IOOO 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



Mayerson et al. (232) or that ultramicroscopic dis- 

 ruption of vessel architecture produces new and still 

 larger apertures. Electron microscopy has shown 

 recently, for instance, that histamine can produce 

 separation of endothelial cells in venules so that 

 carbon particles pass between endothelial cells to 

 rest against the basement membrane (226, 226a). Ad- 

 ditional evidence in favor of enlarged leaks or of 

 new openings in injury has been provided recently 

 by Courtice & Morris (50-52, 54). Concentrations 

 of total cholesterol and of phospholipids were studied 

 in order to determine the plasma to lymph gradients 

 of lipoproteins in the limbs of cats and rabbits before 

 and after injury. These gradients were compared 

 with those for albumin and globulins. In lymph 

 from normal legs the concentrations of albumin, 

 globulins, cholesterol, and phospholipids were, 

 respectively, 48, 35, 24, and 33 per cent of the plasma 

 levels. After thermal injury the corresponding figures 

 for lymph were 81, 74, 60, and 74 per cent of the 

 plasma levels. Increased permeability to protein was 

 accompanied by increased permeability to lipopro- 

 teins, the diameters of which have been placed 

 tentatively at 150 to 350 A (144). Larger fat particles, 

 measuring perhaps 1500 A or more, e.g., the particles 

 in chyle or in an artificial fat emulsion, were not 

 transferred through the capillary wall to lymph to 

 any measurable extent, even after injury. However, as 

 Courtice mentions (52), although the passage of 

 lipoproteins and lipids becomes less as the size of the 

 molecule or complex increases, the exact mechanism 

 of their passage, whether between or through endo- 

 thelial cells, is still obscure. In addition, the molecular 

 mechanism and ultramicroscopic location of capillary 

 damage may well differ, depending upon the type of 

 injurious agent involved (208). Hence the basic nature 

 of Cohnheim's "molecular alteration in the vessel 

 walls" in various types of injury remains still a prime 

 unknown requiring study by pathologists, physi- 

 ologists, and electron microscopists alike. 



7. DIFFUSION, GENERAL PRINCIPLES 



The extravascular circulation caused by capillary 

 filtration and absorption is exceedingly important for 

 homeostasis of blood volume and for removal of large 

 protein molecules via the lymphatics. However, the 

 magnitude of the extravascular circulation is too small 

 to be of significance for the metabolic exchange of 

 small molecules between blood and tissues (see fig. 

 5.2). Metabolic exchange takes place largely by 

 diffusion processes which are almost independent of 

 the magnitude and direction of net fluid movement. 



Evidence to be discussed below indicates that diffusion 

 of lipid-insoluble molecules takes place through 

 aqueous channels between capillary endothelial cells. 

 Lipid-soluble molecules, on the other hand, diffuse 

 rapidly through the lipid plasma membranes of the 

 endothelial cells themselves and are thus free to 

 utilize the entire capillary surface area for the ex- 

 change process. Before undertaking a detailed analysis 

 of diffusion processes in the capillary circulation, it 

 will be helpful to review some physical laws governing 

 molecular diffusion in free solution and in simple 

 membranes. 



A. Free Diffusion 



The fundamental laws of free diffusion were first 

 described by Fick (96) in 1855. 



Adolf Fick (1829-igoi) was Professor of Physiology in 

 Wiirzburg. His most numerous publications were in the field 

 of muscle physiology, but his several classical contributions to 

 science were in the form of short, single publications in unre- 

 lated fields. Among circulatory physiologists he is known chiefly 

 as the originator of the "Fick principle" for determination of 

 cardiac output. Among ophthalmologists he is noted for the 

 development of tonometry and as author of "Fick's law"' 

 relating deformation of the cornea to intraocular pressure. 

 It is probable, however, that his greatest contribution to science 

 was his clear formulation of the laws of diffusion based on 

 analogy with Fourier's description of the flow of heat. "Die 

 Verbreitung eines gelosten Korpers in Losungsmittel geht, 

 wofern sie ungestort unter dem ausschliesslichen Einfluss 

 der Molecularkrafte stattfindet, nach demselben Gesetze 

 vorsich, welches Fourier fur die Verbreitung der Warme in 

 einem Leiter aufgestellt hat. . . Man darf nur in dem 

 Fourier'schen Gesetz das Wort Warmquantitat mit dem Worte 

 Quantitat des gelosten Korpers, und das Wort Temperature 

 mit Losungsdichtigkeit vertauschen." 



According to Fick's formulation, the rate of linear 

 diffusion (quantity, n, per unit time, /) in direction .v 

 and through cross-sectional area, A, is proportional 

 to the concentration gradient, dc dx. 



dn/dt -- D A dc/dx (7. 1) 



The constant of proportionality, D, is known as the 

 diffusion coefficient and its dimensions are Pr 1 . The 

 simplest possible application of equation 7.1 is to 

 steady-state diffusion where dc/dt is constant as a 

 function of both distance and time. In this case, the 

 equation 7.1 can be written 



n -" DA Ac/ Ax (7. 2) 



where the concentration gradient Ae A.v is constant 

 all along the diffusion path. Equation 7.2 is specially 

 applicable to diffusion through thin membranes 

 where the concentrations on the two sides of the 



