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  • Phosphate transport  (4)
  • Dicarboxylate transport  (2)
  • Electron-attracting groups  (2)
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  • 1
    ISSN: 1432-2013
    Keywords: Electron-attracting groups ; Electron-donating groups ; Hydrophobicity ; Amiloride ; Cimetidine ; N-methyl-4-phenylpyridinium (MPP+)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to evaluate whether N-containing substrates interact with the organic “anion” (p-aminohippurate, PAH) or only with the organic “cation” (N 1-methylnicotinamide, NMeN) transport system or with both, the stop-flow peritubular capillary microperfusion method was applied in the rat kidney in situ and the apparent K i values of several classes or organic substrate against contraluminal NMeN and PAH transport were determined. Organic “anion” and organic “cation” transport are in inverted commas because neither transporter sees the degree of ionization in bulk solution, and they also accept nonionizable substrates [Ullrich KJ, Rumrich G (1992) Pflügers Arch 421:286–288]. Amines must be sufficiently hydrophobic (phenylethylamine, piperidine, piperazine) in order to interact with NMeN transport. Additional Cl, Br, NO2 or other electronegative groups render them inhibitory towards PAH transport also. Such bisubstrate amines were identified as follows: metoclopramide, bromopride, diphenhydramine, bromodiphenhydramine, verapamil, citalopram, ketamine, mefloquine, ipsapirone, buspirone, trazodone, H7 and trifluoperazine. Imidazole analogues interact with both transporters if they bear sufficiently hydrophobic alkyl or aryl groups or electronegative sidegroups. Bisubstrate imidazole analogues are tinidazole, pilocarpine, clonidine, azidoclonidine and cimetidine. Pyridines and thiazoles interact with the NMeN transporter if they have an additional ring-attached NH2 group. Again with an additional Cl, Br, or NO2 group the aminopyridines and aminothiazoles also become inhibitors for the PAH transporter. Amongst the guanidines only substances with several electronegative side-groups such as guanfacine, amiloride, benzylamiloride and ranitidine, interact with both transporters. Amongst the phenylhydrazines only 4-bromophenylhydrazine interacts with the NMeN transporter and 4-nitrophenylhydrazine with both transporters. Quinoline (isoquinoline) and its amino and hydroxy analogues interact with both transporters, their pKa values correlate directly with the affinity to the NMeN transporter and reciprocally with their affinity to the PAH transporter. In experiments with labelled substrates only the sufficiently hydrophilic cimetidine, amiloride and ranitidine show a saturable transport, which can be inhibited by probenecid (apalcillin) and tetraethylammonium in an additive manner. The highly hydrophobic substrates verapamil, citalopram, imipramine, diltiazem and clonidine enter the cell very fast in an unsaturable and uninhibitable manner, apparently in the undissociated form, since N-methyl-4-phenylpyridinium, which — disregarding its ionization — is similarly hydrophobic, shows a transport behaviour similar to that of tetraethylammonium [Ullrich et al. (1991) Pflügers Arch 419:84–92]. Ethidium bromide and dimidium bromide, which have a permanent cationic quaternary nitrogen and two sufficiently electronegative NH2 groups, also interact with both transporters. The data indicate that a molecule qualifies as a bisubstrate if it carries both the essentials for organic anion (PAH) transport: hydrophobicity, sufficient acidity or electron-attracting O, OH, Cl, Br, NO2 groups, plus the essentials for organic cation transport: hydrophobicity, sufficient basicity or electron-donating N-containing groups. The nitrogen atoms in the N-containing molecules quinoline (pK a 4.9), isoquinoline (pK a 5.4) and benzylpyridine (pK a 5.13) are of such low basicity that they apparently can also interact with the PAH transporter. Apparent hydrophobicity (disregarding ionization) determines interaction with the transporters, while real hydrophobicity [log (octanol distribution values)] determines the diffusion through the lipid bilayer of the cell membrane.
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  • 2
    ISSN: 1432-2013
    Keywords: Electron-attracting groups ; Electron-donating groups ; Hydrophobicity ; Corticosteroids ; Androstene analogues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to test what chemical structure is required for a substrate to interact not only with the contraluminal organic anion (p-aminohippurate, PAH) transporter, but also with the organic cation (N 1-methylnicotinamide, NMeN, or tetraethylammonium, TEA) transporter, the stop-flow peritubular capillary perfusion method was applied and app. K i values were evaluated. Zwitterionic hydrophobic dipeptides not only interact with PAH but also with NMeN transport although with lower inhibitory potency (K i,PAH=0.2–1.4; K i,NMeN 614 mmol/l). Amongst the zwitterionic cephalosporins, which all inhibit PAH transport, the amino cephalosporin analogue cefadroxil was identified to interact also with NMeN transport (K i,PAH = 3.0, K i,NMeN=11.2 mmol/l). All Zwitterionic naphthyridine and oxochinoline gyrase inhibitors tested inhibit NMeN transport with app. K i,NMeN values between 1.2 mmol/l and 4.7 mmol/l; the naphthyridine analogues show a good inhibitory potency against PAH transport (K i,PAH ≈ 0.4 mmol/l), the piperazine-containing quinolone analogues have a moderate inhibitory potency (K i,PAH=1.1–2.5 mmol/l) and the piperazine-containing pipemidic acid did not inhibit PAH transport at all. Zwitterionic thiazolidine carboxylate phosphamides also interact with both transporters (app. K i,PAH ≈ 3.0; app. K i,NMeN ≈ 18.0 mmol/l). The nonionizable oxo- and hydroxy-group-containing corticosteroid hormones also interact with the two transporters. (a) An OH group in position 21 is necessary for interaction with the PAH transporter, but not for interaction with the TEA transporter. (b) Introduction of an OH group in position 17α abolishes interaction with the TEA transporter, but has different effects with the PAH transporter. (c) Introduction of an OH group in position 6 abolishes interaction with both, the PAH and the TEA transporter. (d) A change of the side-group in position 11 of corticosterone from -OH to -H to=O enhances interaction with the PAH transporter but has no effect on the interaction with the TEA transporter. Nonionizable 4- or 5-androstene analogues inhibit both transporters with app. K i between 0.16 mmol/l and 0.64 mmol/l, if the steroids are soluble in a concentration greater than 1 mmol/l. Nonionizable oxazaphosphorins with more than one chloroethyl group interact with the PAH transporter with app. K i between 0.84mmol/l and 4.9mmol/l and with the NMeN transporter with app. K i between 3.2 mmol/l and 18.7 mmol/l. Thus a substrate interacts with both transporters if it is sufficiently hydrophobic, possesses acidic and/or electron-attracting plus basic and/or electron-donating groups, or possesses several electron-attracting nonionizable groups (O, OH, Cl). A certain spatial arrangement of the interacting groups seems to be necessary.
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  • 3
    ISSN: 1432-2013
    Keywords: Dicarboxylate transport ; Sulfate transport ; Benzoyl compounds ; Phenoxy compounds ; Valproate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to study the specificity of the contraluminal para-aminohippurate (PAH) transport system, the inhibitory potency of monocarboxylates on the3H-PAH influx from the interstitium into cortical tubular cells in situ has been determined. The following was found: if a homologous series of fatty acids with increasing chain length is tested, inhibition of contraluminal PAH influx is first seen with valerate (app.K i 1.4 mmol/l), increasing up to nonanoate (app.K i 0.06 mmol/l) and remaining in this range up to duodecanoate, the last compound of this series which is sufficiently water-soluble. Similarly, the inhibitory potency of aromatic monocarboxylates increases with increasing hydrophobicity. If the fatty acids are esterified, their inhibitory potency is lost. If they are transformed to the respective aldehydes their inhibitory potency is preserved at a reduced degree. Introduction of a hydrophobic methyl-, ethyl-, or propyl-group increases the inhibitory potency. A β-, but not an α-oxo-group augments the inhibitory potency of phenylpropionate analogs, an OH group diminishes it, and a NH2 group abolishes it. Among phenyl-fatty acids an increase in affinity is observed from phenyl- 〈 benzoylamine-〈 phenoxy- 〈 benzoyl-acetate and-propionate. All monocarboxylate compounds, so far tested, do not inhibit contraluminal sulfate and Na+/succinate influx. The data indicate that the PAH transporter interacts with monocarboxylates and also with aldehydes which have a hydrophobic moiety. An additional oxo-group facilitates the interaction. Thus, the benzoyl compounds show the highest affinity observed.
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  • 4
    ISSN: 1432-2013
    Keywords: Renal tubule ; Phosphate transport ; pH dependence ; Micropuncture ; Microperfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Early loops of the proximal convoluted tubule of parathyroidectomized rats (PTX-rats) were microperfused with a phosphate (4 mM) containing perfusate. With a perfusion solution of pH around 7.45 as estimated as anion deficit theP i reabsorption was two times greater than with a perfusion solution of pH around 6.85. TheP i reabsorption is reduced in PTX-rats made chronic alkalotic (PTX-cA-rats) but the same pH dependence ofP i reabsorption was found. The data indicate that the divalent phosphate is preferentially reabsorbed.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Pflügers Archiv 372 (1977), S. 269-274 
    ISSN: 1432-2013
    Keywords: Renal tubule ; Phosphate transport ; Parathyroidectomy ; Parathyroid hormone ; Phosphate diet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The standing droplet method was applied in combination with microperfusion of the peritubular blood capillaries to determine the build up of transtubular concentration differences of phosphate (Pi) in proximal convoluted tubules. As revealed in experiments with chronic parathyroidectomized (PTX) rats, the time dependent decrease of the intraluminal Pi concentration, or increase of transtubular Pi concentration difference ( $$\Delta {\text{c}}_{{\text{P}}_i }$$ ), changes along the proximal convolution in a ratio 4:2:1 in the first quarter: second plus third quarter: fourth quarter. In acute (〉2 h) PTX rats $$\Delta {\text{c}}_{{\text{P}}_i }$$ decreased by 31% in the first and by 41% in the fourth quarter of the convolution when parathyroid hormone (PTH; 5 U initially and 12 U/h continuously) was infused. In chronic (〉2 days) PTX rats the correspondent values of 17% and 29% were significantly smaller. When the rats were kept for 7–11 weeks on a low phosphate diet (〈0,15% P in the dry matter) their Pi transport was in the range of that of the PTX rats. PTH infusion, however, diminished the P i reabsorption rate in the fourth quarter of the convolution only, but not that in the early parts of the convolution. On the contrary, rats kept for the same time on a high phosphate diet (2%) showed all along the proximal convolution one by one third of the phosphate transport rate of animals on a low phosphate diet. Acute parathyroidectomy of the high P diet rats led to 51% increase in P i transport. The data show that 1. the phosphate transport decreases as a function of proximal convolution length, 2. PTH exerts a considerable inhibitory effect on P i transport only in acute PTX rats, while the effect in chronic PTX rats is rather small, 3. the P content of the diet inversely correlates with the P i transport. 4. further with low P diet the PTH inhibits P i transport in late, but not in early segments of the proximal convolution.
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  • 6
    ISSN: 1432-2013
    Keywords: Renal tubule ; Phosphate transport ; Paracellular shunt ; Calcium ; Ca2+ ionophore A 23187
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Proximal inorganic phosphate (P i ) transport was evaluated using the standing droplet method with simultaneous microperfusion of the peritubular blood capillaries. In chronic parathyroidectomized (PTX) rats addition of 3 μM of the Ca2+ ionophore A 23187 to the luminal perfusate had no effect on the P i transport, although the isotonic fluid reabsorption was reduced by 20%. When the Ca2+ concentration in the perfusates was raised from 1.5 mM to 3.0 mM the reabsorption did not change significantly. But when Ca2+ was omitted from the perfusates the P i reabsorption dropped by 19%, and when 2 mM EDTA were added to the perfusates P i transport decreased by 35%. The influx of P i from the interstitial space and from the cell into the phosphate-free luminal perfusate did not change, when the perfusates were Ca2+-free, but it increased by 23% in the presence of 2 mM EDTA. The data indicate that 1. a rise in intracellular Ca2+ above normal is not a factor which modifies “basal” P i transport i.e. when P i transport is independent of the action of parathyroid hormone. 2. A reduction of extracellular Ca2+ concentration from normal toward zero reduces P i transport without changing the paracellular leak permeability for P i . 3. With EDTA the paracellular leak permeability for P i is increased, thus causing an even greater reduction in net P i transport than with Ca2+-free solutions alone.
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  • 7
    ISSN: 1432-2013
    Keywords: Organic anion transport ; Sulfate transport ; Dicarboxylate transport ; Phenolate transport ; Salicylate transport ; Cinnamate transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to study the specificities of the contraluminal anion transport systems, the inhibitory potency of substituted benzene analogs on influx of [3H]PAH, [14C]succinate, and [35S]sulfate from the interstitium into cortical tubular cells has been determined in situ: (1) Contraluminal [3H]PAH influx is moderately inhibited by benzene-carboxylate and benzene-sulfonate, and strongly by benzene-dicarboxylates,-disulfonates and carboxy-benzene-sulfonates, if the substituents are located at positions 1 and 3 or 1 and 4. The affinity of the PAH transporter to polysubstituted benzoates increases with increasing hydrophobicity, decreasing electron density at the carboxyl group and decreasing pKa. Similar dependencies are observed for phenols. Benzaldehydes which do not carry an ionic negative charge are accepted by the PAH-transporter, if they possess a second partially charged aldehyde or NO2-group. (2) Contraluminal [14C]succinate influx is inhibited by benzene 1,3- or 1,4-dicarboxylates,-disulfonates and 1,3-or 1,4-carboxybenzene-sulfonates. Monosubstituted benzoates do not interact with the dicarboxylate transporter, but NO2-polysubstituted benzoates do. Phenol itself and 2-substituted phenol interact weakly possibly due to oligomer formation. (3) The contraluminal sulfate transporter interacts only with compounds which show a negative group accumulation such as 3,5-dinitro- or 3,5-dichloro-substituted salicylates. The data are consistent with three separate anion transport systems in the contraluminal membrane: The PAH transporter interacts with hydrophobic molecules carrying one or two negative charges (−COO−, −SO 3 − ) or two or more than two partial negative charges (−OH, −CHO, −SO2NH2, −NO2). The dicarboxylate transporter requires two electronegative ionic charges (−COO−, −SO 3 − ) at 5–9 Å distance or one ionic and several partial charges (−Cl, −NO2) at a favourable distance. The sulfate transporter interacts with molecules which have neighbouring electronegative charge accumulation.
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  • 8
    ISSN: 1432-2013
    Keywords: Renal tubule ; Phosphate transport ; Extracellular pH ; Intracellular pH ; Acetazolamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Inorganic phosphate (Pi) transport was evaluated using the standing droplet method with simultaneous microperfusion of the peritubular capillaries. To evaluate rather small differences in Pi transport and to eliminate the influence of tubular heterogeneity, the technique of crossed paired samples was applied. 1. In chronic PTX rat changing the luminal or both luminal and peritubular pH by varying the HCO 3 − -concentration between 4 and 50 mmol/l at constant 5% CO2 had no influence on Pi transport. 2. If, however, bicarbonate was omitted from the perfusate and 2 mmol/l phosphate (pH 7.4) was the only buffer, Pi transport was decreased from the control. It was, however, further reduced when the perfusates were gased with 5% CO2 i. e. the starting pH was 5.6. 3. When the solutions contained HEPES buffer (25 mmol/l), Pi transport at pH 8 was much larger than at pH 6.0. 4. Raising the CO2 pressure from 35 to 70 mm Hg did not change the Pi transport when both perfusates had a HCO 3 − -concentration of 25 mmol/l. It reduced, however, the Pi transport, when the luminal perfusate had only 4 mmol/l bicarbonate. 5. Lowering the CO2 pressure from 38 to 7.6 mm Hg did hardly change the Pi transport when the luminal perfusate contained 4 mmol/l bicarbonate. It lowered, however, the Pi transport significantly when the luminal perfusate had 25 mmol/l bicarbonate. 6. Acetazolamide, 10−4 M, lowered the Pi transport when the luminal perfusate contained 4 or 25 mmol/l bicarbonate. At 4 mmol/l luminal HCO 3 − , raising thepCO2 to 228 mmol/l depressed Pi transport even more. At 25 mmol/l luminal bicarbonate, raising thepCO2 from 38 to 114 mm Hg reversed the acetazolamide inhibition of the Pi transport almost completely. The data indicate that luminal acidosis and intracellular alkalosis inhibits the transtubular Pi transport. A shift of the intracellular pH to a more alkaline value seems to be responsible for the inhibition of Pi transport by acetazolamide, while omission of buffer from the perfusate inhibits Pi transport by effecting an acidic luminal pH.
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