620 HANDBOOK OF PHYSIOLOGY ^^ CIRCULATION I 



labeled red cells throughout the red cell mass, so 

 that mixing in the spleen is incomplete after 30 min, 

 but the error in blood volume due to this is less than 

 5 per cent. 



Other labeled-formed elements remain intra- 

 vascular for much shorter periods, reflecting the 

 shorter life spans and less strictly intravascular 

 distribution of white cells and platelets. P"-labeled 

 plasma proteins exchange fairly rapidly (measured 

 in hours) with extravascular proteins. 



Sodium occurs in the body as an essentially extra- 

 cellular ion with some 25 to 50 per cent of the body's 

 sodium in the skeleton. In normal subjects Na-'' 

 introduced intravenously rapidly (10-20 min) be- 

 comes distributed in the extracellular fluid portion 

 of the sodium space (except perhaps the cerebro- 

 spinal and intra-ocular fluids), whereas equilibration 

 with the exchangeable portion of the bone sodium pro- 

 ceeds slowly. In edematous subjects, isotopic equilib- 

 rium between Na-^ in the blood plasma and ascitic 

 fluid or other edema fluids may not be complete 

 at 24 hours after injection, presumably due to slow 

 mixing in the edema fluids. 



Labeled forms of water (with deuterium, tritium, 

 or O'^ as the label) and other substances such as 

 urea, which are distributed in total body water, leave 

 the circulation at rates measured in seconds and 

 minutes (49). The early distribution of tritiated 

 thymidine is in this category, although soon after- 

 wards that thymidine which is not catabolyzed is 

 incorporated in cell nuclei where it remains in- 

 definitely. 



Radioactive potassium (K^-) is one of the sub- 

 stances which disappear most rapidly from the circu- 

 lation. Walker & Wilde (71) found that in the rabbit 

 90 per cent of intravenously injected K*- passes out 

 of the circulation within i min. There is not complete 

 agreement as to why the disappearance of K"*- from 

 the circulation is so much (4 or 5 times) faster than 

 that of Na-^ D2O (1.5 times as fast), or iodine [Shep- 

 pard & Yudilevich (60)] (6 times as fast in the lungs). 

 Since ions of sodium and potassium are so similar 

 in the physical properties affecting mobility, it would 

 be reasonable to expect their difTusion rates to be 

 about equal. Walker & Wilde (71) point out that it 

 is ridiculous to ascribe the rapidity of disappearance 

 of K''^ to preferential uptake in the liver and other 

 viscera, since 96 per cent of the cardiac output would 

 have to pass through the viscera to account for the 

 data. The difiference in distribution of sodium and 

 potassium is an important factor. Since the bulk of 

 potassium is intracellular, the K^- which leaves the 



circulation promptly gets diluted in a large potassium 

 pool, and the relative rate of feedback to the circula- 

 tion from the intracellular pool is low, whereas the 

 sodium in the interstitial fluid is much more favorably 

 situated for feedback to the circulation. Walker & 

 Wilde (71) discuss the possibility that potassium 

 ions have an exclusive ability to traverse the capillary 

 endothelial cells, and Sheppard et al. (61) analyze 

 the role of incomplete mixing in K"*^ disappearance 

 curves. 



THE TRACER CONCEPT 



History 



The idea of labeling a few members of a group of 

 similar objects and, from the behavior of the labeled 

 memljers, drawing conclusions about the behavior 

 of the group, is probably about as old as civilization 

 itself. Who knows, for example, when some ingenious 

 shepherd first put a bell on one sheep in order to 

 make it easier to follow his flock? Possibly the first 

 recorded tracer use is an Apocryphal story of how 

 Daniel trapped the priests by their footprints in 

 ashes strewn on the floor of the temple of the idol, 

 Bel. Somewhat the same concepts are used in modern 

 chemistry when a compound is labeled or "tagged" 

 with radioactive atoms and its metabolic pathway 

 is studied. 



Prior to the development of isotopes as labels, other 

 markers, particularly the dyes mentioned in the 

 introduction, were used in circulatory studies. Their 

 history and present uses are discussed in other chapters 

 of this Handbook. 



The history of isotopic methodology has been 

 reviewed by Hevesy (32). It is of interest to note that 

 radioactive isotopes of some of the heavy metals 

 were used in physiological studies before the dis- 

 covery in 1933 of deuterium and the first production of 

 artificial radioisotopes in the same year. The heavy 

 stable forms of hydrogen and nitrogen first made it 

 possible to study the kinetic behavior of naturally 

 occurring constituents in steady-state situations and 

 led to the now familiar but then revolutionary con- 

 cept of the dynamic state of body constituents. 



The nuclear reactor, supplemented by the 

 cyclotron, has made artificially produced isotopes of 

 every element (including several new elements) 

 available in quantities sufficient for use in physiologi- 

 cal studies. With this availability, of course, the 

 number and \ariety of applications have grown 



