Abstract
The efflux of radiolabelled organic cations from the tubular lumen into proximal tubular cells was investigated by using the stop-flow microperfusion method. The efflux rate increased in the sequence: N 1-methylnicotinamide (NMeN+) < cimetidine < tetraethylammonium (TEA+) < N-methyl-4-phenylpyridinium (MPP+). Preloading the animals by i.v. infusion or pre perfusion of the peritubular capillaries with NMeN+ increased the efflux rate of MPP+. Luminal efflux was also augmented when the tubular solution was made alkaline with HCO −3 or phosphate, whereby HCO −3 is more effective than phosphate. Replacement of Na+ by Cs+ showed no effect. With i.v. preloading the animals with NMeN+ and with 25 mM HCO −3 in the luminal perfusate the 2-s efflux follows kinetics with a Michaelis constant K m=0.21 mmol/l and maximal flux J max=0.42 pmol · cm−1 · s−1 and a permeability term with P=37.7 μm2 · s−1. Comparing the apparent luminal inhibitory constant values for MPP+ \((Ki_{l,MPP^ + } )\) with the apparent contraluminal \(Ki_{cl,NMeN^ + }\) values of substrates of homologous series, it was found that (1) limitation by molecular size occurs at the contraluminal cell side earlier than at the luminal cell side; (2) affinity increases with hydrophobicity of the substrates at the luminal cell side, with a steeper or equal slope than at the contraluminal cell side; (3) affinity increases with basicity (i.e. pKa values) at the luminal cell side with a steeper slope than at the contraluminal cell side. Taken together, substrates with low hydrophobicity and low basicity interact at the luminal cell side more weakly than at the contraluminal cell side. On the other hand large, hydrophobic substrates have, at the luminal cell side, a higher affinity than at the contraluminal cell side. Many substrates, however, have equal affinity at the luminal and contraluminal cell sides.
Similar content being viewed by others
References
Ayer Lazaruk KD, Wright S (1990) MPP+ is transported by the TEA+-H+ exchanger of renal brush border membrane vesicles. Am J Physiol 258:F597-F605
Becker KF, Allmeier H, Höllt V (1992) New mechanisms of hormone secretion: MDR-like gene products as extrusion pumps for hormones. Horm Metab Res 24:210–213
Bendayan R, Sellers EM, Silvermann M (1990) Inhibition kinetics of cationic drugs on N1-methylnicotinamide uptake by brush border membrane vesicles from the dog kidney cortex. Can J Physiol Pharmacol 68:467–475
Besseghir K, Mosig D, Roch-Ramel F (1990) Transport of the organic cation N1-methylnicotinamide by the rabbit proximal tubule: I. Accumulation in the isolated nonperfused tubule. J Pharmacol Exp Ther 253:444–451
Daniel H, Morse, EL, Adibi SA (1992) Determinants of substrate affinity for the oligopeptide/H+ symporter in the renal brush border membrane. J Biol Chem 267:9565–9573
Dantzler WH, Brokl OH (1988) TEA transport by snake renal tubules: choline effects, countertransport, H+-TEA exchange. Am J Physiol 255:F167-F176
Dantzler WH, Brokl OH (1989) Tetraethylammonium (TEA) and N1-methylnicotinamide (NMN) transport by snake renal tubules and brush border membrane vesicles. In: Hirvonen L, Timisjärvi J, Niiranen S (eds) Union of Physiological Sciences Liitoo, Oulu, Finland, pp 5313
Dantzler WH, Brokl OH, Wright SH (1989) Brush-border TEA transport in intact proximal tubules and isolated membrane vesicles. Am J Physiol 256:F290-F297
Dantzler WH, Wright SH, Chatsudthipong V, Brokl OH (1991) Basolateral tetraethylammonium transport in intact tubules: specificity and trans-stimulation. Am J Physiol 261:F386-F392
David C, Ullrich KJ (1992) Substrate specificity of the luminal Na+-dependent sulphate transport system in the proximal renal tubule as compared to the contraluminal sulphate exchange system. Pflügers Arch 421:455–465
Fouda AK, Fauth C, Roch-Ramel F (1990) Transport of organic cations by kidney epithelial cell line (LLC-PK). J Pharmacol Exp Ther 252:286–292
Fritzsch G, Haase W, Rumrich G, Fasold H, Ullrich KJ (1984) A stopped flow capillary perfusion method to evaluate contraluminal transport parameters of methylsuccinate from interstitium into renal proximal tubular cells. Pflügers Arch 400:250–256
Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427
Groves CE, Evans KK, Dantzler WH, Wright SH (1994) Peritubular organic cation transport in isolated rabbit proximal tubules. Am J Physiol 266:F450-F458
Gründemann D, Gorbulev V, Gambaryan S, Veyl M, Koepsell H (1994) Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549–552
Holm J (1976) Trans-stimulatory interaction phenomena in organic cation transport by mouse kidney cortex slices. Acta Physiol Scand 96:41A-44A
Holohan PD, Ross CR (1980) Mechanisms of organic cation transport in kidney plasma membrane vesicles: 1. Counter-transport studies. J Pharmacol Exp Ther 215:191–197
Holohan PD, Ross CR (1981) Mechanisms of organic cation transport in kidney plasma membrane vesicles: 2. 1 pH studies. J Pharmacol Exp Ther 216:294–298
Horio M, Pastan I, Gottesman MM, Handler S (1990) Transepithelial transport of vinblastine by kidney-derived cell lines. Application of a new kinetic model to estimate in situ K m of the pump. Biochim Biophys Acta 1027:116–122
Hsyu PH, Giacomini KM (1987) The pH gradient-dependent transport of organic cations in the renal brush border membrane. Studies with acridine orange. J Biol Chem 262:3964–3968
Katsura T, Takano M, Tomita Y, Yasuhara M, Inui K, Hori R (1993) Characteristics of organic cation transporter in rat renal basolateral membrane. Biochim Biophys Acta 1146:197–202
Lin JH, Los LE, Ulm EH, Duggan DE (1988) Kinetic studies on the competition between famotidine and cimetidine in rats. Evidence for multiple renal secretory systems for organic cations. Drug Metab Dispos Biol Fate Chem 16:52–56
McKinney TD (1982) Heterogeneity of organic base secretion by proximal tubules. Am J Physiol 243:F404-F407
McKinney TD, Kunnemann ME (1985) Procainamide transport in rabbit renal cortical brush border membrane vesicles. Am J Physiol 249:F532-F541
Miyamoto Y, Tiruppathi C, Ganapathy V, Leibach FH (1989) Multiple transport systems for organic cations in renal brush border membrane vesicles. Am J Physiol 256:F540-F548
Montrose-Rafizadeh C, Mingard F, Murer H, Roch-Ramel F (1989) Carrier-mediated transport of tetraethylammonium across rabbit renal basolateral membrane. Am J Physiol 257:F243-F251
Ott RJ, Hui AC, Yuan G, Giacomini KM (1991) Organic cation transport in human renal brush-border membrane vesicles. Am J Physiol 261:F443-F451
Pietruck F, Ullrich KJ (1995) Transport interactions of different organic cations during their excretion by the intact rat kidney. Kidney International 47
Pritchard JB (1988) Coupled transport of p-aminohippurate by rat kidney basolateral membrane vesicles. Am J Physiol 255:F597-F604
Rafizadeh C, Manganel M, Roch-Ramel F, Schäli C (1986) Transport of organic cations in brush border membrane vesicles from rabbit kidney cortex. Pflügers Arch 407:404–408
Schäli C, Schild L, Overney J, Roch-Ramel F (1983) Secretion of tetraethylammonium by proximal tubules of rabbit kidneys. Am J Physiol 245:F238-F246
Schömig E, Babin-Ebell J, Russ H (1993) 1,1′-Diethyl-2,2′-cyanine (decynium 22) potently inhibits the renal transport of organic cations. Naunyn Schmiedebergs Arch Pharmacol 347:379–383
Shimada H, Moewes B, Burckhardt G (1987) Indirect coupling to Na+ of p-aminohippuric acid and uptake into rat renal basolateral, membrane vesicles. Am J Physiol 253:F795-F801
Smith PM, Pritchard JB, Miller DS (1988) Membrane potential drives organic cation transport into teleost renal proximal tubules. Am J Physiol 255:R492-R499
Soares-da-Silva P (1994) Source and handling of renal dopamine; its physiological importance. News Physiol Sci 9:128–134
Sokol PP, Mc Kinney TD (1990) Mechanism of organic cation transport in rabbit renal basolateral membrane vesicles. Am J Physiol 258:F1599-F1607
Sokol PP, Holohan PD, Ross CR (1985) Electroneutral transport of organic cations in canine renal brush border membrane vesicles (BBMV). J Pharmacol Exp Ther 233:694–699
Takano M, Inui K, Okano T, Saito H, Hori R (1984) Carrier-mediated transport systems of tetraethylammonium in rat brush-border and basolateral membrane vesicles. Biochim Biophys Acta 773:113–124
Takano M, Inui K, Okano T, Hori R (1985) Cimetidine transport in rat renal brush border and basolateral membrane vesicles. Life Sci 37:1579–1585
Tarloff JB, Brand PH (1986) Active tetraethylammonium uptake across the basolateral membrane of rabbit proximal tubule. Am J Physiol 251:F141-F149
Ulkich KJ (1994) Specificity of transporters for ‘organic anions’ and ‘organic cations’ in the kidney. Biochim Biophys Acta 1197:45–62
Ullrich KJ, Rumrich G (1990) Kidney: microperfusion-double perfused tubule in situ. Methods Enzymol 191:98–107
Ullrich KJ, Radtke HW, Rumrich G (1971) The role of bicarbonate and other buffers on isotonic fluid absorption in the proximal convolution of the rat kidney. Pflügers Arch 330:149–161
Ullrich KJ, Papavassiliou F, David C, Rumrich G, Fritzsch G (1991) Contraluminal transport of organic cations in the proximal tubule of the rat kidney. I. Kinetics of N1-methylnicotinamide and tetraethylammonium, influence of K+, HCO3 −, pH; inhibition by aliphatic primary, secondary and tertiary amines, and mono- and bisquarternary compounds. Pflügers Arch 419:84–92
Ullrich KJ, Rumrich G, Neiteler K, Fritzsch G (1992) Contraluminal transport of organic cations in the proximal tubule of the rat kidney. II. Specificity: anilines, phenylalkylamines (catecholamines), heterocyclic compounds (pyridines, quinolines, acridines). Pflügers Arch 420:29–38
Ullrich KJ, Rumrich G, David C, Fritzsch G (1993) Bisubstrates: substances that interact with renal contraluminal organic anion and organic cation transport systems. I. Amines, piperidines, piperazines, azepines, pyridines, quinolines, imidazoles, thiazoles guanidines, and hydrazines. Pflügers Arch 425:280–299
Ullrich KJ, Rumrich G, David C, Fritzsch G (1993) Bisubstrates: substances that interact with renal contraluminal organic anion and organic cation transport systems: II. Zwitterionic substrates: dipeptides, cephalosporins, quinolone-carboxylate gyrase inhibitors, and phosphamide thiazine carboxylates; nonionizable substrates: steroid hormones and cyclophosphamides. Pflügers Arch 425:300–312
Ullrich KJ, Fritzsch G, Rumrich G, David C (1994) Polysubstrates: substances that interact with renal contraluminal PAH, sulfate, and NMeN transport: sulfamoyl-, sulfonylurea-, thiazide- and benzeneamino-carboxylate (nicotinate) compounds. J Pharmacol Exp Ther 269:684–692
Wright SH, Wunz TM (1987) Transport of tetraethylammonium by rabbit renal brush-border and basolateral membrane vesicles. Am J Physiol 253:F1040-F1050
Wright SH, Wunz TM, Wunz TP (1992) A choline transporter in renal brush-border membrane vesicles: energetics and structural specificity. J Membr Biol 126:51–65
Wright SH, Wunz TM, Wunz TP (1995) Structure and interaction of inhibitors with the TEA/H+ exchanger of rabbit renal brush border membranes. Pflügers Arch 429:313–324
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
David, C., Rumrich, G. & Ullrich, K.J. Luminal transport system for H+/organic cations in the rat proximal tubule. Pflugers Arch. 430, 477–492 (1995). https://doi.org/10.1007/BF00373884
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00373884