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EDITORIAL FOCUS
ESSAYS ON APS CLASSIC PAPERS
Departments of Physiology and Biophysics, and Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294
ABSTRACT
This essay looks at the historical significance of four APS classic papers that are freely available online:
Jolliffe N, Shannon JA, and Smith HW. The excretion of urine in the dog. III. The use of non-metabolized sugars in the measurement of the glomerular filtrate. Am J Physiol 100: 301—312, 1932 (http://ajplegacy.physiology.org/cgi/reprint/100/2/301).
Shannon JA. The excretion of inulin by the dog. Am J Physiol 112: 405—413, 1935 (http://ajplegacy.physiology.org/cgi/reprint/112/3/405).
Shannon JA and Fisher S. The renal tubular reabsorption of glucose in the normal dog. Am J Physiol 122: 765—774, 1938 (http://ajplegacy.physiology.org/cgi/reprint/122/3/765).
Shannon JA, Farber S, and Troast L. The measurement of glucose Tm in the normal dog. Am J Physiol 133: 752—761, 1941 (http://ajplegacy.physiology.org/cgi/reprint/133/3/752).
Several investigators in the first half of the 20th century had suggested that the loop of Henle was a key element in urinary concentration in mammals and birds. In 1908 Hirokawa (12), using cryoscopic osmometry of tissue slices, showed that urine osmolality increases progressively in the medullary interstitium and along the loop of Henle and the collecting duct. Also, the beautiful morphological studies published by Karl Peter in 1909 (15) established the direct correlation between the length of the loop of Henle and the maximal urine concentration that existed among species, and by the early 1930s it was recognized that, among vertebrates, only birds and mammals responded to vasopressin by concentrating their urine and only they possessed a loop of Henle (4, 5). Some investigators concluded that the urine became concentrated in the loop of Henle, but this view was contradicted by tentative results from the first micropuncture study in mammals by Walker et al. (22), in which two of the three samples of fluid obtained from the elusive distal tubules of rats were hyposmotic to plasma while the third was isosmotic. Thus, when Homer Smith published his classic book The Kidney. Structure and Function in Health and Disease (18) in 1951, urinary concentration was ascribed to active water reabsorption, a hypothesis that was quickly demonstrated to be impossible on thermodynamic grounds (3). Little attention was paid to the loop of Henle in Smith's book, largely due to the lack of any knowledge of its function, and schematic diagrams of the nephron depicted the loop of Henle as if it were a piece of plumbing connecting the proximal and distal portions of the nephron, and even the most critical aspect of that plumbing, i.e., the hairpin loop, was omitted.
Heinrich Wirz and his colleagues provided more complete data that addressed the countercurrent model directly. They convincingly established that urine collected from the early distal tubule was hyposmotic (26), whereas vasa recta blood was hyperosmotic to systemic blood plasma (24). Some questioned the reliability of the observations or proposed mechanisms alternative to the countercurrent mechanism. One of the most outstanding renal physiologists of recent times, Robert Berliner, and his associates (2) proposed that the loop of Henle reabsorbed solute in excess of water. Although this mechanism could account for the medullary hypertonicity needed to abstract water from the collecting duct, it also predicted that the tubular fluid would be dilute along both descending and ascending limbs of the loop of Henle (see also Ref. 1).
It was in this intellectual and historical context that the studies of Gottschalk and Mylle (9) and Ullrich et al. (21) were conducted. After his internship at the Massachusetts General Hospital, Carl W. Gottschalk (Fig. 1) learned the art of fluid sampling and measuring hydrostatic pressure in capillaries using micropipettes in the laboratory of Eugene Landis in the Department of Physiology at Harvard. In 1952 he joined the Department of Medicine at the University of North Carolina, where he established the Chapel Hill Micropuncture Laboratory and recruited Margaret Mylle, who came to be described as "one of the most skilled micropuncturists in the world" (23). Together they conducted the time-consuming and technically challenging collection of tubular fluid samples from different nephron segments and the equally demanding task of measuring the osmolality of those samples.
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Carl Gottschalk began his studies of the concentrating mechanism with the expectation that his findings would confirm the key prediction of the Berliner model, i.e., that urine at the tip of the loop of Henle should be hypotonic.1 To test this prediction, Gottschalk and Mylle used hamsters and two desert rodents (the kangaroo rat and Psammomys obesus) because their elongated renal papillae allowed micropuncture sampling of the thin segments of the longer loops of Henle. They found that urine samples from the tip of the loop of Henle were uniformly hyperosmotic to systemic blood plasma (9) and not hyposmotic as predicted by the hypothesis of Berliner et al. (2). They also established that, in hydropenia, the hypertonic urine at the tip of the loop was isosmotic to urine in the collecting duct and vasa recta plasma near the papillary tip (9). Over the next two years, Gottschalk and Mylle also demonstrated the high water permeability of the descending limb and water impermeability of the ascending limb of the loop of Henle, as well as demonstrating that the osmolality of the urine was regulated by the water permeability of the collecting duct (6, 7). In summary, Gottschalk and Mylle provided the convincing experimental data that supported all of the predictions of the countercurrent model, and they had demonstrated that the generation of the medullary osmotic gradient was dependent on the reabsorption of solute without water in the ascending limb of the loop, thus localizing the "single effect" mechanism of the model.
Although a new and exciting paradigm had been established by the work of Gottschalk and Mylle (9), there were important details that remained to be addressed. Among these was the role of urea in urinary concentration, which was the interest of Bodil Schmidt-Nielsen and Karl Ullrich. Karl Ullrich and his associates had analyzed micro-samples of interstitial fluid from the medulla and had shown that NaCl and urea were the primary contributors, in approximately equal proportion, to the medullary hypertonicity, and that the concentrations of both solutes rose progressively from the corticomedullary junction to the tip of the papilla (19, 20). Schmidt-Nielsen (Fig. 2) was a comparative physiologist who had studied the kangaroo rat, camel, and other desert mammals as well as many marine and fresh water species (see Ref. 17). These studies led to her Bowditch Award Lecture for the American Physiological Society in 1957 (16), and to her firm conviction that urea played an important role in the concentrating mechanism (16, 17).
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This exceptional collaboration produced two landmark publications (8, 21). In the first of these papers (21), inulin, Na+, urea, and the osmolality were measured in tubular fluid sampled along the proximal and distal tubules of rats. Of particular note in the context of the countercurrent model, they showed that amount of urea delivered to the early distal tubule approximated the amount filtered despite reabsorption of nearly half that amount in the proximal tubule. These data established that urea must be recirculated from the medullary interstitium into the loop of Henle (21). In their second paper, these investigators analyzed micropuncture samples from the loop of Henle and collecting duct of hamsters and Psammomys and provided the first unequivocal demonstration that Na+ was actively reabsorbed in the water-impermeable thick ascending limb (8).
These studies appeared in the American Journal of Physiology between 1959 and 1963 and provided the key data in support of the countercurrent multiplication mechanism as well as the essential transport properties of the ascending and descending limbs of the loop of Henle and the collecting duct. They also clearly established the role of countercurrent exchange in the vasa recta in maintaining the medullary concentration gradient. In the present era, in which we now know the molecular structure of key elements in the process of urinary concentration, including aquaporins, urea transporters, and the NaK2Cl cotransporter, it is gratifying to reflect on how this knowledge accrued. Early morphological observations led to hypotheses that could be tested experimentally. These hypotheses derived not only from biological insight, but also incorporated concepts from physical chemistry and from conceptual and computational models. Finally, the hypotheses were verified by critical, very careful, experimental testing using the most advanced physiological approaches of the time, which in turn depended on concurrent advances in methodologies that permitted the analysis of ultramicro fluid samples.
I wish to conclude by acknowledging my debt in writing this essay to the superb book Renal Physiology: People and Ideas, and in particular the chapters by Berliner (1) and Windhager (23). I highly recommend these sources to those seeking more information about this exciting era in physiology. I am also very grateful to Dr. Bodil Schmidt-Nielsen, who provided verbal confirmation and elaboration for many of the events described, and to Dr. William E. Arendshorst, who provided helpful criticisms of the manuscript.
FOOTNOTES
Address for correspondence: J. A. Schafer, UAB, Dept. of Physiology and Biophysics, 1918 Univ. Blvd., Rm. 834 MCLM, Birmingham, AL 35294-0005 (E-mail: jschafer{at}uab.edu)
1 Verbal account by Dr. Bodil Schmidt-Nielsen to J. A. Schafer during a telephone conversation about an early draft of this essay on February 5, 2004. 
2 Some of the details concerning this international collaboration come from the unpublished recollections of Dr. Schmidt-Nielsen (see footnote 1) and differ slightly from the account of Berliner (1).
REFERENCES
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