Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Renal Handling of Urea

Donald J. Marsh, Mark A. Knepper

10.1002/cphy.cp080229

Source: Supplement 25: Handbook of Physiology, Renal Physiology

Originally published: 1992

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Urea Synthesis
2 Role of Urea in Systemic Metabolism
2.1 Role of Urea in Systemic Nitrogen Balance
2.2 Role of Urea in Systemic Acid‐Base Balance
2.3 Regulation of Urea Production and Excretion
3 Effects of Urea on Cellular Function: Role of Methylamines
4 Membrane Transport of Urea
4.1 Lipid Bilayers
4.2 Erythrocytes and Other Nonepithelial Cells
4.3 Nonrenal Epithelia
5 Urea Transport in the Kidney
5.1 Introduction
5.2 Individual Tubule Segments
6 Role of Urea in the Urinary Concentrating Mechanism
7 Questions Remaining
Figure 1. Figure 1.

Urea cycle and related metabolic reactions in liver. (1) Bicarbonate in cell is supplied in part by hydration of CO2 catalyzed by carbonic anhydrase 62, (2) carbamoyl phosphate synthetase, (3) ornithine carbamoyl tranferase, (4) argininosuccinate synthetase, (5) argininosuccinate lyase, (6) arginase, (7) fumarase, (8) malate dehydrogenase, (9) glutamate‐oxaloacetate transaminase.
Figure 2. Figure 2.

Mass flow of urea in mammalian nephron. Diameter of each tubule is drawn proportional to mass flow of urea; numbers refer to millimolar concentrations. Two populations of nephrons are represented, short and long looped, the latter shown extending completely to tip of papilla. This diagrammatic representation oversimplifies distribution of urea flow in long‐looped nephrons, but reflects the fact that mass flow of urea decreases in collecting ducts of inner medulla and is returned to Henle's loops.
Figure 3. Figure 3.

Restricted routes of urea distribution dictated by three‐dimensional structure of renal medulla. Solid lines represent short‐looped nephron (left) and long‐looped nephron (right). Transfer of urea between nephron segments indicated by dashed arrows labeled a, b, and c PST, proximal straight tubule: DL, descending limb; tAL, thin ascending limb; TAL, thick ascending limb; DCT, distal convoluted tubule; CD, collecting duct; vr, vasa recta.

Modified from Knepper and Roch‐Ramel 100
Figure 4. Figure 4.

Diagram showing nephron that has been distorted to indicate relative permeabilities of rat nephron segments to urea. Width of segment in diagram is proportional to measured urea permeability. Values for segments indicated by asterisk (*) have not been determined for rat and were estimated based on measurements in analogous segments in rabbit. PCT, proximal convoluted tubule; PST, proximal straight tubule; OMDL, outer medullary part of thin descending limb; IMDL, inner medullary part of thin descending limb; tAL, thin ascending limb; MTAL (IS), inner stripe of medullary thick ascending limb; MTAL (OS), outer stripe of medullary thick ascending limb; CTAL, cortical thick ascending limb; DCT, distal convoluted tubule; CCD, cortical collecting duct; OMCD, outer medullary collecting duct; IMCDi initial part of inner medullary collecting duct; IMCDt, terminal part of inner medullary collecting duct.
Figure 5. Figure 5.

Comparison of measured urea permeabilities (closed circles) with predicted urea permeabilities assuming transport by lipid phase diffusion across cell membranes as sole mechanism of transepithelial transport (solid line). Predicted values assume that urea permeabilities of apical and basolateral membranes are same as in lipid bilayers [4 × 10−6 cm/s; 48]. Because epithelial permeabilities are calculated using virtual surface area (Si) calculated from inner diameter (Di) and length (L) of tubule (Si = π Di L) rather than actual membrane surface areas, calculation of predicted epithelial permeability must take into account membrane amplification of apical and basolateral membranes (see text). Membrane amplification is expressed in terms of ratio of actual apical membrane area to virtual inner surface area (Ra) and ratio of actual basolateral membrane area to virtual inner surface area (Rb). Overall membrane amplification factor (RaRb/[Ra + Rb]) is obtained by considering that overall resistance to passive urea penetration across epithelium is determined by two lipid membrane barriers in series. Thus predicted epithelial urea permeability is calculated as lipid membrane permeability multiplied by overall membrane amplification factor. Ra and Rb were calculated from data of Welling et al. 235,236,237,238 for rabbit proximal convoluted tubule (PCT), rabbit proximal straight tubule (PST), rabbit cortical thick ascending limb (CTAL), and rabbit cortical collecting duct (CCD). Ra and Rb for rat outer medullary and inner medullary collecting ducts were estimated from data of Rastegar et al. 161. Ra and Rb for rabbit medullary thick ascending limb (MTAL) were assumed to be same as for CTAL. Ra values in thin ascending limb (tAL) and rabbit papillary surface epithelium (PSE) were assumed to be 1.0 based on electron micrographs 69,88. Measured permeabilities were obtained from Table 1. Values were from rabbit nephron segments with exception of those for inner medullary (IMCD) and outer medullary (OMCD) collecting ducts, which were from rats.


Figure 1.

Urea cycle and related metabolic reactions in liver. (1) Bicarbonate in cell is supplied in part by hydration of CO2 catalyzed by carbonic anhydrase 62, (2) carbamoyl phosphate synthetase, (3) ornithine carbamoyl tranferase, (4) argininosuccinate synthetase, (5) argininosuccinate lyase, (6) arginase, (7) fumarase, (8) malate dehydrogenase, (9) glutamate‐oxaloacetate transaminase.



Figure 2.

Mass flow of urea in mammalian nephron. Diameter of each tubule is drawn proportional to mass flow of urea; numbers refer to millimolar concentrations. Two populations of nephrons are represented, short and long looped, the latter shown extending completely to tip of papilla. This diagrammatic representation oversimplifies distribution of urea flow in long‐looped nephrons, but reflects the fact that mass flow of urea decreases in collecting ducts of inner medulla and is returned to Henle's loops.



Figure 3.

Restricted routes of urea distribution dictated by three‐dimensional structure of renal medulla. Solid lines represent short‐looped nephron (left) and long‐looped nephron (right). Transfer of urea between nephron segments indicated by dashed arrows labeled a, b, and c PST, proximal straight tubule: DL, descending limb; tAL, thin ascending limb; TAL, thick ascending limb; DCT, distal convoluted tubule; CD, collecting duct; vr, vasa recta.

Modified from Knepper and Roch‐Ramel 100


Figure 4.

Diagram showing nephron that has been distorted to indicate relative permeabilities of rat nephron segments to urea. Width of segment in diagram is proportional to measured urea permeability. Values for segments indicated by asterisk (*) have not been determined for rat and were estimated based on measurements in analogous segments in rabbit. PCT, proximal convoluted tubule; PST, proximal straight tubule; OMDL, outer medullary part of thin descending limb; IMDL, inner medullary part of thin descending limb; tAL, thin ascending limb; MTAL (IS), inner stripe of medullary thick ascending limb; MTAL (OS), outer stripe of medullary thick ascending limb; CTAL, cortical thick ascending limb; DCT, distal convoluted tubule; CCD, cortical collecting duct; OMCD, outer medullary collecting duct; IMCDi initial part of inner medullary collecting duct; IMCDt, terminal part of inner medullary collecting duct.



Figure 5.

Comparison of measured urea permeabilities (closed circles) with predicted urea permeabilities assuming transport by lipid phase diffusion across cell membranes as sole mechanism of transepithelial transport (solid line). Predicted values assume that urea permeabilities of apical and basolateral membranes are same as in lipid bilayers [4 × 10−6 cm/s; 48]. Because epithelial permeabilities are calculated using virtual surface area (Si) calculated from inner diameter (Di) and length (L) of tubule (Si = π Di L) rather than actual membrane surface areas, calculation of predicted epithelial permeability must take into account membrane amplification of apical and basolateral membranes (see text). Membrane amplification is expressed in terms of ratio of actual apical membrane area to virtual inner surface area (Ra) and ratio of actual basolateral membrane area to virtual inner surface area (Rb). Overall membrane amplification factor (RaRb/[Ra + Rb]) is obtained by considering that overall resistance to passive urea penetration across epithelium is determined by two lipid membrane barriers in series. Thus predicted epithelial urea permeability is calculated as lipid membrane permeability multiplied by overall membrane amplification factor. Ra and Rb were calculated from data of Welling et al. 235,236,237,238 for rabbit proximal convoluted tubule (PCT), rabbit proximal straight tubule (PST), rabbit cortical thick ascending limb (CTAL), and rabbit cortical collecting duct (CCD). Ra and Rb for rat outer medullary and inner medullary collecting ducts were estimated from data of Rastegar et al. 161. Ra and Rb for rabbit medullary thick ascending limb (MTAL) were assumed to be same as for CTAL. Ra values in thin ascending limb (tAL) and rabbit papillary surface epithelium (PSE) were assumed to be 1.0 based on electron micrographs 69,88. Measured permeabilities were obtained from Table 1. Values were from rabbit nephron segments with exception of those for inner medullary (IMCD) and outer medullary (OMCD) collecting ducts, which were from rats.

References
 1. Addis, T. The renal lesion in Bright's disease. Am. J. Med. Sci. 176: 617‐637, 1928.
 2. Adolph, E. F. The metabolism of ammonium salts and of urea in man. Am. J. Physiol. 71: 355‐361, 1924.
 3. Andersen, B., and H. H. Ussing. Solvent drag on non‐electrolytes during osmotic flow through isolated toad skin and its response to antidiuretic hormone. Acta Physiol. Scand. 39: 228‐239, 1957.
 4. Armsen, T., and H. W. Reinharut. Transtubular movement of urea at different degrees of water diuresis. Pflugers Arch. 326: 270‐280, 1971.
 5. Aronson, P. S. Identifying secondary active solute transport in epithelia. Am. J. Physiol. 240 (Renal Fluid Electrolyte Physiol. 9): F1‐F11, 1981.
 6. Atkinson, D. E., and E. Bourke. The role of ureagenesis in pH homeostasis. Trends Biochem. Sci. 9: 291‐300, 1984.
 7. Atkinson, D. E., and M. N. Camien. The role of urea synthesis in the removal of metabolic carbonate and the regulation of blood pH. Curr. Top. Cell. Regul. 21: 261‐302, 1982.
 8. Ausiello, D. A., and D. Hall. Regulation of vasopressin sensitive adenylate cyclase by calmodulin. J. Biol. Chem. 256: 9796‐9798, 1981.
 9. Bagnasco, S., R. Balaban, H. M. Fales, Y. M. Yang, and M. Burg. Predominant osmotically active organic solutes in rat and rabbit renal medullas. J. Biol. Chem. 261: 5872‐5877, 1986.
 10. Balaban, R. S., and M. A. Knepper. Nitrogen‐14 nuclear magnetic resonance spectroscopy of mammalian tissues. Am. J. Physiol. 245: C439‐C444, 1983.
 11. Baldamus, C. A., H. W. Radtke, G. Rumrich, F. Sauer, and K. J. Ullrich. Reflection coefficient and permeability of urea in the proximal convolution of the rat kidney. J. Membr. Biol. 7: 377‐390, 1972.
 12. Bankir, L., N. Bouby, and M.‐.M. Trinh‐Trang‐Tan. Organization of the medullary circulation: functional implications. In: Proc. IXth Int. Congr. Nephrol, edited by R. R. Robinson. New York: Springer‐Verlag, 1984, p. 84‐106.
 13. Bargman, J., S. L. Leonard, E. McNeely, C. Robertson, and R. L. Jamison. Examination of transepithelial exchange of water and solute in the rat renal pelvis. J. Clin. Invest. 74: 1860‐1870, 1984.
 14. Baylis, C., and B. M. Brenner. Mechanism of the glucocorticoid‐induced increase in glomerular filtration rate. Am. J. Physiol. 234 (Renal Fluid Electrolyte Physiol. 3): F166‐F170, 1970.
 15. Bean, E. S., and D. E. Atkinson. Regulation of the rate of urea synthesis in liver by extracellular pH. J. Biol. Chem. 259: 1552‐1559, 1984.
 16. Berliner, R. W., N. G. Levinsky, D. G. Davidson, and M. Eden. Dilution and concentration of the urine and the action of antidiuretic hormone. Am. J. Med. 24: 730‐744, 1958.
 17. Bonventre, J. V., and C. Lechene. Renal medullary concentrating process: an integrative hypothesis. Am. J. Physiol. 239 (Renal Fluid Electrolyte Physiol. 8): F578‐F588, 1980.
 18. Bonventre, J. V., R. J. Roman, and C. Lechene. Effect of urea concentration of pelvic fluid on renal concentrating ability. Am. J. Physiol. 239 (Renal Fluid Electrolyte Physiol. 8): F609‐F618, 1980.
 19. Bott, P. A. Micropuncture study of renal excretion of water, K, Na, and CI in Necturus. Am. J. Physiol. 203: 662‐679, 1962.
 20. Brahm, J. Urea permeability of human red cells. J. Gen. Physiol. 82: 1‐23, 1983.
 21. Bray, G. A., and A. S. Preston. Effect of urea on urine concentration in the rat. J. Clin. Invest. 40: 1952‐1960, 1961.
 22. Brebnor, L., E. Phillips, and J. B. Balinsky. Control of urea cycle enzymes in rat liver by glucagon. Enzyme 26: 265–270, 1981.
 23. Bright, R. Cases and observations illustrative of renal disease accompanied with the secretion of albuminous urine. Guys Hosp. Rep. 1: 338‐379, 1936.
 24. Brown, G. W., Jr. Some evolutionary aspects of urea biosynthesis. In: Urea and the Kidney, edited by B. Schmidt‐Nielsen and D. W. S. Kerr. Amsterdam: Excerpta Medica, 1970, p. 3‐14.
 25. Burg, M. B., S. Helman, J. Grantham, and J. Orloff. Effect of vasopressin on the permeability of isolated rabbit cortical collecting tubules to urea, acetamide and thiourea. In: Urea and the Kidney, edited by B. Schmidt‐Nielsen and D. W. S. Kerr. Amsterdam: Excerpta Medica, 1970, p. 193‐199.
 26. Capek, K., G. Fuchs, G. Rumrich, and K. J. Ullrich. Harnstoffpermeabilitaet der corticalen Tubulusabschnitte von Ratten in Antidiurese und Wasserdiurese. Pflugers Arch. 290: 237‐249, 1966.
 27. Carvounis, C. P., N. Franki, S. D. Levine, and R. M. Hays. Membrane pathways for water and solutes in the toad bladder: I. Independent activation of water and urea transport. J. Membr. Biol. 49: 253‐268, 1979.
 28. Carvounis, C. P., S. D. Levine, N. Franki, and R. M. Hays. Membrane pathways for water and solutes in the toad bladder: II. Reflection coefficients of the water and solute channels. J. Membr. Biol. 49: 269‐281, 1979.
 29. Casavola, V., S. Curci, and C. Lippe. Effect of cycloheximide on urea facilitated transport through toad gallbladder epithelium. Pflugers Arch. 384: 155‐158, 1980.
 30. Chandhoke, P. S., G. M. Saidel, and M. A. Knepper. Role of inner medullary collecting duct NaCl transport in urinary concentration. Am. J. Physiol. 249 (Renal Fluid Electrolyte Physiol. 18): F688‐F697, 1985.
 31. Chou, C.‐L., and M. A. Knepper. Urea and sodium chloride permeabilities of long‐loop thin limb segments from chinchilla, abstracted. J. Am. Soc. Nephrol. 1: 673, 1990.
 32. Chou, C.‐L., and M. A. Knepper. Inhibition of urea transport in inner medullary collecting duct by phloretin and urea analogs. Am. J. Physiol. 257 (Renal Fluid Electrolyte Physiol. 26): F359‐F365, 1989.
 33. Chou, C.‐L., J. M. Sands, H. Nonoguchi, and M. A. Knepper. Concentration dependence of urea/thiourea transport in rat inner medullary collecting duct. Am. J. Physiol. 258 (Renal Fluid Electrolyte Physiol. 27): F486‐F494, 1990.
 34. Chou, C.‐L., J. M. Sands, H. Nonoguchi, and M. A. Knepper. Urea‐gradient associated fluid absorption with urea‐1 in rat terminal collecting duct. Am. J. Physiol. 258 (Renal Fluid Electrolyte Physiol. 27): F1173‐F1180, 1990.
 35. Christison, R. Observations on the variety of dropsy which depends on diseased kidney. Edinb. Med. Surg. J. 32: 262‐292, 1929.
 36. Christowitz, D., F. J. Mattheyse, and J. B. Balinsky. Dietary and hormonal regulation of urea cycle enzymes in rat liver. Enzyme 26: 113‐121, 1981.
 37. Chuang, E. L., H. J. Reineck, R. W. Osgood, R. T. Kunau, Jr., and J. H. Stein. Studies on the mechanism of reduced urinary osmolality after exposure of the renal papilla. J. Clin. Invest. 61: 633‐639, 1978.
 38. Clapp, J. R. Renal tubular reabsorption of urea in normal and protein‐depleted rats. Am. J. Physiol. 210: 1304‐1308, 1966.
 39. Crawford, J. D., A. P. Doyle, and J. H. Probst. Service of urea in renal water conservation. Am. J. Physiol. 196: 545‐548, 1959.
 40. Curci, S., V. Casavola, D. Cremaschi, and C. Lippe. Facilitated transport of urea across the toad gallbladder. Pflugers Arch. 362: 109‐112, 1976.
 41. Danielson, R. A., and B. Schmidt‐Nielsen. Recirculation of urea analogs from renal collecting ducts of high‐ and low‐protein‐fed rats. Am. J. Physiol. 223: 130‐137, 1972.
 42. Danielson, R. A., B. Schmidt‐Nielsen, and C. Hohberger. Micropuncture study of the regulation of urea excretion by the collecting ducts in rats on high and low protein diets. In: Urea and the Kidney, edited by B. Schmidt‐Nielsen and D. W. S. Kerr. Amsterdam: Excerpta Medica, 1970, p. 375‐384.
 43. de Rouffignac, C., and F. Morel. Micropuncture study of water, electrolytes, and urea movements along the loops of Henle in Psammomys. J. Clin. Invest. 48: 474‐486, 1969.
 44. Edkins, E., and N. C. Raiha. Changes in the activities of the enzymes of urea synthesis caused by dexamethasone and di‐butyryladenosine 3′‐5′‐cyclic monophosphate in foetal rat‐liver maintained in organ‐culture. Biochem. J. 160: 159‐162, 1976.
 45. Exton, J. H. Role of calcium and phosphoinositides in the actions of certain hormones and neurotransmitters. J. Clin. Invest. 75: 1753‐1757, 1985.
 46. Forster, R. P. Active cellular transport of urea by frog renal tubules. Am. J. Physiol. 179: 372‐377, 1954.
 47. Furst, P., B. Josephson, G. Maschio, and E. Vinnars. Nitrogen balance after intravenous and oral administration of ammonium salts to man. J. Appl. Physiol. 26: 13‐22, 1969.
 48. Gallucci, E. S., S. Micelli, and C. Lippe. Nonelectrolyte permeability across thin lipid membranes. Arch. Int. Biochim. 79: 881‐887, 1971.
 49. Gamble, J. L., C. F. McKhann, A. M. Butler, and E. Tuthill. An economy of water in renal function referable to urea. Am. J. Physiol. 109: 139‐154, 1934.
 50. Gargus, J. J., B. Brunner‐Jackson, and L. Malone. Cloning the human gene encoding a putative urea transport mechanism. FASEB J. 2: A300, 1988.
 51. Garrod, O., S. A. Davies, and G. Cahill, Jr. The action of cortisone and desoxycorticosterone acetate on glomerular filtration rate and sodium and water exchange in the adrenalectomized dog. J. Clin. Invest. 34: 761‐776, 1955.
 52. Gebhardt, R., and D. Mecke. Permissive effect of dexamethasone on glucagon induction of urea‐cycle enzymes in perfused primary monolayer cultures of rat hepatocytes. Eur. J. Biochem. 97: 29‐35, 1979.
 53. Goldstein, D., and A. K. Solomon. Determination of equivalent pore radius for human red cell by osmotic pressure measurement. J. Gen. Physiol. 44: 1‐17, 1967.
 54. Gottschalk, C. W., W. E. Lassiter, and M. Mylle. Studies of the composition of vasa recta plasma in the hamster kidney. In: Proc. XXth Int. Congr. Physiol. Amsterdam: Excerpta Med., 1962, p. 375‐376.
 55. Gottschalk, C. W., W. E. Lassiter, M. Mylle, K. J. Ullrich, B. Schmidt‐Nielsen, R. O'Dell, and G. Pehling. Micropuncture study of composition of loop of Henle fluid in desert rodents. Am. J. Physiol. 204: 532‐535, 1963.
 56. Gottschalk, C. W., and M. Mylle. Micropuncture study of the mammalian urinary concentrating mechanism: evidence for the countercurrent hypothesis. Am. J. Physiol. 196: 927‐936, 1959.
 57. Gunther, R. A., and L. Rabinowitz. Urea and renal concentrating ability in the rabbit. Kidney Int. 17: 205‐222, 1980.
 58. Hagel, P., J. J. T. Gerding, W. Fieggen, and H. Bloemendal. Cyanate formation in solutions of urea. I. Calculation of cyanate concentrations at different temperature and pH. Biochim. Biophys. Acta 243: 366‐373, 1971.
 59. Halperin, M. L., C. B. Chen, S. Cheema‐Dhadli, M. L. West, and R. L. Jungas. Is urea formation regulated primarily by acid‐base balance in vivo? Am. J. Physiol. 250 (Renal Fluid Electrolyte Physiol. 19): F605‐F612, 1986.
 60. Halperin, M. L., and R. L. Jungas. Metabolic production and renal disposal of hydrogen ions. Kidney Int. 24: 709‐713, 1983.
 61. Hardy, M. A., and H. M. Ware. Roles of Ca++ and Na+ on the modulation of antidiuretic hormone action on urea permeability in toad urinary bladder. J. Clin. Invest. 75: 921‐931, 1985.
 62. Haussinger, D., and W. Gerok. Hepatic urea synthesis and pH regulation. Role of CO2, HCO3−, pH and the activity of carbonic anhydrase. Eur. J. Physiol. 152: 381‐386, 1985.
 63. Haussinger, D., W. Gerok, and H. Sies. Regulation of flux through glutaminase and glutamine synthetase in isolated perfused rat liver. Biochim. Biophys. Acta 755: 272‐278, 1983.
 64. Haussinger, D., W. Gerok, and H. Sies. Hepatic role in pH regulation: role of the intercellular glutamine cycle. Trends Biochem. Sci. 9: 300‐302, 1984.
 65. Hays, R. M., S. D. Levine, J. D. Myers, H. O. Heinemann, M. A. Kaplan, N. Franki, and H. Berliner. Urea transport in the dogfish kidney. J. Exp. Zool. 199: 309‐316, 1977.
 66. Hediger, M. A., and M. Stelzner. Functional expression of the vasopressin‐regulated urea transport in RNA injected Xenopus oocytes. J. Am. Soc. Nephrol. 1: 675, 1990.
 67. Hensgens, H. E., A. J. Verhoeven, and A. J. Meijer. The relationship between intramitochondrial N‐acetylglutamate and activity of carbamoyl‐phosphate synthetase (ammonia): the effect of glucagon. Eur. J. Biochem. 107: 197‐205, 1980.
 68. Hilger, H. H., J. D. Kluemper, and K. J. Ullrich. Wasserrueckresorption und Ionentransport durch die Sammelrohren der Saeugertierniere. Pflugers Arch. 267: 218‐237, 1958.
 69. Hogg, R. J., and J. P. Kokko. Urine concentrating and diluting mechanisms in mammalian kidneys. In: The Kidney (3rd ed.), edited by B. M. Brenner and F. C. Rector, Jr. Philadelphia: W. B. Saunders, 1986, p. 251‐279.
 70. Holz, R., and A. Finkelstein. The water and nonelectrolyte permeability induced in thin lipid membranes by the polyene antibiotics nystatin and amphotericin. J. Gen. Physiol. 56: 125‐145, 1970.
 71. Hunter, R. F. Facilitated diffusion in human erythrocytes. Biochim. Biophys. Acta 211: 216‐222, 1970.
 72. Husson, A., and R. Vaillant. Effects of glucocorticosteroids and glucagon on argininosuccinate synthetase, argininosuccinase, and arginase in fetal rat liver. Endocrinology 110: 227‐232, 1982.
 73. Ichikawa, I., M. L. Purkerson, S. Klahr, J. L. Troy, M. Martinez‐Maldonaldo, and B. M. Brenner. Mechanism of reduced glomerular filtration rate in chronic malnutrition. J. Clin. Invest. 65: 982‐988, 1980.
 74. Imai, M. Function of the thin ascending limb of Henle of rats and hamsters perfused in vitro. Am. J. Physiol. 232 (Renal Fluid Electrolyte Physiol. 1): F201‐F209, 1977.
 75. Imai, M., M. Hayashi, and M. Araki. Functional heterogeneity of the descending limbs of Henle's loop. I. Internephron heterogeneity in the hamster kidney. Pflugers Arch. 402: 385‐392, 1984.
 76. Imai, M., and J. P. Kokko. Sodium chloride, urea, and water transport in the thin ascending limb of Henle: generation of osmotic gradients by passive diffusion of solutes. J. Clin. Invest. 53: 393‐402, 1974.
 77. Imai, M., and J. P. Kokko. Mechanism of sodium and chloride transport in the thin ascending limb of Henle. J. Clin. Invest. 58: 1054‐1060, 1976.
 78. Imai, M., and Y. Kondo. Effects of vasopressin along the nephron segments: an in vitro study, abstracted. In: Proc. XXXth Int. Un. Physiol. Sci. Congr., p. 283, 1986.
 79. Imai, M., J. Taniguchi, and K. Yoshitomi. Transition of permeability properties along the descending limb of long‐loop nephron. Am. J. Physiol. 254 (Renal Fluid Electrolyte Physiol. 23): F323‐F328, 1988.
 80. Imai, M., J. Taniguchi, and K. Yoshitomi. Osmotic work across inner medullary collecting duct accomplished by difference in reflection coefficient for urea and NaCl. Pflugers Arch. 412: 557‐567, 1988.
 81. Imbert, M., and C. de Rouffignac. Role of sodium and urea in the renal concentrating mechanism in Psammomys obesus. Pflugers Arch. 361: 107‐114, 1976.
 82. Ishikawa, S., T. Saito, and T. Kuzuya. Calmodulin regulation of cellular cyclic AMP production in response to arginine vasopressin, prostaglandin E2 and forskolin in rat renal papillary collecting tubule cells in culture. J. Endocrinol. 107: 15‐22, 1985.
 83. Jaenike, J. R. The influence of vasopressin on the permeability of the mammalian collecting duct to urea. J. Clin. Invest. 40: 144‐151, 1961.
 84. Jamison, R. L., J. Buerkert, and F. Lacy. A micropuncture study of Henle's thin loop in Brattleboro rats. Am. J. Physiol. 224: 180‐185, 1973.
 85. Jamison, R. L., N. Roinel, and C. de Rouffignac. Urinary concentrating mechanism in the desert rodent Psammomys obesus. Am. J. Physiol. 236 (Renal Fluid Electrolyte Physiol. 5): F448‐F453, 1979.
 86. Joppich, R., and P. Deetjen. The relation between the reabsorption of urea and of water in the distal tubule of the rat kidney. Pflugers Arch. 329: 172‐185, 1971.
 87. Kachadorian, W. A., S. D. Levine, J. B. Wade, V. A. DiScala, and R. M. Hays. Relationship of aggregated intramembranous particles to water permeability in vasopressin‐treated toad urinary bladder. J. Clin. Invest. 59: 576‐581, 1977.
 88. Kaissling, B., and W. Kriz. Structural analysis of the rabbit kidney. Adv. Anat. Embryol. Cell Biol. 56: 1‐123, 1979.
 89. Kamemoto, E. S., and D. E. Atkinson. Modulation of the activity of rat liver acetylglutamate synthase by pH and arginine concentration. Arch. Biochem. Biophys. 243: 100‐107, 1985.
 90. Kashiwagura, T., M. Erecinska, and D. F. Wilson. pH dependence of hormonal regulation of gluconeogenesis and urea synthesis from glutamine in suspensions of hepatocytes. J. Biol. Chem. 260: 407‐414, 1985.
 91. Kauker, M. L., W. E. Lassiter, and C. W. Gottschalk. Micropuncture study of effects of urea infusion on tubular reabsorption in the rat. Am. J. Physiol. 219: 45‐50, 1970.
 92. Kawamura, S., and J. P. Kokko. Urea secretion by the straight segment of the proximal tubule. J. Clin. Invest. 58: 604‐612, 1976.
 93. King, P. A., and L. Goldstein. Renal excretion of nitrogenous compounds in vertebrates. Renal Physiol. 8: 261‐278, 1985.
 94. Kleinberg, M. E., and A. Finkelstein. Single‐length and double‐length channels formed by nystatin in lipid bilayers membranes. J. Membr. Biol. 80: 257‐269, 1984.
 95. Kluemper, J. D., K. J. Ullrich, and H. H. Hilger. Das Verhalten des Harnstoffs in den Sammelrohren der Saeugertierniere. Pflugers Arch. 267: 238‐243, 1958.
 96. Knepper, M. A. Urea transport in nephron segments from medullary rays of rabbits. Am. J. Physiol. 244: F622‐F627, 1983.
 97. Knepper, M. A. Urea transport in isolated thick ascending limbs and collecting ducts from rats. Am. J. Physiol. 245 (Renal Fluid Electrolyte Physiol. 14): F634‐F639, 1983.
 98. Knepper, M. A., R. A. Danielson, G. M. Saidel, and K. H. Johnston. Effects of dietary protein restriction and glucocorticoid administration on urea excretion in rats. Kidney Int. 8: 303‐315, 1975.
 99. Knepper, M. A., C. V. Gunter, and R. A. Danielson. Effects of glucagon on renal function in protein‐deprived rats. Surg. Forum 27: 29‐31, 1976.
 100. Knepper, M. A., and F. Roch‐Ramel. Pathways of urea transport in the mammalian kidney. Kidney Int. 31: 629‐633, 1987.
 101. Knepper, M. A., J. M. Sands, and C.‐L. Chou. Independence of urea and water transport in rat inner medullary collecting duct. Am. J. Physiol. 256 (Renal Fluid Electrolyte Physiol. 25): F610‐F621, 1989.
 102. Knepper, M. A., and R. A. Star. The vasopressin‐regulated urea transporter in renal inner medullary collecting duct. Am. J. Physiol. 259 (Renal Fluid Electrolyte Physiol. 28): F393‐F401, 1990.
 103. Kokko, J. P. Urea transport in the proximal tubule and the descending limb of Henle. J. Clin. Invest. 51: 1999‐2008, 1972.
 104. Kokko, J. P., and F. C. Rector, Jr. Countercurrent multiplication system without active transport in the inner medulla. Kidney Int. 2: 214‐223, 1972.
 105. Kondo, Y., and M. Imai. Effects of glutaraldehyde fixation on renal tubular function: I. Preservation of vasopressin‐stimulated water and urea pathways in rat papillary collecting duct. Pflugers Arch. 408: 479‐483, 1987.
 106. Kondo, Y., and M. Imai. Effect of glutaraldehyde on renal tubular function. II. Selective inhibition of Cl transport in the hamster thin ascending limb of Henle's loop. Pflugers Arch. 408: 484‐490, 1987.
 107. Krebs, H. A., and K. Henseleit. Untersuchungen ueber die Harnstoffbildung im Tierkoerper. Hoppe‐Seylers Z. Physiol. Chem. 210: 33‐66, 1932.
 108. Kriz, W. Structural organization of the renal medulla: comparative and functional aspects. Am. J. Physiol. 241 (Regulatory Integrative Comp. Physiol. 10): R3‐R16, 1981.
 109. Kriz, W., J. Schnermann, and H. Koepsell. The position of short and long loops of Henle in the rat kidney. Z. Anat. Entwicklungsgesch. 138: 301‐319, 1972.
 110. Lassiter, W. E., C. W. Gottschalk, and M. Mylle. Micropuncture study of net transtubular movement of water and urea in nondiuretic mammalian kidney. Am. J. Physiol. 200: 1139‐1146, 1961.
 111. Lassiter, W. E., M. Mylle, and C. W. Gottschalk. Net transtubular movement of water and urea in saline diuresis. Am. J. Physiol. 206: 669‐673, 1964.
 112. Lassiter, W. E., M. Mylle, and C. W. Gottschalk. Micropuncture study of urea transport in rat renal medulla. Am. J. Physiol. 210: 965‐970, 1966.
 113. Leaf, A., and R. M. Hays. Permeability of the isolated toad bladder to solutes and its modification by vasopressin. J. Gen. Physiol. 45: 921‐932, 1962.
 114. Levine, S., N. Franki, and R. M. Hays. Effect of phloretin on water and solute movement in the toad bladder. J. Clin. Invest. 52: 1435‐1442, 1973.
 115. Levine, S., N. Franki, and R. M. Hays. A saturable, vasopressin‐sensitive carrier for urea and acetamide in the toad bladder epithelial cell. J. Clin. Invest. 52: 2083‐2086, 1973.
 116. Levine, S. D., M. Jacoby, and A. Finkelstein. The water permeability of toad urinary bladder. I. Permeability of barriers in series with the luminal membrane. J. Gen. Physiol. 83: 529‐542, 1984.
 117. Levine, S. D., M. Jacoby, and A. Finkelstein. The water permeability of the toad urinary bladder. II. The value of Pf/Pd (w) for the antidiuretic‐hormone induced water permeation pathway. J. Gen. Physiol. 83: 543‐561, 1984.
 118. Levine, S. D., W. A. Kachadorian, D. N. Levin, and D. Schlondorff. Effects of trifluoperazine on function and structure of toad urinary bladder: role of calmodulin in vasopressin‐stimulation of water permeability. J. Clin. Invest. 67: 662‐672, 1981.
 119. Levine, S. D., W. A. Kachadorian, N. C. Verna, and D. Schlondorff. Effect of hydrazine on transport in toad urinary bladder. Am. J. Physiol. 239 (Renal Fluid Electrolyte Physiol. 8): F319‐F327, 1980.
 120. Levine, S. D., D. N. Levin, and D. Schlondorff. Calcium flow‐independent actions of calcium channel blockers in toad urinary bladder. Am. J. Physiol. 244 (Cell Physiol. 13): C243‐C249, 1983.
 121. Levinsky, N. G., and R. W. Berliner. The role of urea in the urine concentrating mechanism. J. Clin. Invest. 38: 741‐748, 1959.
 122. Levitt, D. G., and H. J. Mlekoday. Reflection coefficient and permeability of urea and ethylene glycol in the human red cell membrane. J. Gen. Physiol. 81: 239‐253, 1983.
 123. Levy, M., and N. L. Starr. The mechanism of glucagon‐induced natriuresis in dogs. Kidney Int. 2: 76‐84, 1972.
 124. Long, W. S. Renal secretion of urea in Rana catesbeiana. In: Urea and the Kidney, edited by B. Schmidt‐Nielsen and D. W. S. Kerr. Amsterdam: Excerpta Medica Foundation, 1970, p. 216‐22.
 125. Lueck, J. D., and L. L. Miller. The effect of perfusate pH on glutamine metabolism in the isolated perfused rat liver. J. Biol. Chem. 245: 5491‐5497, 1970.
 126. Macey, R. I., and R. E. L. Farmer. Inhibition of water and solute permeability in human red cells. Biochim. Biophys. Acta 211: 104‐106, 1970.
 127. Maddox, D. A., and F. C. Rector, Jr. Effects of surgery on plasma volume and salt and water excretion in rats. Am. J. Physiol. 233 (Renal Fluid Electrolyte Physiol. 2): F600‐F606, 1977.
 128. Maffly, R. H., R. M. Hays, E. Lamdin, and A. Leaf. The effect of neurohypophyseal hormones on the permeability of the toad bladder to urea. J. Clin. Invest. 39: 630‐641, 1960.
 129. Marsh, D. J. Solute and water flows in thin limbs of Henle's loop in the hamster kidney. Am. J. Physiol. 218: 824‐831, 1970.
 130. Marsh, D. J. Computer simulation of renal countercurrent systems. Federation Proc. 42: 2398‐2404, 1983.
 131. Marsh, D. J., and S. P. Azen. Mechanism of NaCl reabsorption by hamster thin ascending limbs of Henle's loop. Am. J. Physiol. 228: 71‐79, 1975.
 132. Marsh, D. J., and C. M. Martin. Lack of water of urea movement from pelvic urine to papilla in hydropenic hamsters. Miner. Electrolyte Metab. 3: 81‐86, 1980.
 133. Marshall, E. K., Jr. The secretion of urea in the frog. J. Cell. Comp. Physiol. 2: 349‐353, 1932.
 134. Marshall, M., R. L. Metzenberg, and P. P. Cohen. Physical and kinetic properties of carbamyl phosphate synthetase from frog liver. J. Biol. Chem. 236: 2229‐2237, 1961.
 135. Mayrand, R. R., and D. G. Levitt. Urea and ethylene glycol‐facilitated transport systems in the human red cell membrane: saturation, competition, and asymmetry. J. Gen. Physiol. 81: 221‐237, 1983.
 136. Moeller, E., J. F. McIntosh, and D. D. Van Slyke. Studies of urea excretion. II. Relationship between urine volume and the rate of urea excretion by normal adults. J. Clin. Invest. 6: 427‐465, 1929.
 137. Moore, L. C. and D. J. Marsh. How descending limb of Henle's loop permeability affects hypertonic urine formation. Am. J. Physiol. 239 (Renal Fluid Electrolyte Physiol. 8): F57‐F71, 1980.
 138. Moore, L. C., D. J. Marsh, and C. M. Martin. Loop of Henle during the water‐to‐antidiuresis transition in Brattleboro rats. Am. J. Physiol. 239 (Renal Fluid Electrolyte Physiol. 8): F72‐F83, 1980.
 139. Morel, F., C. de Rouffignac, D. J. Marsh, M. Guinnebault, and C. Lechene. Etude par microponction de l'elaboration de l'urine. II. Chez le Psammomys non diuretique. Nephron 6: 553‐570, 1969.
 140. Morgan, T., and R. W. Berliner. Permeability of the loop of Henle, vasa recta, and collecting duct to water, urea, and sodium. Am. J. Physiol. 215: 108‐115, 1968.
 141. Morgan, T., B. Rayson, and D. Haberle. The effects of sodium chloride, urea, and mannitol on the permeability in vitro of rat papillary collecting ducts to THO, 14C urea, and 22Na. Clin. Exp. Pharmacol. Physiol. 4: 565‐574, 1977.
 142. Murdaugh, H. V., E. D. Robin, and C. D. Hearn. Urea: apparent carrier‐mediated transport by facilitated diffusion in dogfish erythrocytes. Science 144: 52‐53, 1964.
 143. Murdaugh, H. V., B. Schmidt‐Nielsen, E. M. Doyle, and R. O'Dell. Renal tubular regulation of urea excretion in man. J. Appl. Physiol. 13: 263‐268, 1958.
 144. Neilsen, A. L., and H. O. Bang. The influence of diet on the renal function of healthy persons. Acta Med. Scand. 130: 382‐388, 1948.
 145. Niessl, W., and H. Roeskenbleck. Konzentrierung von Loesungen unterschiedlicher Zusammenstzung durch alleinige Gegenstromdiffusion und Gegenstromosmose als moeglicher Mechanismus der Harkonzentrierung. Pflugers Arch. 283: 230‐241, 1965.
 146. Nonoguchi, H., M. A. Knepper, and V. C. Manganiello. Effects of atrial natriuretic factor on cyclic guanosine monophosphate and cyclic adenosine monophosphate accumulation in microdissected nephron segments from rats. J. Clin. Invest. 79: 500‐507, 1987.
 147. Nonoguchi, H., J. M. Sands, and M. A. Knepper. Atrial natriuretic factor inhibits vasopressin stimulated osmotic water permeability in rat inner medullary collecting duct. J. Clin. Invest. 82: 1383‐1390, 1988.
 148. O'Connor, W. J., and R. A. Summerhill. The excretion of urea by dogs following a meat meal. J. Physiol. 256: 81‐91, 1976.
 149. O'Connor, W. J., and R. A. Summerhill. The effect of a meal of meat on glomerular filtration rate in dogs at normal urine flows. J. Physiol. 256: 81‐91, 1976.
 150. Oliver, J., and E. Bourke. Adaptation in urea ammonium excretion in metabolic acidosis in the rat: a reinterpretation. Clin. Sci. Mol. Med. 48: 515‐520, 1975.
 151. Oliver, J., A. M. Koeltz, J. Costello, and E. Bourke. Acid‐base induced alterations in glutamine metabolism and ureagenesis in perfused muscle and liver of the rat. Eur. J. Clin. Invest. 7: 445‐449, 1977.
 152. Oliver, R. E., D. R. Roy, and R. L. Jamison. Urinary concentration in the papillary collecting duct of the rat: role of the ureter. J. Clin. Invest. 69: 157‐164, 1982.
 153. Pennell, J. P., F. B. Lacy, and R. L. Jamison. An in vivo study of the concentrating process in the descending limb of Henle's loop. Kidney Int. 5: 337‐347, 1974.
 154. Pennell, J. P., V. Sanjana, N. R. Frey, and R. L. Jamison. The effect of urea infusion on the urinary concentrating mechanism in protein‐depleted rats. J. Clin. Invest. 55: 399‐409, 1975.
 155. Phromphetcharat, V., A. Jackson, P. D. Dass, and T. C. Welbourne. Ammonia partitioning between glutamine and urea: interorgan participation in metabolic acidosis. Kidney Int. 20: 598‐605, 1981.
 156. Pitts, R. F. The effects of infusing glycin and of varying the dietary protein intake on renal hemodynamics in the dog. Am. J. Physiol. 142: 355‐365, 1944.
 157. Pitts, R. F. Renal production and excretion of ammonia. Am. J. Physiol. 36: 20‐742, 1964.
 158. Pitts, R. F. Control of renal production of ammonia. Kidney Int. 1: 297‐305, 1972.
 159. Pullman, T. N., A. R. Lavender, and I. Aho. Direct effects of glucagon on renal hemodynamics and excretion of inorganic ions. Metabolism 16: 358‐373, 1967.
 160. Rabinowitz, L., R. A. Gunther, E. S. Shoji, R. A. Freedland, and E. H. Avery. Effects of high and low protein diets on sheep renal function and metabolism. Kidney Int. 4: 188‐207, 1973.
 161. Rastegar, A., D. Biemesderfer, M. Kashgarian, and J. P. Hayslett. Changes in membrane surfaces of collecting duct cells in potassium adaptation. Kidney Int. 18: 293‐301, 1980.
 162. Reddi, P. K., W. E. Knox, and A. Herzfeld. Types of arginase in rat tissues. Enzyme 20: 305‐314, 1975.
 163. Reif, M. C., S. L. Troutman, and J. A. Schafer. Sustained response to vasopressin in isolated rat cortical collecting tubule. Kidney Int. 26: 725‐732, 1984.
 164. Robinson, R. R., and E. E. Owen. Intrarenal distribution of ammonia during diuresis and antidiuresis. Am. J. Physiol. 208: 129‐134, 1965.
 165. Robinson, R. R., and B. Schmidt‐Nielsen. Distribution of arginase within the kidneys of several vertebrate species. J. Cell. Comp. Physiol. 62: 147‐157, 1963.
 166. Roch‐Ramel, F., J. Diezi, F. Chomety, P. Michoud, and G. Peters. Disposal of large urea overloads by the rat kidney: a micropuncture study. Am. J. Physiol. 218: 1524‐1532, 1970.
 167. Rocha, A. S., and J. P. Kokko. Permeability of medullary nephron segments to urea and water: effect of vasopressin. Kidney Int. 6: 379‐387, 1974.
 168. Rocha, A. S., and L. H. Kudo. Water, urea, sodium, chloride, and potassium transport in the in vitro isolated perfused capillary collecting duct. Kidney Int. 22: 485‐491, 1982.
 169. Sakai, T., D. Craig, A. Wexler, and D. J. Marsh. Fluid waves in renal tubules. Biophys. J. 50: 805‐813, 1986.
 170. Sands, J. M., and M. A. Knepper. Urea permeability of mammalian inner medullary collecting duct system and papillary surface epithelium. J. Clin. Invest. 79: 138‐147, 1987.
 171. Sands, J. M., H. Nonoguchi, and M. A. Knepper. Effects of arginine vasopressin and atrial natriuretic factor on osmotic water permeability and urea permeability of rat inner medullary collecting ducts, abstracted. Kidney Int. 31: 450, 1987.
 172. Sands, J. M., H. Nonoguchi, and M. A. Knepper. Vasopressin effects on urea and H2O transport in inner medullary collecting duct subsegments. Am. J. Physiol. 253 (Renal Fluid Electrolyte Physiol. 22): F823‐F832, 1987.
 173. Sanjana, V. M., C. R. Robertson, and R. L. Jamison. Water extraction from the inner medullary collecting tubule system: a role for urea. Kidney Int. 10: 139‐146, 1976.
 174. Sato, M., and M. J. Dunn. Interactions of vasopressin, prostaglandins, and cAMP in rat renal papillary collecting tubule cells in culture. Am. J. Physiol. 247 (Renal Fluid Electrolyte Physiol. 16): F423‐F433, 1984.
 175. Schafer, J. A., and T. E. Andreoli. The effect of antidiuretic hormone on solute flows in mammalian collecting tubules. J. Clin. Invest. 51: 1279‐1286, 1972.
 176. Schimke, R. T. Adaptive characteristics of urea cycle enzymes in the rat. J. Biol. Chem. 237: 459‐468, 1962.
 177. Schimke, R. T. Studies on factors affecting levels of urea cycle enzymes in rat liver. J. Biol. Chem. 238: 1012‐1018, 1963.
 178. Schlondorff, D., C. P. Carvounis, M. Jacoby, J. A. Satriano, and S. D. Levine. Multiple sites for interaction of prostaglandin and vasopressin in toad urinary bladder. Am. J. Physiol. 241 (Renal Fluid Electrolyte Physiol. 10): F625‐F631, 1981.
 179. Schlondorff, D., and S. D. Levine. Inhibition of vasopressin‐stimulated water flow in toad bladder by phorbol myristate acetate, dioctanoylglycerol, and RHC‐80267: evidence for modulation of action of vasopressin by protein kinase C. J. Clin. Invest. 76: 1071‐1078, 1985.
 180. Schlondorff, D., and J. A. Satriano. Interactions of vasopressin, cAMP, and prostaglandins in toad urinary bladder. Am. J. Physiol. 248 (Renal Fluid Electrolyte Physiol. 17): F454‐F458, 1985.
 181. Schmidt‐Nielsen, B. Urea excretion in mammals. Physiol. Rev. 38: 139‐168, 1958.
 182. Schmidt‐Nielsen, B., M. Churchill, and L. N. Reinkinc. Occurrence of renal pelvic refluxes during rising urine flow rate in rats and hamsters. Kidney Int. 18: 419‐431, 1980.
 183. Schmidt‐Nielsen, B., and R. O'Dell. Effect of diet on distribution of urea and electrolytes in kidneys of sheep. Am. J. Physiol. 197: 856‐860, 1959.
 184. Schmidt‐Nielsen, B., and H. Osaki. Renal response to changes in nitrogen metabolism in sheep. Am. J. Physiol. 193: 657‐661, 1958.
 185. Schmidt‐Nielsen, B., H. Osaki, H. V. Murdaugh, Jr., and R. O'Dell. Renal regulation of urea excretion in sheep. Am. J. Physiol. 194: 221‐228, 1958.
 186. Schmidt‐Nielsen, B., and R. R. Robinson. Contribution of urea to urinary concentrating ability in the dog. Am. J. Physiol. 218: 1363‐1369, 1970.
 187. Schmidt‐Nielsen, B., and C. R. Shrauger. Handling of urea and related compounds by the renal tubules of the frog. Am. J. Physiol. 205: 483‐488, 1963.
 188. Schroeck, H., and L. Goldstein. Interorgan relationships for glutamine metabolism in normal and acidotic rats. Am. J. Physiol. 240 (Endocrinol. Metab. 3): E519‐E525, 1981.
 189. Schuetz, W., and J. Schnermann. Pelvic urine composition as a determinant of inner medullary solute concentration and urine osmolality. Pflugers Arch. 334: 154‐166, 1972.
 190. Sha'afi, R. I., C. M. Gary‐Bobo, and A. K. Solomon. Permeability of red cell membranes to small hydrophilic and lipophilic solutes. J. Gen. Physiol. 58: 238‐258, 1971.
 191. Shannon, J. A. Glomerular filtration and urea excretion in relation to urine flow in the dog. Am. J. Physiol. 117: 206‐225, 1936.
 192. Shannon, J. A. Urea excretion in the normal dog during forced diuresis. Am. J. Physiol. 122: 782‐787, 1938.
 193. Shannon, J. A., N. Jolliffe, and H. W. Smith. The excretion of urine in the dog. IV. The effect of maintenance diet, feeding, etc. upon the quantity of glomerular filtrate. Am. J. Physiol. 101: 625‐638, 1932.
 194. Shi, L.‐B., D. Brown, and A. S. Verkman. Water, proton and urea transport in toad bladder endosomes which contain the vasopressin‐sensitive water channel. J. Gen. Physiol. 95: 941‐960, 1990.
 195. Smith, H. W. De urina. Kaiser Found. Med. Bull. 6: 1‐17, 1958.
 196. Snodgrass, P. J., R. C. Lin, W. A. Muller, and T. T. Aoki. Induction of urea cycle enzymes of rat liver by glucagon. J. Biol. Chem. 253: 2748‐2753, 1978.
 197. Somero, G. N. Protons, osmolytes, and fitness of internal milieu for protein function. Am. J. Physiol. 251 (Regulatory Integrative Comp. Physiol. 20): R197‐R213, 1986.
 198. Sonnenberg, H., and C. Chong. Comparison of micropuncture and microcatheterization in papillary collecting duct. Am. J. Physiol. 239 (Renal Fluid Electrolyte Physiol. 8): F92‐F95, 1980.
 199. Sonnenberg, H., and D. R. Wilson. Urea handling by the medullary collecting duct of the rat kidney during hydropenia and urea infusion. Pflugers Arch. 390: 131‐137, 1981.
 200. Sonnenberg, H., and D. R. Wilson. Urea handling by the distal tubule and collecting duct of the rat during urea‐saline, isotonic saline, or urea diuresis. Can. J. Physiol. Pharmacol. 60: 128‐133, 1982.
 201. Star, R. A. Apical membrane limits urea permeation across the rat inner medullary collecting duct. J. Clin. Invest. 86: 1172‐1178, 1990.
 202. Star, R. A., H. Nonoguchi, R. Balaban, and M. A. Knepper. Calcium and cyclic adenosine monophosphate as second messengers for vasopressin in the rat inner medullary collecting duct. J. Clin. Invest. 81: 1879‐1888, 1988.
 203. Stephenson, J. L. Concentration of the urine in a central core model of the renal counterflow system. Kidney Int. 2: 85‐94, 1972.
 204. Stephenson, J. L. The renal concentrating mechanism: fundamental concepts. Federation Proc. 42: 2386‐2391, 1983.
 205. Stephenson, J. L., R. P. Tewarson, and R. Mejia. Quantitative analysis of mass and energy balance in non‐ideal models of the renal counterflow system. Proc. Natl. Acad. Sci. USA 71: 1618‐1622, 1974.
 206. Stewart, P. M., and M. Walser. Short term regulation of ureagenesis. J. Biol. Chem. 255: 5270‐5280, 1980.
 207. Stokes, R. H. Tracer diffusion in binary solutions subject to a dimerization equilibrium. J. Phys. Chem. 69: 4012‐4017, 1965.
 208. Stokes, R. H. Osmotic coefficients of concentrated aqueous urea solutions from freezing point measurements. J. Phys. Chem. 70: 1199‐1203, 1966.
 209. Stoner, L., and F. Roch‐Ramel. The effects of pressure on the water permeability of the descending limb of Henle's loops of rabbits. Pflugers Arch. 382: 15, 1979.
 210. Tannen, R. L. Ammonia metabolism. Am. J. Physiol. 235 (Renal Fluid Electrolyte Physiol. 4): F265‐F277, 1978.
 211. Taylor, W. M., E. Van de Pol, and F. L. Bygrave. On the stimulation of respiration by alpha‐adrenergic agonists in perfused rat liver. Eur. J. Biochem. 155: 319‐322, 1986.
 212. Titheradge, M. A., and R. C. Haynes, Jr. The hormonal stimulation of ureagenesis in isolated hepatocytes through increases in mitochondrial ATP production. Arch. Biochem. Biophys. 201: 44‐55, 1980.
 213. Triebwasser, K. L., and R. A. Freedland. The effect of glucagon on ureagenesis from ammonia by isolated rat hepatocytes. Biochem. Biophys. Res. Commun. 76: 1159‐1165, 1977.
 214. Truniger, B., and B. Schmidt‐Nielsen. Intrarenal distribution of urea and related compounds: effects of nitrogen intake. Am. J. Physiol. 207: 971‐978, 1964.
 215. Ullrich, K. J., and K. H. Jarausch. Untersuchungen zum Problem der Harnkonzentrierung und Harnverduennung. Pflugers Arch. 262: 537‐550, 1956.
 216. Ullrich, K. J., and G. Pehling. Glycerylphosphorylcholin‐Umsatz und Glycerylphosphoryl‐Diesterase in der Saeugetierniere. Biochem. Z. 331: 98‐102, 1959.
 217. Ullrich, K. J., G. Rumrich, and C. A. Baldamus. Mode of urea transport across the mammalian nephron. In: Urea and the Kidney, edited by B. Schmidt‐Nielsen and D. W. S. Kerr. Amsterdam: Excerpta Medica, 1970, p. 175‐185.
 218. Ullrich, K. J., G. Rumrich, and G. Fuchs. Wasserpermeabilitaet und transtubulaerer Wasserfluss corticaler Nephron‐abschnitte bei verschiedenen Diuresezustaenden. Pflugers Arch. 280: 99‐119, 1964.
 219. Ullrich, K. J., G. Rumrich, and B. Schmidt‐Nielsen. Urea transport in the collecting duct of rats on normal and low protein diet. Pflugers Arch. 295: 147‐156, 1967.
 220. Ullrich, K. J., B. Schmidt‐Nielsen, R. O'Dell, G. Pehling, C. W. Gottschalk, W. E. Lassiter, and M. Mylle. Micropuncture study of composition of proximal and distal tubular fluid in rat kidney. Am. J. Physiol. 204: 527‐531, 1963.
 221. Ussing, H. H., and K. Zerahn. Active transport of sodium as the source of electric current in the short circuited isolated frog skin. Acta Physiol. Scand. 23: 110‐127, 1951.
 222. van Os, C. H., M. D. de Jong, and J. F. G. Slegers. Dimensions of polar pathways through rabbit gallbladder epithelium: the effect of phloretin on nonelectrolyte permeability. J. Membr. Biol. 15: 363‐382, 1974.
 223. Verkman, A. S., J. A. Dix, and J. L. Seifter. Water and urea transport in renal microvillus membrane vesicles. Am. J. Physiol. 248 (Renal Fluid Electrolyte Physiol. 17): F650‐F655, 1985.
 224. Verkman, A. S., J. A. Dix, J. L. Seifter, K. L. Skorecki, C. Y. Jung, and D. A. Ausiello. Radiation inactivation studies of renal brush border water and urea transport. Am. J. Physiol. 249 (Renal Fluid Electrolyte Physiol. 18): F806‐F812, 1985.
 225. Verkman, A. S., and H. Ives. Water permeability and fluidity of renal basolateral membranes. Am. J. Physiol. 250 (Renal Fluid Electrolyte Physiol. 19): F633‐F643, 1986.
 226. Walker, A. M., and C. L. Hudson. The role of the tubule in the excretion of urea by the amphibian kidney. Am. J. Physiol. 118: 130‐141, 1937.
 227. Walker, L. A., and J. C. Froelich. Dose‐dependent stimulation of renal prostaglandin synthesis by deamino‐8‐D‐arginine vasopressin (DDAVP). J. Pharmacol. Exp. Therap. 217: 87‐91, 1981.
 228. Walser, B. L., Y. Yagil, and R. L. Jamison. Urea flux in the ureter. Am. J. Physiol. 255 (Renal Fluid Electrolyte Physiol. 24): F244‐F249, 1988.
 229. Walser, M. Determinants of ureagenesis, with particular reference to renal failure. Kidney Int. 17: 709‐721, 1980.
 230. Walser, M. Urea cycle disorders and other hereditary hyper‐ammonemic syndromes. In: Metabolic Basis of Inherited Disease (5th ed.), edited by J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, and J. L. Goldstein. New York: McGraw‐Hill, 1982, p. 402‐438.
 231. Walser, M. Urea metabolism: regulation and sources of nitrogen. In: Amino Acids: Metabolism and Medical Application, edited by J. Wright. Boston: PSG, 1983, p. 77‐87.
 232. Walser, M. Roles of urea production, ammonium excretion, and amino acid oxidation in acid‐base balance. Am. J. Physiol. 250 (Renal Fluid Electrolyte Physiol. 19): F181‐F188, 1986.
 233. Welbourne, T. C. Effect of metabolic acidosis on hind‐quarter glutamine and alanine release. Metabolism 35: 614‐618, 1986.
 234. Welbourne, T. C., V. Phromphetcharat, G. Givens, and S. Joshi. Regulation of interorganal glutamine flow in metabolic acidosis. Am. J. Physiol. 250 (Endocrinol. Metab. 13): E457‐E463, 1986.
 235. Welling, L. W., A. P. Evan, and D. J. Welling. Shape of cells and extracellular channels in rabit cortical collecting ducts. Kidney Int. 20: 211‐222, 1981.
 236. Welling, L. W., and D. J. Welling. Surface areas of the brush border and lateral cell walls in the rabbit proximal nephron. Kidney Int. 8: 343‐348, 1975.
 237. Welling, L. W., and D. J. Welling. Shape of epithelial cells and intercellular channels in the rabbit proximal nephron. Kidney Int. 9: 385‐394, 1976.
 238. Welling, L. W., D. J. Welling, and J. J. Hill. Shape of cells and intercellular channels in the rabbit thick ascending limb of Henle. Kidney Int. 13: 114‐151, 1978.
 239. Wexler, A. S., R. E. Kalaba, and D. J. Marsh. The one‐dimensional, passive countercurrent model cannot explain hypertonic urine formation. Am. J. Physiol. 253 (Renal Fluid Electrolyte Physiol. 22): F1020‐F1030, 1987.
 240. Wexler, A. S., R. E. Kalaba, and D. J. Marsh. Three dimensional anatomy and the renal concentrating mechanism. I. Modeling results. Am. J. Physiol. 260 (Renal Fluid Electrolyte Physiol. 29): F368‐F383, 1991.
 241. Wexler, A. S., R. E. Kalaba, and D. J. Marsh. Three dimensional anatomy and the renal concentrating mechanism. II. Sensitivity results. Am. J. Physiol. 260 (Renal Fluid Electrolyte Physiol. 29): F384‐F394, 1991.
 242. Wiederholt, M., and B. Wiederholt. Der Einfluss von Dexamethasone auf die Wasser‐ und Electrolytausscheidung adrenalektomierter Ratten. Pflugers Arch. 302: 57‐78, 1968.
 243. Wieth, J. O., J. Funder, R. B. Gunn, and J. Brahm. Passive transport pathways for chloride and urea through the red cell membrane. In: Comparative Biochemistry and Physiology of Transport, edited by L. Bolis, K. Bloch, S. E. Luria, and F. Lynen. Amsterdam: Elsevier, 1974, p. 317‐337.
 244. Wilczewski, T. W., H. Sonnenberg, and G. Carrasquer. Permeability of superficial proximal tubules and loops of Henle to urea in rats. Proc. Soc. Exp. Biol. Med. 135: 609‐612, 1970.
 245. Wilson, D. R., and H. Sonnenberg. Urea secretion in medullary collecting duct of the rat kidney during water and mannitol diuresis. Am. J. Physiol. 240 (Renal Fluid Electrolyte Physiol. 9): F165‐F171, 1981.
 246. Wilson, D. R., and H. Sonnenberg. Urea reabsorption in the medullary collecting duct of protein‐depleted young rats before and after urea infusion. Pflugers Arch. 393: 302‐307, 1982.
 247. Wirz, H. Der osmotische Druck des Blutes in der Nierenpapille. Helv. Physiol. Acta 11: 20‐29, 1953.
 248. Wirz, H. Der osmotische Druck in den corticalen Tubuli der Rattenniere. Helv. Physiol. Acta 14: 353‐362, 1956.
 249. Wirz, H., B. Hargitay, and W. Kuhn. Lokalisation des Konzentrierungsprozesses in der Niere durch direkte Kryoskopie. Helv. Physiol. Acta 9: 196‐207, 1951.
 250. Woodhall, P. B., and C. C. Tisher. Response of the distal tubule and cortical collecting duct to vasopressin in the rat. J. Clin. Invest. 52: 3095‐3108, 1973.
 251. Wright, E. M., and R. J. Pietras. Routes of nonelectrolyte permeation across epithelial membranes. J. Membr. Biol. 17: 293‐312, 1974.
 252. Yancey, P. H., M. E. Clark, S. C. Hand, R. D. Bowlus, and G. N. Somero. Living with water stress: evolution of osmolyte systems. Science 217: 1214‐1222, 1982.
 253. Yancey, P. H., and G. N. Somero. Counteraction of urea destabilization of protein structure by methylamine osmoregulatory compounds of elasmobranch fishes. Biochem. J. 183: 317‐323, 1979.
 254. Zhang, R., and A. S. Verkman. Urea transport in freshly isolated and cultured cells from rat inner medullary collecting duct. J. Membr. Biol. 117: 253‐261, 1990.
 255. Zhang, R., and A. S. Verkman. Expression of mRNA coding for kidney, toad bladder and red cell water and urea transporters in Xenopus oocytes. J. Am. Soc. Nephrol. 1: 681, 1990.
 256. Zusman, R. M., J. R. Reiser, and J. S. Handler. Vasopressin‐stimulated prostaglandin E biosynthesis in the toad urinary bladder. J. Clin. Invest. 60: 1339‐1347, 1977.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Renal Handling of Urea
 

How to Cite

Donald J. Marsh, Mark A. Knepper. Renal Handling of Urea. Compr Physiol 2011, Supplement 25: Handbook of Physiology, Renal Physiology: 1317-1347. First published in print 1992. doi: 10.1002/cphy.cp080229