membrane of the thin limb of the loop of Henle can be the first site of nucleation, as recently shown by the impressive work by Evan et al. The aim of this minireview is to verify the consistency of the Evan and Bushinsky theory with the current literature in the field.

Basement Membrane↗

The function of (Na+, K+)-ATPase in the thick ascending limb of Henles loop.

The content and the properties of (Na+, K+)-ATPase in the thick ascending limb of the loop of Henle (TAL) are related to the rate and the characteristics of the transport of NaCl which has been measured in the isolated perfused cortical portion of the TAL by Burg and Green (Am. J. Physiol, 224, 659, 1973) and in the medullary portion of the TAL by Rocha and Kokko (J. Clin. Invest. 52, 612, 1973). It is concluded that the ouabain-sensitive, active transport of NaCl across the epithelium consists of primary active transport of Na and secondary active transport of Cl and that it is driven by the sodium pump or (Na+, K+)-ATPase.

Adenosine Triphosphatases↗

Sodium reabsorption by the Henle loop in humans.

In a previous study, we described a new method [3] to measure Na reabsorption by each segment of the human nephron independently. Reabsorption was expressed as equivalent volumes of solute-free water (CH2O) generated by the loop of Henle (CH2O-HL) and by the distal tubule (CH2O-DT), and dissipated by back diffusion (BD) across collecting ducts (CH2O-BD). These data were obtained during maximal water diuresis (MWD). The present study was undertaken to calculate CH2O-HL by experiments performed during maximal antidiuresis (MA). For this purpose, a new theoretical approach was devised, described by algebraic equations which allowed calculations of segmental transport during MA alone, where only CH2O-HL could be calculated independently. The study was performed on 14 normal volunteers who were studied twice by clearance measurements, firstly during MWD and again during MA. In each experiment, clearance periods were performed during baseline conditions and during the administration of furosemide (0.7 mg/kg bolus injection followed by 0.06 mg/kg/min maintenance infusion). From the values measured during either condition, segmental reabsorption was calculated. During MWD, CH2O-HL averaged 19.4 + 10.4, during MA 20.4 + 8.0 ml/min/GFR X 100; p greater than 0.05. The paired measurements were significantly correlated (r = 0.80; p less than 0.01). These data demonstrate that CH2O-HL obtained with the original theory is a reproducible result that can be confirmed with independent measurements obtained during different experimental conditions. Thus, measurements of segmental Na transport in the human nephron are feasible and can contribute important informations on disease states.

Absorption↗

Effect of inhibitors of prostaglandin synthesis on the furosemide action in the loop Henle of rat kidney.

Inhibitors of prostaglandin synthesis such as indomethacin and meclofenamate may attenuate the diuretic response to furosemide. The purpose of the present study was to clarify whether an inhibition of furosemide's action in the loop of Henle is involved in this interaction. In a first set of experiments, the effect of indomethacin and meclofenamate on the diuretic response to furosemide was re-evaluated in anaesthetized rats. Single loops of Henle of rat kidneys were perfused in vivo in a second group of rats. Furosemide was added to the perfusion fluid and the effect of indomethacin (5 mg/kg i.v.) and meclofenamate (5 mg/kg i.v.) on furosemide's action in the loops was tested. In the absence of furosemide, indomethacin and meclofenamate did not significantly affect urine flow and sodium chloride excretion, or the loop's sodium and chloride reabsorption. Both prostaglandin inhibitors, however, significantly attenuated the diuretic effect of furosemide (1 mg/kg i.v.) and the inhibitory action of the diuretic, at a concentration of 10(-4) M, on the loop's sodium and chloride transport. The results identify the loop of Henle as a tubular site of interaction between furosemide and prostaglandin inhibitors. The interaction may be related to a furosemide-induced stimulation of renal prostaglandins.

Animals↗

An oscillating intratubular pressure response to alterations in Henle loop flow in the rat kidney.

We describe in gas anesthetized rats an oscillating intratubular pressure response, probably of vascular origin, sensitive to small physiological changes in fluid delivery to the distal tubule. The oscillation apparently indicates that an adjustment of vascular resistance is in operation, but at present it reveals neither the effector site (afferent and/or efferent arteriole) nor the effector mechanism (vasoconstriction and/or dilatation). The renin-angiotensin system seems to be involved in this phenomenon.

Animals↗

Inhibition of active NaCl reabsorption in the thick ascending limb of the loop of Henle by torasemide.

The new diuretic torasemide (1-isopropyl-3- ([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea) was tested in isolated in vitro perfused cortical thick ascending limbs of Henle loops of rabbit kidney. The equivalent short circuit current (Isc) corresponding in this nephron segment to the rate of secondarily active Cl-reabsorption was measured continuously. Torasemide led to a rapid and reversible inhibition of Isc when added to the luminal perfusate. The IC50 for this effect was 3 x 10(-7) mol/l. A similar effect was also exerted by torasemide addition to the peritubular bath. However, 100 times larger doses were needed. The data are compatible with the view that torasemide interacts with both, the Na+2Cl-K+ carrier, localized in the luminal membrane, and, at higher concentrations, with the chloride channels present in the basolateral membrane of this nephron segment. Under normal conditions, and in the intact kidney, the former effect, i.e. interference with the Na+2Cl-K+ carrier will be the dominant action of this drug.

Absorption↗

Effect of renal nerve stimulation on NaCl and H2O transport in Henle's loop of the rat.

To assess the effect of renal nerve stimulation on sodium, chloride, and water transport in the loop of Henle, experiments were performed in anesthetized hydropenic and isotonic saline volume-expanded rats using renal clearance and Henle's loop microperfusion techniques (end-proximal convoluted tubule perfusion site, early distal convoluted tubule collection site). As compared with the control period values, low-frequency (less than 1.0 Hz) renal nerve stimulation decreased absolute and fractional urinary flow rate and sodium and chloride excretion without affecting mean arterial pressure, glomerular filtration rate, renal blood flow, or renal vascular resistance. In the loop of Henle, the absorptive transport of water was not affected, whereas the absorptive transport of sodium and chloride was increased in both hydropenic (Na 111 +/- 49 peq/min) and isotonic saline volume-expanded rats (Na 154 +/- 69 peq/min, Cl 180 +/- 52 peq/min) during low-frequency renal nerve stimulation. Low-frequency renal nerve stimulation decreases urinary sodium and chloride excretion via a direct effect of increasing renal tubular sodium and chloride reabsorption. In addition to the established effect of increasing proximal tubular sodium reabsorption, Henle's loop sodium and chloride absorption are also increased, supporting a physiological role for the adrenergic innervation of these structures.

Animals↗

Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease.

BACKGROUND: Lung disease in preterm infants is often complicated with lung edema. OBJECTIVES: The aim of this review was to assess the risks and benefits of administration of a diuretic acting on the loop of Henle (loop diuretic) in preterm infants with or developing chronic lung disease (CLD). Primary objectives were to assess changes in need for oxygen or ventilatory support and effects on long-term outcome, and secondary objectives were to assess changes in pulmonary mechanics and potential complications of therapy. SEARCH STRATEGY: We used the standard search method of the Cochrane Neonatal Review Group. We used the following keywords: ¿ or ¿ and , limited to and limited to or . We searched Medline (1966-1998), Embase (1974-1998) and the Cochrane Controlled Trials Register (CCTR) from the Cochrane Library (1998, issue 4). In addition, we hand searched several abstract books of national and international American and European Societies. SELECTION CRITERIA: We included in this analysis trials in which preterm infants with or developing chronic lung disease and at least 5 days of age were all randomly allocated to receive a loop diuretic either enterally or intravenously. Eligible studies needed to assess at least one of the outcome variables defined a priori for this systematic review. Primary outcome variables included important clinical outcomes, and secondary outcome variables included toxicity and pulmonary mechanics (e.g., lung compliance and airway resistance). DATA COLLECTION AND ANALYSIS: We used the standard method for the Cochrane Collaboration which is described in the Cochrane Collaboration Handbook. Two investigators extracted, assessed and coded separately all data for each study, using a form that was designed specifically for this review. Any disagreement was resolved by discussion. We combined parallel and cross-over trials and, whenever possible, transformed baseline and final outcome data measured on a continuous scale into change scores using Follmann's formula. MAIN RESULTS: The only loop diuretic used in the studies which met the selection criteria was furosemide. Most studies focused on pathophysiological parameters and did not assess effects on important clinical outcomes defined in this review, or the potential complications of diuretic therapy. In preterm infants < 3 weeks of age developing CLD, furosemide administration has either inconsistent effects or no detectable effect. In infants > 3 weeks of age with CLD, a single intravenous dose of 1 mg/kg of furosemide improves lung compliance and airway resistance for 1 hour. Chronic administration of furosemide improves both oxygenation and lung compliance. REVIEWER'S CONCLUSIONS: In preterm infants > 3 weeks of age with CLD, acute and chronic administration of furosemide improve lung compliance. Chronic administration of intravenous or enteral furosemide improves oxygenation. In view of the lack of data from randomized trials concerning effects on important clinical outcomes, routine or sustained use of systemic loop diuretics in infants with (or developing) CLD cannot be recommended based on current evidence. Randomized trials are needed to assess the effects of furosemide administration on survival, duration of ventilatory support and oxygen administration, length of hospital stay, potential complications and long-term outcome.

Chronic Disease↗

[Diuretics].

Microaspiration techniques and clearance studies have shown that reabsorption of filtered sodium approximates 65% in the proximal tubule, 25 to 30% in the ascending limb of the loop of Henle and 5 to 10% in the dilution segment. Reabsorption in the Henle loop is of special significance as it governs the process of dilution-concentration of urine. Moreover, inhibition of sodium reabsorption in the loop of Henle necessarily produces a substantial loss of sodium since only a fairly small fraction of urinary sodium is reabsorbed beyond the Henle loop (dilution segment, distal tubule). Excretion of water and electrolytes is regulated by humoral factors, such as the renin-angiotensin-aldosterone system, some prostaglandins and certain kinins. Factors that promote excretion of sodium, produced in particular by the myocardium, have recently been demonstrated. The correlation between blood pressure and salt has been substantiated by many findings. Diuretics are commonly used to treat high blood pressure as well as edema. Recent evidence indicates that sodium transport is altered in idiopathic hypertension, at least in red blood cells. Clinical trials of diuretics are designed to localize the drug's action and quantify its saluretic activity (evaluation of potency and effectiveness--single doses, sustained treatment). Furthermore, the minimal efficient antihypertensive dosage should be determined. Diuretics can be divided into two groups according to whether they produce an increase or decrease in serum potassium. Diuretics that are capable of producing hypokalemia belong to two main families. One consists of the Henle loop diuretics that interfere with the mechanisms of dilution-concentration of urine. Action of these drugs is potent and short-lived. For instance, following a single dose of furosemide, excretion of sodium can reach 25-30% of filtered sodium; renal blood flow increases; CH2O and TCH2O decrease. With furosemide, induction of diuresis is rapid (within a few minutes after IV injection and 20 mn after oral ingestion); elimination half-life is 50 mn; absolute bioavailability is 50-70%; 95% of the drug is bound to plasma proteins; elimination is mainly through the kidneys. Other Henle loop diuretics include ethacrynic acid, whose elimination half-life is less than one hour; bumetanide, which is 40 times more potent than furosemide; muzolimine, whose action is more lasting despite the fact that only 65% of the drug is bound to plasma proteins; and ozolinone, which has a saliuretic action comparable to that of furosemide and in addition exerts a direct vasodilating effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid-Base Equilibrium↗

Evidence for tubuloglomerular feedback in juxtamedullary nephrons of young rats.

To determine whether the filtration rate of juxtamedullary nephrons is regulated by tubuloglomerular feedback (TGF), we developed two micropuncture techniques suitable for the papilla of young rats. One consisted of measuring the tubular flow in descending limbs of Henle loops (VDLH) while the ascending limbs of the loop of Henle (ALH) were perfused at various rates with three different solutions: modified Ringer, artificial Henle loop solution, and Ringer containing 10(-4) M furosemide. SNGFR was also measured in several juxtamedullary nephrons. The other protocol consisted of measuring the tubular stop-flow pressure (PSF) in descending limbs of the loop of Henle upstream to a wax block. Distal to the block Ringer was perfused at various rates through ALH. Our results provide the first evidence of a TGF response in juxtamedullary nephrons. VDLH and SNGFR decreased during Ringer perfusion to 42 +/- 4 and 44 +/- 4% of their values at zero perfusion. The same pattern was observed using Henle loop solution as perfusate, whereas with furosemide VDLH did not change. The maximal decrease in PSF was 14.1 +/- 1.4 mmHg. The perfusion rate necessary to induce a half-maximal PSF decrease was 9.1 +/- 0.9 nl/min. Similar micropuncture techniques were used in proximal tubules of surface nephrons in these rats, which in comparison to the deep nephrons showed smaller feedback responses. The mechanism seems to be active at physiological nephron flow rates in both nephron populations. Thus, TGF can exert its effect on GFR of the whole kidney by acting in both deep and surface nephrons.

Animals↗

Fluid reabsorption in Henle's loop and urinary excretion of sodium and water in normal rats and rats with chronic hypertension.

The function of the short loops of Henle was investigated by micropuncture technique in normal rats, in rats with spontaneous hypertension, and in the untouched kidney of rats with experimental renal hypertension. All animals received a standard infusion of 1.2 ml of isotonic saline per hr. With increasing arterial blood pressure (range from 90 to 220 mm Hg), a continuous decrease in transit time of Lissamine green through Henle's loop from 32 to 10 sec was observed. Fractional water reabsorption along the loop declined progressively from 26 to 10%, and fractional sodium reabsorption decreased from 40 to 36% of the filtered load. The fluid volume in Henle's loop calculated from transit time and mean flow rate also decreased with increasing blood pressure. There was no change in superficial single nephron filtration rate but there was a slight increase in total glomerular filtration rate (GFR). Sodium and water reabsorption in the proximal tubule remained unchanged. Urine flow rate, sodium excretion, osmolar clearance, and negative free water clearance increased with increasing blood pressure. The osmolal urine to plasma (U/P) ratio declined but did not fall below a value of 1.5. It is concluded that the increase in sodium and water excretion with chronic elevation of arterial blood pressure is caused by a decrease of sodium and water reabsorption along the loop of Henle, presumably as a consequence of increased medullary blood pressure.

Animals↗

Amino acid transport: microinfusion and micropuncture of Henle's loops and vasa recta.

Amino acids appear to be reabsorbed distal to the tips of loops of Henle and may be recycled between loops and vasa recta in rat papilla. These possibilities were examined further by microinfusion and micropuncture of loops of Henle and vasa recta. To obtain information on the specificity of amino acid transport distal to the tips of the loops, ascending limbs were continuously microinfused with radioactively labeled L- and D-alanine, L-glutamate, taurine, and mannitol. About 30% of the L- and D-alanine and L-glutamate but none of the taurine or mannitol appeared to be reabsorbed. These results suggest that an acidic and a neutral amino acid are reabsorbed to a similar extent, that reabsorption is not stereospecific, but that it does not occur indiscriminately for all amino acids or for all molecules of similar size. Continuous microinfusion of ascending vasa recta with radioactively labeled L- and D-alanine suggests that amino acids may be able to move from vasa recta into tubules (apparently loops of Henle) without first entering the systemic circulation. However, micropuncture measurements of concentrations of endogenous amino acids in thin ascending limbs and adjacent descending vasa recta do not demonstrate a gradient for passive movement out of loops.

Alanine↗

Amino acid fluxes in rat thin limb segments of Henle's loop during in vitro microperfusion.

Amino acids are apparently recycled between loops of Henle and vasa recta in the rat papilla in vivo. To examine more closely papillary amino acid transport, we measured transepithelial fluxes of L-[(14)C]alanine and [(14)C]taurine in thin limbs of Henle's loops isolated from rat papilla and perfused in vitro. In descending thin limbs (DTL) in vitro, unidirectional bath-to-lumen fluxes tended to exceed unidirectional lumen-to-bath fluxes for both radiolabeled amino acids, although the difference was statistically significant only for taurine. In ascending thin limbs (ATL) in vitro, unidirectional lumen-to-bath fluxes tended to exceed unidirectional bath-to-lumen fluxes, although the difference was again statistically significant only for taurine. These results are compatible with apparent directional movements of amino acids in vivo. However, none of the unidirectional fluxes was saturable or inhibitable, an observation compatible with apparent reabsorption from the ATL in vivo but not compatible with apparent movement from vasa recta to DTL in vivo. There was no evidence of net active transepithelial transport when concentrations of radiolabeled amino acids were matched on both sides of perfused tubule segments. These data suggest that regulation of amino acid movement in vivo may involve the vasa recta, not the DTL of Henle's loops. The data also suggest that transepithelial movement of amino acids in thin limbs of Henle's loop may occur via a paracellular route.

Alanine↗

Reabsorption of betaine in Henle's loops of rat kidney in vivo.

This study was designed 1) to localize and 2) to characterize betaine reabsorption from the tubular lumen in rat kidney in vivo, and 3) to test whether reabsorption is modulated by the diuretic state. [(14)C]betaine (+ [(3)H]inulin) was microperfused through the proximal convoluted tubule (PCT) and microinfused into late proximal (LP) and early distal (ED) tubules, long loops of Henle (LLH), and vasa recta of the rat in vivo et situ, and the fractional recovery of the (14)C label was determined end proximally (PCT) and in the final urine, respectively. [(14)C]betaine was not reabsorbed during ED microinfusion, whereas fractional reabsorption during LP microinfusion was 82% at 0.06 mM betaine and decreased gradually to 4.8% at 60 mM. L-Proline had lower Michaelis-Menten constant (K(m)) and sarcosine a higher K(m) than betaine. Chronic, but not acute, diuresis inhibited betaine reabsorption in Henle's loops. Fractional [(14)C]betaine reabsorption in PCT was much smaller than that during LP microinfusion. [(14)C]betaine (7.28 mM) microinfused 1) into LLH was reabsorbed to 30% and 2) into vasa recta appeared in the ipsilateral urine to a much higher extent than contralaterally. In both cases, no saturation was detected at 70 mM. We conclude that betaine is reabsorbed by mediated transport from descending limbs of short Henle's loops by a proline-preferring carrier in a diuresis-modulated manner. In the deep medulla, bidirectional blood/urine betaine transport exists.

Absorption↗

Effect of acute potassium load on reabsorption in Henle's loop in chronic renal failure in the rat.

To determine the effect of an acute load of potassium on potassium reabsorption by the loop of Henle in chronic renal failure, the right kidney was removed and branches of the left renal artery were ligated in 17 rats. One week later and after 2 days of a potassium-free diet, rats were studied before (period 1) and after (period 2) acute loads of potassium chloride (KCl group), equimolar sodium chloride (NaCl group) or no solute (time control). The KCl load increased urinary potassium excretion to a greater extent (from 5 to 50%, P less than 0.005) than in NaCl (14 to 27%) or time control (9 to 14%), and caused as great a diuresis and natriuresis as did NaCl. Fractional delivery of water, sodium, and potassium to the end-proximal tubule increased similarly in the NaCl and KCl groups and slightly less so in the time control group in period 2. The major finding was a striking increase in potassium delivery to the beginning of the distal tubule (from 17 to 37%) in period 2 which was substantially greater than in the combined control groups (13 to 19%, P less than 0.025) and was equivalent to three-quarters of urinary potassium excretion. This was the consequence of an increase in the filtered load of potassium, an increase in absolute delivery of potassium from the proximal tubule (P less than 0.005), and a decrease in fractional potassium reabsorption by the loop of Henle from 64 to 48%, versus 72 to 69% in the control groups (P less than 0.01). These results suggest that the proximal tubule and, in particular, Henle's loop play a role in excreting an acute potassium load in chronic renal failure.

Animals↗

Taurine reabsorption by a carrier interacting with furosemide in short and long Henle's loops of rat nephrons.

Taurine is net reabsorbed in the proximal convolution by Cl- -stimulated Na+ symport specific for beta-amino acids but not in later nephron segments. However, large unidirectional taurine transport takes place there. To investigate unidirectional taurine reabsorption, we comicroinfused [3H]taurine and [14C]inulin into late proximal (LP), early distal (ED), and late distal (LD) tubule segments, as well as into the tips of long loops of Henle (LLH) of rats in vivo, and determined fractional reabsorption of [3H]taurine (FR) in the ipsilateral urine. FR (9 micromol/l taurine) was 80-93 (LP), 16 (ED), and 8% (LD). At 26 mmol/l taurine, FR decreased to 13 (LP) and 6% (ED). FR also decreased when Na+ or Cl- was absent or furosemide (5 x 10(-5) mol/l) was added. Bumetanide (5 x 10(-5) mol/l) had no effect, whereas aniline-2-sulfonic acid (ASA) inhibited. During LLH microinfusion, FR was 55% at 66 micromol/l and 17% at 228 micromol/l and was again inhibited by furosemide and ASA but not by bumetanide. [14C]taurine reabsorption from microperfused proximal convolutions was not influenced by furosemide. Chronic water diuresis did not affect taurine reabsorption in short Henle's loops. We conclude that taurine can enter cells of the distal nephron from the lumen by an Na+- and partly Cl- -dependent carrier with which C alpha,beta-substituted taurine (ASA) and C alpha,beta- and N-substituted beta-alanine (furosemide) directly interact. Thus proximal and distal taurine carriers seem to be different.

Absorption↗

Convective uphill transport of NaCl from ascending thin limb of loop of Henle.

In this paper we describe a mathematical model of the renal inner medulla based on a previously proposed model [A.S. Wexler, R.E. Kalaba, and D.J. Marsh. Am. J. Physiol. 260 (Renal Fluid Electrolyte Physiol. 29): F368-F383, 1991] in which in the inner medullary ascending thin limb of Henle's loop (ATL) and collecting duct (CD) exchange with a local capillary node with the reabsorbed water and solutes flowing radially toward a central vascular bundle. Our model differs in that ascending and descending vasa recta and surrounding interstitial space are replaced by a central core. Our analysis of the coupled ATL-CD system shows that it is theoretically capable of transporting NaCl out of the ATL into the central vascular space (approximated by the central core) against a concentration gradient, which in the absence of radial diffusion can be arbitrarily large. By numerical solution of the model with the radial diffusion coefficient (D(r)) for NaCl of 0, we find that the ATL can be more than 100 mosmol/l hypotonic with respect to the core. We also find that with restricted diffusion the osmolality of the CD at the papilla is significantly greater than that of the loop of Henle. As D(r) approaches the diffusion coefficient of NaCl in free solution, the osmolality of the loop increases and that of the CD decreases. Thus, overall, contrary to intuitive expectations, the radial separation and uphill transport of NaCl do not give any significant increase in loop concentration, which depends primarily on the quantity of urea reabsorbed from the CD.

Animals↗