ioo8 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



SERUM ALBUMIN 

 MW 69,000 



fig. 8.1. Disappearance of substances from arterial plasma 

 of rabbits. Data for albumin are from Gitlin et al. (118), data 

 for inulin and sucrose are from Kruhoffer (190, 191), and data 

 for NaCl are from Morel (257). C is concentration in arterial 

 plasma at time /, C,„ is concentration in plasma at equilibrium; 

 C is initial concentration in arterial plasma obtained by 

 extrapolation to zero time. 



of the test molecules in tissue spaces, again at rates 

 which vary inversely with molecular size. Most 

 tissues of the body participate in the distribution 

 process, though at widely different rates. 



The rapid penetration of capillary walls by mole- 

 cules as large as sucrose or inulin implies a high order 

 of permeability to lipid-insoluble molecules. Cell 

 membranes generally (i.e., the plasma membranes 

 which envelop the protoplasm of all living cells) are 

 virtually impermeable to metabolically inert, lipid- 

 insoluble molecules as large as sucrose; indeed they 

 generally have a low order of permeability to most 

 ions. The behavior illustrated in figure 8.1 is more 

 characteristic of artificial porous membranes and this 

 resemblance has given rise to the hypothesis that 

 capillarv blood communicates directly with extra- 

 vascular fluid via a system of aqueous pores or 

 channels. Recent studies of capillary ultrastructure 

 (93) support earlier views (37, 276) that the structural 

 basis for this type of permeability is associated with 

 junctional regions between capillary endothelial cells. 

 The number, dimensions, and properties of trans- 

 capillary pores which would be necessary to account 



for observed capillary permeability to lipid-insoluble 

 molecules will be considered more fully in section g. 

 Initial experiments with isotopic tracers led to the 

 suggestion that arterial disappearance curves might 

 provide a quantitative measure of capillary perme- 

 ability (106, 138). For this purpose it was assumed 

 that diffusion from blood to extravascular space 

 could be represented by a simple two-compartment 

 diffusion system separated by the capillary membranes 

 and that concentrations in each compartment would 

 be uniform at each moment during the diffusion 

 process. The theoretical equation describing diffusion 

 in this simplified model is easily derived from Fick's 

 law and leads to the expression 



X- 



DA S (Vi + Vg) 



Ax 



V V 



V 2 



(8.1) 



where X is the (negative) slope of the observed ex- 

 ponential disappearance curve, V\ is plasma volume 

 and Fo is extravascular distribution volume (106, 233). 

 Reference to equation 7.2 shows that the term DA Sx 

 is the flux per unit concentration difference, n A< , 

 and is therefore a direct measure of capillary perme- 

 ability to the test molecules. More complex equations 

 describing arterial disappearance curves have been 

 derived to take account of loss by the kidneys, loss 

 by metabolism and distribution between more than 

 two compartments in series or in parallel (318, 319, 



33°. 34'- 3 6 3)- 



Equation 8.1 is specially applicable to the case of 



large, lipid-insoluble molecules such as proteins or 

 synthetic polymers. Diffusion of such substances 

 from the vascular system is so slow that their concen- 

 trations in arterial plasma may be taken as a close 

 approximation of mean concentration in capillary 

 plasma, i.e., the concentration gradient along the 

 length of each capillary is negligible at all times during 

 the diffusion process. In the example of figure 8.1 the 

 slope, \, for albumin is about — 0.1 per cent of the 

 initial concentration per min, or 100 per cent of the 

 plasma albumin every 16.6 hours. Similar values for 

 transcapillary exchange rates of serum albumin have 

 been observed in dog (370) and man (352). The free 

 diffusion coefficient of albumin is 0.085 X io -5 cm 2 

 per sec. Given a normal plasma volume, V\ t of 4 per 

 cent of body weight and a normal extracellular fluid 

 volume, r 2 , of 20 per cent then from equation 8.1 

 the effective capillary pore area per unit path length 

 available for restricted diffusion of serum albumin is 

 65 cm per 100 g tissue. This value may be compared 

 with the value of 70 cm per 100 g muscle calculated 



