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PubMed1984

Mode of action of conventional and potassium-sparing diuretics--aspects with relevance to Mg-sparing effects. Review of the present state of the art and recent findings.

The sites and modes of action of five groups of diuretics within the nephron, and their effects on magnesium excretion are outlined. More than 60% of the glomerularly filtered magnesium is reabsorbed in the loop of Henle. Hence, the loop diuretics induce a strong magnesium excretion. The benzothiadiazine diuretics increase magnesium excretion only moderately. In contrast, the potassium-sparing diuretics amiloride and triamterene, as well as the aldosterone antagonists, increase magnesium reabsorption and therefore may be designated as magnesium-conserving diuretic drugs. The possible modes of action of this property are discussed.

Amiloride↗
PubMed2000

Epithelial magnesium transport and regulation by the kidney.

Magnesium is the fourth most abundant cation in the body and the second most common cation in the intracellular fluid. It is the kidney that provides the most sensitive control for magnesium balance. About a 80% of the total serum magnesium is ultrafilterable through the glomerular membrane. In all of the mammalian species studied to date, the proximal tubule of the adult animal reabsorbs only a small fraction, 10-15%, of the filtered magnesium. Unlike the adult proximal convoluted tubule that of young rats (aged 13-15 days) reabsorbs 50-60% of filtered magnesium along the proximal tubule together with sodium, calcium, and water. Micropuncture experiments, in every species studied to date, indicates that a large part (approximately 60%) of the filtered magnesium is reabsorbed in the loop of Henle. Magnesium reabsorption in the loop occurs within the cortical thick ascending limb (cTAL) by passive means driven by the transepithelial voltage through the paracellular pathway. Micropuncture experiments have clearly showed that the superficial distal tubule reabsorbs significant amounts of magnesium. Unlike the thick ascending limb of the loop of Henle, magnesium reabsorption in the distal tubule is transcellular and active in nature. Many hormones and nonhormonal factors influence renal magnesium reabsorption to variable extent in the cTAL and distal tubule. Moreover, nonhormonal factors may have important implications on hormonal controls of renal magnesium conservation. Dietary magnesium restriction leads to renal magnesium conservation with diminished urinary magnesium excretion. Adaptation of magnesium transport with dietary magnesium restriction occurs in both the cTAL and distal tubule. Elevation of plasma magnesium or calcium concentration inhibits magnesium and calcium reabsorption leading to hypermagnesiuria and hypercalciuria. The identification of an extracellular Ca2+/Mg2+ -sensing receptor located on the peritubular side of cTAL and distal tubule cells explains this phenomenon. Loop diuretics, such as furosemide and bumetanide, diminish salt absorption in the cTAL whereas the distally acting diuretics, amiloride and chlorothiazide stimulate magnesium reabsorption within the distal convoluted tubule. Finally, metabolic acidosis, potassium depletion or phosphate restriction can diminish magnesium reabsorption within the loop and distal tubule. Research in the 90's have greatly contributed to our understanding of renal magnesium handling.

Animals↗
PubMedDate not supplied

Physiology and molecular biology of renal carbonic anhydrase.

Carbonic anhydrase (CA) is an important enzyme in the kidney and facilitates renal acidification by catalvzing the reversible hydration of CO2 and the dehydration of bicarbonate. Currently, 14 isoforms of CA have been identified, of which CA II, CA IV, CA XII and possibly CA XIV are expressed by the kidney. Cytosolic CA II comprises -95% of renal CA, with the remainder being membrane-associated. CA II, while being nearly ubiquitous in the body, is also expressed by a large number of nephron segments, including proximal convoluted and straight tubules, thin descending limbs of Henle's loop, thick ascending limbs of Henle's loop in some species, intercalated cells of the cortical and medullary collecting ducts, and weakly in principal cells and inner medullary collecting ducts of some species; CA II is not found in glomeruli. Most membrane-associated CA is attributed to isoform IV, which is linked to the apical membrane via a glycosylphosphatidylinositol anchor; however, there is data showing that CA IV is also localized on the basolateral membranes of proximal tubule cells. How the basolateral form is linked to the membrane is not yet understood. CA IV is expressed on the luminal membrane of proximal convoluted and straight tubules, alpha-intercalated cells of cortical and medullary collecting ducts, and all cells of initial inner medullary collecting ducts. Another membrane isoform, CA XII, is also present in the kidney and probably situated in the basolateral membrane as a single-pass transmembrane protein. One study localizes CA XII to the distal nephron, while another places it in proximal tubules and inner medullary collecting ducts; confirmatory studies are needed for CA XII. The localization of CA XIV in the kidney is still under investigation. Functional studies clearly show the importance of apical and basolateral membrane CAs in mediating bicarbonate and fluid absorption in proximal tubules and of the apical membrane CA activity in mediating H+ secretion in the collecting duct. To establish other roles for CA in the kidney will require further kinetic, functional, immunolocalization and cloning studies.

Animals↗
PubMed1986

Effect of atrial natriuretic factor on adenylate cyclase in various nephron segments.

The effects of rat synthetic atrial natriuretic factor (ANF) [Arg101, Tyr126] were studied on adenylate cyclase activity in various renal structures such as glomeruli, proximal tubules, loops of Henle, and collecting ducts from dog kidney. ANF inhibited adenylate cyclase activity in glomeruli, loops of Henle, and collecting ducts, but not in proximal tubules, in a concentration-dependent manner. The maximal inhibitions observed were approximately 45% in glomeruli and collecting ducts with an apparent Ki of 10(-10)-10(-9) M and 30% in loops of Henle with an apparent Ki of 10(-11)-5 X 10(-10) M. ANF also inhibited the stimulatory responses of various hormones and forskolin on adenylate cyclase in glomeruli, collecting ducts, and loops of Henle. However, the extent of inhibition varied in the three fractions. In addition, ANF showed an additive effect with the inhibitory response of angiotensin II on adenylate cyclase in glomeruli. These data indicate that ANF receptors coupled to adenylate cyclase are present in glomeruli, loops of Henle, and collecting ducts and not in proximal tubules, and it can be suggested that the inhibition of adenylate cyclase by ANF may be one of the mechanisms through which ANF regulates kidney functions.

Adenylyl Cyclase Inhibitors↗
PubMed1981

Exaggerated natriuresis in the hypertensive man: clinical evidence for intrarenal hemodynamic heterogeneity.

7 hypertensive patients (H) and 8 normotensive volunteers (N) were loaded with NaCl (4.5 mEq Na +/kg body weight i.v.) during water diuresis (A) and antidiuresis (B). In 6 antidiuretic subjects (3H and 3N) urine volume (V) was progressively raised up to over 30 ml/min, by intravenous infusion (12 ml/min) of hypertonic (3%) saline (C). It is assumed that in (A) CH2O is an index of Na+ reabsorption in short Henle's loops. In (B) and (C) TcH2O is proportional to Na+ reabsorption in long Henle's loops. In (A) CcH2O was significantly lower in H. In (B) TcH2O was similar in H and N. In (C), TcH2O reached an earlier plateau in H than in N. These results demonstrate that exaggerated natriuresis depends on defective Na+ reabsorption in Henle's loops, suggesting that the defect depends upon the transmission of hypertension to medullary circulation. The increase in hemodynamic pressure in vasa recta opposes Na+ reabsorption both in short and in long Henle's loops. However, the effects on TcH2O of the decrease in Na+ reabsorption in long loops is blunted by the greater Na+ delivery, secondary to the increase in GFR, that follows the rise in filtration pressure.

Adult↗
PubMed1986

Angiotensin II binding sites in individual segments of the rat nephron.

The sites of action of angiotensin II along the nephron are not well defined and both proximal and distal effects are suggested. Using a microassay that permits measurement of hormone binding in discrete tubule segments, we determined the binding sites of 125I-angiotensin II along the nephron of Sprague-Dawley rats. Specific binding in proximal convoluted tubule (PCT) (at 25 degrees C, pH 7.4) was linearly related to tubule length and saturable, with an apparent maximal binding capacity of approximately 300 amol X cm-1. Binding specificity was verified in competition experiments that revealed significant (P less than 0.001) and comparable competition for radioligand binding by angiotensin II and angiotensin precursor, metabolite, and analogues, whereas unrelated peptides of similar size (bradykinin, ACTH [1-10]) were without effect. The profile of specific angiotensin II binding along the nephron was: PCT, 216 +/- 13; pars recta, 86 +/- 14; medullary thick ascending limb of Henle's loop, 46 +/- 8; cortical thick ascending limb of Henle's loop, 77 +/- 8; distal convoluted tubule, 49 +/- 10; cortical collecting tubule, 15 +/- 1; medullary collecting tubule, 32 +/- 7 amol X cm-1. These results indicate the presence of specific angiotensin II binding sites in all tubule segments studied, but binding capacity was highest in the proximal convoluted tubule, in agreement with transport studies that localize the effects of the hormone in this segment.

Angiotensin II↗
PubMed1994

Urinary tract glycoprotein: distribution and antigenic specificity.

It has previously been demonstrated that the urinary tract contains a unique glycoprotein (GP1) that appears to serve a function in the clearance of pathogenic bacteria. We prepared a panel of monoclonal antibodies (mAbs) to human GP1 and examined its antigenic specificity and distribution in the human urinary tract. This was also observed in relation to another glycoprotein associated with infection, Tamm-Horsfall protein (THP), as well as to URO-5, a protein used in identifying the lower urinary tract. In enzyme-linked immunoadsorbent assays (ELISA), all of the GP1 mAbs reacted with GP1 prepared from both human urine and rabbit bladder mucosa. No immunoreactivity was observed with either THP mAbs or URO-5 mAbs. Western-blot analyses using GP1 mAbs with human urine GP1 preparations detected a single band of approximately 50-52 kDa. Human urinary tract tissues were also examined by immunohistochemical techniques using the GP1 mAbs, commercial THP, and URO-5 mAbs. In paraffin-embedded bladder sections, only GP1 mAbs reacted with the urothelium. Selective staining of distal collecting tubules, renal pelvis, and ureters was demonstrated for GP1 mAbs. Proximal convoluted tubules, loops of Henle, and Bowman's capsule failed to stain for GP1. In the same tissues, THP mAbs reacted with the thick and thin segments of medullary loops of nephrons (Henle's loops). URO-5 mAbs stained fresh frozen sections of bladder urothelium, distal collecting tubules, and portions of Henle's loops; however, they failed to stain paraffin-embedded tissue sections. These GP1 mAbs provide a new tool for biochemical and histochemical investigations of the mucin layer in both healthy and diseased urinary tract tissue.

Animals↗
PubMed1983

Studies on the renal receptors of loop diuretics.

The principal renal action of loop diuretics is to inhibit active NaCl transport in the thick ascending limb of the loop of Henle. However, apart from their specific tubular action, kidney function may be affected in other ways. By employing the enantiomeres of the new loop diuretic ozolinone, non-stereospecific increase in renal blood flow and inhibition of tubular secretion of p-aminohippurate and urate were found. In contrast, electrolyte transport in the loop of Henle was inhibited stereospecifically. Perfusion of single loops of rat kidneys in vivo with sugar-specific lectins suggested that a fucose-containing glycoprotein is involved in electrolyte transport in this tubular segment. Loop diuretics might interact with this glycoprotein, leading to inhibition of electrolyte transport. Evidence is presented to suggest that this protein is the Tamm-Horsfall protein. This fucose-containing glycoprotein is localized in the cell membranes of the thick ascending limb of the loop of Henle. It binds furosemide at concentrations very close to those required for inhibition of electrolyte transport in vivo. Furthermore, there is complete agreement between the sodium concentration necessary for stimulation of active transport in isolated thick ascending limbs of the loop of Henle and that necessary for binding of furosemide to the Tamm-Horsfall glycoprotein.

Animals↗
PubMed1975

Effects of diuretic states on collecting duct fluid flow resistance in the hamster kidney.

Hydrostatic pressures were measured in cortical tubules, long loops of Henle, terminal collecting ducts, and in vasa recta in hamsters. In hydropenia, the loops of Henle and terminal collecting ducts provided the major fluid flow resistances, as judged by the location of hydrostatic pressure drops. In mannitol or saline diuresis, hydrostatic pressures in all tubular segments increased, but pressure drops in loops of Henle disappeared, indicating dilatation of loops. The major pressure drop was in terminal collecting ducts, especially in ducts of Bellini, even though these tubular segments also dilated. At highest urine flows, cortical tubule pressures were higher with the ureter and renal pelvis intact than when they were excised, suggesting laminar flow in the ureter adds a flow resistance at high flows. The pressure drop across the medullary capillary bed was 1-2 mmHg. The summation of medullary capillary hydrostatic and colloid osmotic pressures favored fluid uptake from the interstitium, a relationship enhanced by vasa recta geometry which ensures that descending vasa recta offer 4 times the flow resistance of ascending vessels.

Animals↗
PubMed1983

Tubular reabsorptive capacity for magnesium in the dog kidney.

Micropuncture studies were performed on 27 thyroparathyroidectomized dogs to determine the segmental reabsorption of magnesium before and after graded magnesium infusion. Overall kidney reabsorption, as determined by the difference between filtered magnesium and urinary excretion, initially increased with elevation of plasma magnesium up to 3.5 meq/liter. Further elevation of plasma magnesium resulted in the appearance in the urine of all additional increments in filtered magnesium. Thus, renal magnesium reabsorption followed a pattern characteristic of a maximal transport rate (Tm). Evaluation of the proximal tubule by micropuncture demonstrated that net reabsorption of magnesium rose proportional to the increase in filtered magnesium and accounted for a constant fractional reabsorption of 14%. In contrast, magnesium reabsorption in Henle's loop initially increased with low delivery rates but peaked and fell with high plasma magnesium concentrations. Little magnesium reabsorption was observed between the distal collection site and final urine. Accordingly, the overall urinary excretion pattern was a summation of the different effects occurring in the proximal tubule and Henle's loop. Thus, renal magnesium reabsorption is not characterized by a Tm process but is a composite of distinct transport properties of the proximal tubule and the loop of Henle.

Absorption↗
PubMed1992

Distal nephron function in Bartter's syndrome: abnormal conductance to chloride in the cortical collecting tubule?

Five patients with the clinical patterns of Bartter's syndrome underwent a series of clearance studies in order to characterize the underlying tubule defect. Free water generation during maximal water diuresis (CH2O), expressed as percentage of the distal delivery (CH2O + CCl), was lower in the patients (72.5 +/- 3.2%) than in controls (84.4 +/- 5.5, p < 0.0001). During maximal water diuresis and furosemide administration (40 mg i.v. as bolus), NaCl reabsorption along the diluting nephron segments could be separated into 2 components, that occurring in the loop of Henle (DRNaHL) and that occurring in tubule segments beyond the macula densa (DRNaDT): DRNaHL was normal, while DRNaDT was reduced (3.1 +/- 0.8 vs. 6.2 +/- 2.5 ml/min in controls, p < 0.015). Thus, according to this furosemide protocol, our patients had normal solute reabsorption in the loop of Henle but reduced NaCl reabsorption in tubule segments beyond the macula densa. During 0.9% saline infusion (2 liters in 2 h, after stimulation of distal Na reabsorption with fludrocortisone) fractional excretion (FE) of K showed a linear rise with the increase of FECl-FEK, however, was much higher in the patients than in controls for every FECl level. In contrast, the infusion of Na2SO4, after fludrocortisone administration, induced similar FEK increases in patients and in controls. Thus, in these patients Na reabsorption in the distal nephron (possibly the cortical collecting tubule) was associated with the generation of a higher than normal electric potential gradient in the presence of Cl but not of another poorly reabsorbable anion, such as SO4(2-). These observations indicate that, in our patients, Henle's loop function is normal, while the collecting tubule function is abnormal. We suggest that NaCl wasting and enhanced tubular secretion of H+ and K in our patients might result from an abnormally low conductance to Cl in distal nephron site(s) where Na reabsorption is electrogenic, possibly the cortical collecting tubule. A larger than normal transtubular electric gradient would be generated by Na reabsorption, causing: (1) a direct stimulation of tubular secretion of K and H+ (leading to hypokalemia and alkalosis) and (2) inhibition of the reabsorption of Na ('trapped' into the tubular lumen by electric forces), with consequent extracellular volume contraction, hyperreninemia and hyperaldosteronism.

Adolescent↗
PubMed1987

Transepithelial ammonia concentration gradients in inner medulla of the rat.

Transport of NH3 from loops of Henle to medullary collecting ducts has been proposed to play an important role in renal ammonia excretion. To determine whether transepithelial ammonia concentration gradients capable of driving this transport are present in the inner medulla, micropuncture experiments were performed in control rats and in rats with chronic metabolic acidosis. In situ pH and total ammonia concentrations were measured to calculate NH3 concentrations ([NH3]) for base and tip collecting duct, loop of Henle, and vasa recta. In control and acidotic rats, [NH3] in the loop of Henle was significantly greater than [NH3] in the collecting ducts. [NH3] did not differ in loop of Henle and adjacent vasa recta in either group of rats, indicating that NH3 concentration gradients between loop and collecting duct represent NH3 gradients that are present between medullary interstitium and collecting duct. During acidosis, an increase in collecting duct ammonia secretion was associated with an increase in the NH3 concentration difference between loop of Henle and collecting duct but occurred in the absence of a fall in collecting duct pH. The NH3 concentration gradient favoring diffusion of NH3 into the collecting ducts increased during acidosis because [NH3] in the loop of Henle and medullary interstitium increased more than [NH3] in the collecting duct. These findings indicate that transport processes involved in medullary ammonia accumulation play an important role in regulating ammonia secretion into the inner medullary collecting duct in vivo and that a fall in inner medullary collecting duct pH is not necessarily required for ammonia secretion by this segment to increase during chronic metabolic acidosis.

Acidosis↗
PubMed1996

TGF and nitric oxide: effects of salt intake and salt-sensitive hypertension.

The tubuloglomerular feedback response (TGF) entails vasoconstriction of the afferent arteriole (AA) and a fall in the glomerular capillary pressure (PGC) and single nephron glomerular filtration rate (SNGFR) during NaCl reabsorption in the macula densa (MD) segment. Recent studies have concluded that nitric oxide (NO) is synthesized by the MD and blunts the TGF response. Since a high salt (HS) diet has been found to blunt TGF, we tested the effects of salt intake on the response to blockade of nitric oxide synthesis. For the first series, the TGF was assessed from changes in proximal stop-flow pressure (PSF, an index of PGC in response to graded perfusion of the loop of Henle (LH) with name tubular fluid (NTF). Loop perfusion with 10(-3) M L-NMA did not affect the PSF responses of low salt (LS) rats, but reduced (P < 0.01) the PSF of HS rats during perfusion at 20 nl.min-1 (-1.5 +/- 0.4 mm Hg; P < 0.01) and at 40 nl.ml-1 (-2.2 +/- 0.5 mm Hg; P < 0.001). For the second series, the TGF responses of salt sensitive Dahl/Rapp (ssDR) rats were compared to Sprague-Dawley (SD) rats. Both groups were studied 8 to 10 days after starting HS or LS diets by loop perfusion of artificial tubular fluid at 40 nl.min-1. Compared to Sprague-Dawley rats, the ssDR had blunted maximal TGF responses during LS (SD, 8.2 +/- 0.3 vs. ssDR, 6.4 +/- 0.3 mm Hg; P < 0.001), but not during HS. During LS intake, addition of L-NMA to ATF perfusing the loop of Henle did not alter the maximal TGF response of either strain. However, during HS intake L-NMA increased the maximal TGF response of SD rats (4.4 +/- 0.4 to 6.7 +/- 0.5 mm Hg; P < 0.001) but did not significantly change the PSF of ssDR rats (5.2 +/- 0.3 to 5.7 +/- 0.5 mm Hg; NS). We conclude that the TGF response is enhanced by blockade of NOS during HS, but not LS intakes; this response to NOS blockade during HS intake is lost in salt sensitive Dahl/Rapp rats.

Animals↗
PubMed1996

Mechanism of the impaired natriuretic response to frusemide during sodium depletion: a micropuncture study in rats.

1. The nephron sites involved in the blunted natriuretic response to frusemide during sodium depletion were investigated using micropuncture techniques in anaesthetized rats. 2. Glomerular filtration rate was lower, and fractional sodium reabsorption in the proximal convoluted tubule higher, in sodium-depleted than in sodium-replete rats. Consequently, sodium delivery to the loop of Henle was reduced (by approximately 35%) in the sodium-depleted animals. Intravenous frusemide (2.5 mg h-1 kg-1; urinary water and electrolyte losses replaced) had no effect on glomerular filtration rate or proximal tubular sodium reabsorption in either group. 3. The inhibitory effect of intravenous frusemide on fractional sodium reabsorption in the nephron segments constituting the loop of Henle (measured by free-flow micropuncture) was attenuated during sodium depletion. However, when loops of Henle were microperfused at identical rates with artificial late proximal tubular fluid, no difference in the responses of sodium-depleted and sodium-replete rats to intraluminal frusemide (10(-5) mol/l) could be detected. 4. In sodium-replete animals, the increased load of sodium delivered from the loop of Henle during frusemide administration resulted in a lowering of fractional sodium reabsorption in the distal tubule. In contrast, in sodium-depleted rats given frusemide, fractional distal sodium reabsorption tended to increase, so that values in the two groups of frusemide-treated animals were markedly different (0.30 +/- 0.04 versus 0.51 +/- 0.03). 5. It is concluded that the blunted natriuretic response to frusemide during sodium depletion results from at least three factors: a reduced sodium delivery to the loop of Henle; a reduced inhibitory effect of frusemide on fractional sodium reabsorption in the loop of Henle, which may be a consequence of the reduced sodium load; and enhanced fractional reabsorption of sodium in the distal tubule, which partially buffers the diuretic-induced increase in sodium delivery from the loop.

Animals↗
PubMed1987

Effect of vasopressin on Na+-K+-ATPase activity in rat cortical collecting duct.

Vasopressin (V) causes a sustained increase in Na reabsorption and K secretion in isolated cortical collecting ducts (CCD) from rats. Because increased Na reabsorption may be associated with increased Na+-K+-ATPase activity, we investigated effects of V, given either in vivo or in vitro, on Na+-K+-ATPase activity in isolated nephron segments of rats. Na+-K+-ATPase activities were measured by coupling the hydrolysis of ATP to the production of a fluorescent nucleotide. In addition to CCD, other microdissected structures were medullary thick ascending limbs of Henle's loop, cortical thick ascending limbs of Henle's loop, and outer medullary collecting duct. To determine the time course of the response, Na+-K+-ATPase activities were measured in CCD 1 h, 3 h, 1 day, 3 days, and 7 days after intramuscular administrations of V. There was a significant increase in Na+-K+-ATPase activity in CCD after in vivo V administration for 7 days but not in any other segment. The activities increased after 3 days of administration of V. For in vitro experiments, CCD were incubated with 10(-6) M V for 1-3 h. Na+-K+-ATPase activities did not change after 1- or 3-h exposure of V in CCD in vitro. We conclude that prolonged V administration in vivo increases Na+-K+-ATPase activity in CCD. Because, in vitro exposure to V does not increase Na+-K+-ATPase activity, we conclude that rapid V-dependent increases in Na and K transport previously demonstrated in isolated perfused tubules are not dependent on a change in maximal Na+-K+-ATPase activity.

Animals↗
PubMed1989

Evaluation of lithium clearance as a marker of proximal tubule sodium handling.

Estimations of proximal tubule sodium reabsorption with the FELi method come closer to direct measurements than any other indirect method. There is little doubt that most lithium reabsorption takes place in the proximal tubules, very likely in proportion to the reabsorption of sodium and water. It is also likely that changes in proximal tubule sodium reabsorption due to changes in volume status are paralleled by changes in proximal tubule lithium reabsorption, at least in the superficial nephrons. Nonetheless, changes in FELi probably do not purely reflect changes in proximal reabsorption, since lithium is also handled beyond the proximal tubules. Acknowledged problems are lithium reabsorption in Henle's loop and in the late distal and collecting tubules. The latter occurs in the rat and the dog, but not or much less in men. Sodium restriction enhances this lithium transport considerably. It is as yet uncertain whether other conditions, such as increased vasopressin activity or lowering of renal perfusion pressure, also influence this transport. Amiloride appears to prevent this reabsorption of lithium. Therefore, this drug can be used in lithium clearance studies whenever unwanted "distal" lithium reabsorption is expected. Lithium reabsorption in Henle's loop forms a greater problem as it cannot be prevented by any drug without influencing proximal tubule reabsorption. It is estimated that about 7% of the filtered lithium (one-tenth of total lithium reabsorption) is normally taken up here, preferentially in deep nephrons. In view of studies with furosemide, this reabsorption probably varies with sodium intake, but the proportion of this variation to that of proximal tubule lithium reabsorption is obscure. This remains an uncertain factor in any circumstance where the lithium clearance method is used. In some conditions the change in FELi may be so large relative to the expected changes in proximal reabsorption, that use of FELi as marker of end-proximal solute delivery seems unjustified. Disproportionately large suppression is likely during mineralo-corticoid-induced volume expansion, and stimulation during prostaglandin synthesis inhibition and vasopressin. Based on observations in these conditions the potential range of lithium reabsorption in the loop of Henle would be 0 to 15% of filtered load. In this review attention was paid mainly to the validity of lithium clearance as a pure "proximal marker". Many of our interpretations suffer from incomplete certainty with respect to the renal effects of tested maneuvers, a problem which is acknowledged.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Evaluation of the renal site of action of a novel, eukalemic diuretic, ICI 207,828.

ICI 207,828 is a novel eukalemic diuretic in animals that is comparable in effect to hydrochlorothiazide. We used micropuncture and microperfusion techniques to determine the site(s) of action of this compound in the rat nephron. Either furosemide (FUR) or ICI 207,828 were perfused through the loop of Henle in situ. Both compounds caused significant reduction in water and electrolyte reabsorption by the loop. The effect of ICI 207,828 was significantly less than that of FUR. Both amiloride and ICI 207,828 were perfused, in situ, through the superficial distal tubule. ICI 207,828 had an effect similar to amiloride. Sodium and water reabsorption and potassium secretion were inhibited. In free-flow micropuncture studies, ICI 207,828, infused continuously i.v., had little effect on electrolyte and water reabsorption by the superficial proximal tubule. This compound significantly inhibited water and electrolyte reabsorption by the loop of Henle. Distal tubule secretion of potassium was inhibited. In addition, fractional potassium reabsorption beyond the superficial, late distal tubule was inhibited by ICI 207,828. From these results, we conclude that ICI 207,828 significantly inhibits electrolyte and water transport by the loop of Henle and distal tubule, and at sites beyond the superficial distal tubule such as either the collecting duct system or juxtamedullary nephrons. The reduction in distal potassium secretion, in concert with reduced loop of Henle and postdistal reabsorption, results in no net potassium loss in the urine, thus rendering this compound eukalemic.

Amiloride↗
PubMed1994

Renal magnesium handling and its hormonal control.

Our understanding of renal Mg handling has been expanded in recent years with the use of electron probe, ultramicroanalysis, and fluorescent dye techniques to determine total Mg and free Mg2+ in individual tubule segments and cells, respectively. Recent studies have shown that [Mg2+]i is a highly mobile cation that may be altered by a number of influences including hormones. It is likely that the hormonal changes in [Mg2+]i, reported here and elsewhere, are involved in intracellular metabolism and regulation rather than transepithelial transport. The role of intracellular Mg2+ in control of cell function is poorly understood. However, it is evident that [Mg2+]i may be rapidly charged through a number of different influences that may have important effects on cell function. These kinds of data have enlarged our understanding of Mg conservation by the renal tubule but have posed many questions for further study. Magnesium is handled in different ways along the nephron. About 80% of the total plasma Mg (1.5-2.0 mM) is ultrafilterable across the glomerular membrane. Of the ultrafilterable Mg (1.2-1.6 mM), only 20-25% is reabsorbed by the proximal tubule, including the convoluted and straight portions. This is in contrast to Na and Ca reabsorption, which amounts to approximately 70 and 60%, respectively, in the proximal nephron. Accordingly, the fractional delivery of Mg to the thick ascending limb of the loop of Henle is much greater than that of Na or Ca. It is now evident from micropuncture studies that proportionally greater amounts of Mg (50-60%) are reabsorbed in the loop compared with Na (20-25%) or Ca (30-35%). Because the terminal nephron segments, including the DCT and collecting tubule, reabsorb only a small portion of the filtered Mg (approximately 5%), the loop of Henle plays a major role in the determination of Mg reabsorption, and it is in this segment that the major regulatory factors act to maintain Mg balance. Magnesium reabsorption in the thick ascending limb takes place in the cortical segments, at least in the mouse and rat. Evidence summarized here suggests that Mg is passively reabsorbed via the paracellular pathway in the cTAL of the loop of Henle. Several factors affect Mg reabsorption in the loop of Henle. Hypermagnesemia and hypercalcemia inhibit reabsorption leading to increased urinary excretion of Mg and Ca. These effects have been reviewed in detail elsewhere (113, 149). Magnesium depletion, for instance through dietary Mg deprivation, enhances Mg reabsorption in the loop of Henle before the fall in plasma Mg concentration and filtered Mg load.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗