UNIPROT:P41181 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P41181 (collecting duct)
5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diuretics act primarily by blocking reabsorption of sodium at four major sites in the nephron. Clinically useful agents that block sodium reabsorption effectively in the proximal tubule are lacking. Furosemide (Lasix), ethacrynic acid (Edecrin), and possibly organomercurial agents are effective in the ascending limb of Henle's loop. Thiazides are the major agents acting in the early distal tubule. In the late distal tubule and collecting duct, spironolactone (Aldactone) and triamterene (Dyrenium) are useful, especially in combination with diuretics which act more proximally. In treating edematous states, initial therapy with thiazides is effective in most patients who do not exhibit moderate or severe renal insufficiency, severe hyperaldosteronism with excessive distal reabsorption of sodium in exchange for potassium, or excessive sodium reabsorption in the proximal tubule or ascending limb. Nonedematous states in which diuretic therapy is useful include hypertension, hypercalcemia, hypercalciuria, diabetes insipidus, and acute renal failure.
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PMID:Diuretic agents. Mechanisms of action and clinical uses. 126 95

Free-flow micropuncture and in situ microperfusion techniques were used to define the site of action and relative effect of MK447 [2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride] vs. furosemide in the rat kidney. MK447 was administered i.v. at 5 mg/kg/hr. Infusion of this drug had little effect on proximal tubule reabsorption of water, Na+ and K+. In contrast, reabsorption of these constituents by the loop of Henle was significantly reduced. There was a tendency for water and Na+ reabsorption to rise and for K+ secretion to fall along the distal tubule. These latter effects can be explained by the contributions of an increased distal flow rate and increased tubule fluid K+ concentration. Net addition of K+ beyond the distal tubule was observed. This may be due to effect of the drug on the collecting duct system or juxtamedullary nephrons. The effects of MK447 and furosemide on loop of Henle reabsorption were compared in microperfusion experiments. Furosemide reduced Na+, K+ and water reabsorption by the loop, whereas MK447 had no effect. A 6-bromophenol sulfate ester of MK447 significantly reduced loop reabsorption. From these observations, we conclude that MK447 affects water and electrolyte reabsorption by the loop of Henle and beyond the superficial late distal tubule. The fact that a potential metabolite, but not MK447, significantly reduced reabsorption by the in situ, perfused loop of Henle supports the hypothesis that the p.o. and i.v. effects of MK447 are dependent on metabolism.
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PMID:Micropuncture evaluation of the site of action of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK447) in the rat kidney. 199 96

To determine the exact site and mechanism of action of thiazide diuretics, effects of 10(-4) M trichlormethiazide (TCM) on NaCl transport were examined in the distal convoluted tubule (DCT), the connecting tubule (CNT) and the cortical collecting duct (CCD) of rabbit kidney by the in vitro microperfusion technique. TCM added to the lumen decreased lumen-to-bath 36Cl flux (JCl(LB)) only in the CNT without changing the transmural voltage (VT). In the DCT, 10(-4) M furosemide did not change JCl(LB) even if it was added to the lumen with 10(-4) M TCM, whereas 10(-5) M amiloride in the lumen decreased the lumen-to-bath 22Na flux (JNa(LB)) and VT. In the CNT, TCM added to the lumen did not affect the bath-to-lumen 36Cl flux. Addition of TCM to the bath slightly decreased JCl(LB). Luminal addition of 10(-4) M TCM also decreased JNa(LB). Amiloride at 10(-5) M in the lumen decreased both JNa(LB) and VT. Addition of TCM with 10(-5) M amiloride further decreased JNa(LB) without affecting VT, indicating that TCM affects the electroneutral Na+ transport, which is distinct from the amiloride-sensitive conductive Na+ pathway. When Na+ was removed from the lumen, JCl(LB) was markedly decreased, but addition of TCM did not cause further decrease in JCl(LB). Furosemide did not affect JCl(LB), but addition of both 10(-4) M TCM and furosemide decreased JCl(LB), indicating that Na+-K+-2Cl- cotransport is not involved in the action of TCM. Removal of HCO3- slightly decreased JCl(LB), and TCM caused further decrease in JCl(LB). Amiloride at 10(-3) M, a concentration supposed to inhibit the Na+/H+ antiport, slightly decreased JCl(LB), and addition of TCM caused a further marked decrease in JJl(LB). The similar results were also obtained when the combined effects of 10(-3) M 4,4'-diisothiocyano-stilben-2,2'-disulfonate(DIDS) and 10(-4) M TCM were examined. These findings suggest that the parallel antiport of Na+/H+ and Cl-/HCO3- is not involved in the action of TCM. By excluding other possible mechanisms involving neutral Na+-dependent Cl- transport, we conclude that TCM inhibits Na+-Cl- cotransport in the luminal membrane of the rabbit CNT.
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PMID:Site and mechanism of action of trichlormethiazide in rabbit distal nephron segments perfused in vitro. 284 60

We examined the effects of a chronic increase in tubular sodium delivery on the structure of the distal convoluted tubule (DCT), connecting tubule (CNT), and cortical collecting duct of male Sprague-Dawley rats. Furosemide (12 mg/day) was administered by osmotic minipump for 6 days to increase the rate of sodium delivery to these segments and thereby stimulate sodium uptake. To prevent volume depletion, the furosemide-treated animals were given a drinking solution containing 0.8% NaCl and 0.1% KCl. Control animals were given vehicle (0.9% NaCl) by osmotic minipump and they drank tap water. Furosemide dramatically increased urinary fluid and sodium excretion and decreased urine osmolality threefold vs. control. Furosemide treatment was associated with an increase in epithelial volume of DCT cells, CNT cells, and principal cells and an increase in the basolateral membrane area and mitochondrial volume of each cell type. These alterations in cell structure were not related to changes in plasma aldosterone, glucocorticoid, or arginine vasopressin levels. We conclude that an increase in cell sodium uptake regulates the ultrastructure of the distal tubule.
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PMID:Adaptation of distal tubule and collecting duct to increased sodium delivery. I. Ultrastructure. 320 89

To assess the intrinsic effects of treatment with furosemide on free-water excretion in patients with chronic renal failure, two groups of patients with and without replacement of diuretic-induced salt losses have been studied. Furosemide therapy was administered for 1 week during constant sodium intake (100 mEq/day). In neither of the groups did furosemide cause hyponatremia, while it did decrease the urine to plasma osmolality ratio, an effect lasting even when the diuretic effect was exhausted. During water diuresis, furosemide decreased the fractional sodium reabsorption in diluting segments but not the absolute rate of the free-water generation (CH2O). Presumably the expected decrease of CH2O was masked by the increased distal delivery of tubular fluid mainly due to an additional effect of the diuretic on the proximal tubule. The hypotonicity of urine after furosemide treatment may be secondary to the dissipation of medullary hypertonicity, caused by furosemide, in the condition of decreased water permeability of the collecting duct due to uremic disease.
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PMID:Effects of furosemide therapy on free-water excretion in uremic patients. 323 71

The effect of furosemide on inner medullary collecting duct chloride reabsorption has not been determined, and the blunting of furosemide action by drugs that inhibit prostaglandin synthesis, while known to occur, has not been examined in detail. The effect of indomethacin and meclofenamate on furosemide diuresis was studied in the rat using clearance and collecting duct microcatheterization methods. Furosemide-treated control animals showed complete inhibition of chloride, sodium, and water reabsorption in the inner medullary collecting duct. Rats given indomethacin or meclofenamate before and during furosemide administration showed marked reduction of the chloriuresis, natriuresis, and diuresis. Reduced delivery of sodium and chloride to the beginning of the inner medullary collecting duct, associated with a decrease in glomerular filtration rate and increased reabsorption in more proximal nephron segments, was largely responsible for the reduced natriuresis and chloriuresis during inhibition of prostaglandin synthesis. In addition, indomethacin increased collecting duct NaCl reabsorption toward normal, but meclofenamate showed no such effect. The results indicate that furosemide inhibits medullary collecting duct reabsorption of chloride, sodium, and water in the rat. The blunting of diuretic action seen with inhibition of prostaglandin synthesis is largely, although not entirely, due to effects of indomethacin and meclofenamate on furosemide action at nephron sites proximal to the collecting duct.
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PMID:Furosemide action on collecting ducts: effect of prostaglandin synthesis inhibition. 685 58

Previously, we demonstrated that the mIMCD-K2 cell line, derived from the inner medullary collecting duct (IMCD) of a transgenic mouse, secretes Cl- by an electrogenic mechanism [N. L. Kizer, B. Lewis, and B. A. Stanton, Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F347-F355, 1995]. The objective of the present study was to characterize the cellular mechanisms of electrogenic Cl- secretion (IscCl) and to determine whether arginine vasopressin (AVP) and adenosine 3',5'-cyclic monophosphate (cAMP) stimulate IscCl. To this end, we measured IscCl across monolayers of mIMCD-K2 cells mounted in Ussing-type chambers. AVP increased IscCl with a Michaelis constant (Km) of 2.1 +/- 0.7 x 10(-12) M. 1-Desamino-8-D-AVP, a specific V2 receptor agonist, increased IscCl from 3.3 +/- 0.4 to 17.4 +/- 1.3 microA/cm2, 8-(4-Chlorophenylthio)-cAMP, a cell-permanent analogue of cAMP, a second messenger of AVP, increased IscCl from 1.4 +/- 0.3 to 15.2 +/- 1.2 microA/cm2. Furosemide and bumetanide, inhibitors of Na(+)-2Cl(-)-K+ cotransport, and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of Cl-/HCO3- exchange, reduced IscCl when added to the basolateral solution. Our data suggest that AVP, via V2 receptors, and the second messenger cAMP stimulate IscCl and that Cl- secretion by mIMCD-K2 cells involves uptake of Cl- across the basolateral membrane by Na(+)-2Cl(-)-K+ cotransport and Cl-/HCO3- exchange and diffusion out of the cells across the apical membrane by cystic fibrosis transmembrane conductance regulator Cl- channels.
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PMID:Vasopressin and cAMP stimulate electrogenic chloride secretion in an IMCD cell line. 777 14

Facilitated urea transport is regulated acutely by arginine vasopressin (AVP) and hyperosmolality in rat terminal inner medullary collecting duct (IMCD). This study tested whether chronic diuresis or antidiuresis regulates facilitated urea transport. Basal and AVP-stimulated urea permeabilities (Purea) were measured in perfused IMCD subsegments. Rats were made: (1) diuretic by giving them sugar water (with or without food) or furosemide; or (2) antidiuretic by water deprivation. They were then compared with untreated rats given food and water ad libitum. Terminal IMCD from untreated rats had a high basal Purea that was significantly increased by AVP. Diuresis significantly increased basal Purea in terminal IMCD in all five diuresis protocols. Water deprivation for 1 or 3 d had no effect on basal or AVP-stimulated Purea in the IMCD2 subsegment of the terminal IMCD. In contrast, 3 d of water deprivation significantly increased both basal and AVP-stimulated Purea in the IMCD3 subsegment; 1 d of water deprivation had no effect on basal or AVP-stimulated Purea. Next, initial IMCD (IMCD1) were studied. Initial IMCD from untreated rats had a low basal Purea that was not increased by AVP (10 nM). Water diuresis (with or without food) for 3 to 5 d had no effect on basal Purea but significantly increased AVP-stimulated Purea. Furosemide diuresis and water diuresis for 1 or 7 d had no effect on either basal or AVP-stimulated Purea in initial IMCD. Water deprivation for 2 to 3 d, but not for 1 d, significantly increased basal Purea in initial IMCD, whereas water deprivation for 1 d increased AVP-stimulated Purea. It is concluded that chronic changes in hydration cause heterogeneous changes in facilitated urea transport in rat IMCD subsegments.
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PMID:Long-term regulation of inner medullary collecting duct urea transport in rat. 959 70

While in vivo data suggests that diuretics such as furosemide and hydrochlorothiazide alter inner medulla collecting duct (IMCD) cell electrolyte transport, this has not been confirmed by in vivo studies nor have the mechanisms been evaluated. This study evaluated the direct effect of these diuretics as well as amiloride on sodium and chloride unidirectional permeability in the isolated perfused rat IMCD. In the absence of diuretics, the permeability of sodium was lower than that of chloride (0.63 +/- 0.05 compared with 0.83 +/- 0.08 micrometer/s), although both were relatively impermeable when compared to water. Furosemide (10(-4)) and hydrochlorothiazide (10(-3)) both increased the diffusional permeability of chloride by approximately 30% (0.80 +/- 0.06 to 1.04 +/- 0.09 micrometer/s, p < 0.01, and 0.74 +/- 0.09 to 0.98 +/- 0.10 micrometer/s, p < 0.02, respectively). However, sodium permeability was unaltered. Inhibition of Na+, K+-ATPase by ouabain or cooling (4 degrees C) inhibited basal sodium but not chloride permeability while a maximal antidiuretic AVP concentration did not alter sodium or chloride permeability. However, increasing the lumen and bath sodium chloride concentration from 150 to 300 and 600 mM significantly increased both sodium and particularly chloride conductance. In contrast, amiloride (10(-4)) significantly reduced both sodium and chloride permeability. These studies support a direct effect of furosemide and hydrochlorothiazide on the IMCD and suggest that their in vivo effect is primarily mediated by facilitating the passive movement of chloride into the lumen via a favourable electrochemical gradient. These results also demonstrate that amiloride inhibits both sodium and chloride unidirectional permeability by mechanisms separate to that of the sulphonamide-related diuretics.
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PMID:Effect of diuretics on sodium and chloride permeability in the rat papillary collecting duct. 976 78

Loop-diuretic-sensitive 86Rb+(K+) transmembrane fluxes were determined in cells of a mouse inner medullary collecting duct cell line (mIMCD-K2). The furosemide-sensitive (0.1 mM) influx was a substantial fraction of the total influx (0.39+/-0.04 or 0.42+/-0.03, n=5 in the presence or absence of ouabain, respectively). Furosemide also reduced 86Rb+(K+) efflux by a similar fraction (0.46). RT-PCR analysis revealed expression of mRNA for the Na+-K+-2Cl- cortransporter-1 (NKCC1), but not NKCC2. Loop-diuretic-sensitive 86Rb+(K+) influx was confined to the basolateral membrane, confirming its localisation there. The physiological properties of NKCC1 expressed in mIMCD-K2 cells, including the dependence upon medium Na+, K+ and Cl- and the relative sensitivity to loop diuretics as assessed by the concentration required for half-maximal inhibition (IC50) (bumetanide 3.3+/-1.4x10-7 M>piretanide 2.5+/-0.15x10-6 M>furosemide 2.3+/-1.2x10-5 M) were typical for NKCC1. Possible functions of NKCC1 were tested; furosemide did not inhibit the majority of forskolin-stimulated secretory short-circuit current (Isc) (83.5+/-5.3% of the maintained response at 5 min). Secondly, total 86Rb+(K+) influx was stimulated markedly when external osmolarity was increased to 600 mosmol/l by mannitol due to an increase via NKCC1 from 55+/-11 to 191+/-2 nmol/106 cells per 15 min, (both n=4, P<0.01). In contrast, 10-5 M forskolin did not stimulate total 86Rb+(K+) influx. Finally, the ability of both K+ and NH4+ to compete for ouabain-insensitive 86Rb+(K+) influx via NKCC1 was confirmed with similar concentrations for half-maximal influx reduction (K0.5). Apical exposure to NH4+ elicited rapid cytosolic alkalinisation in 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-loaded epithelial layers, consistent with selective permeability of the apical membrane to NH3. Conversely, NH4+ (5 mM) at the basal cell surface resulted in progressive acidification, the initial rate being reduced by 43% by furosemide. We conclude that NKCC1 participates in selective uptake of NH4+ at the basal surface, and that IMCD may function in direct NH4+ deposition to urine.
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PMID:Expression and role of sodium, potassium, chloride cotransport (NKCC1) in mouse inner medullary collecting duct (mIMCD-K2) epithelial cells. 1169 76

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