936 7. MERCURIALS 



Mechanism of Transport Inhibition 



If one knows essentially nothing of the cellular site of action of the mer- 

 curials, and is completely ignorant of the molecular nature of ion transport, 

 it is difficult to discuss possible mechanisms of inhibition without becoming 

 ethereal. All the evidence points to a lack of significant depression of the 

 exergonic phases of renal metabolism at concentrations markedly affecting 

 transport, so it is likely that the action is on some component of the func- 

 tional system. If the postulated specific receptor for mercurials is a carrier, 

 then there is the problem of accounting for the inhibition of many types 

 of transport; furthermore, it is not at all certain that a carrier is involved 

 in ion transport. On the basis of what was said in the previous section on 

 the effects of mercurials on membranes and permeabilities, it is most likely 

 that the site of action is the tubular cell membrane. The Na+ pump is prob- 

 ably located in the peritubular membrane and the diffusion of Na+ across 

 the lumenal membrane is passive along concentration and electrical gra- 

 dients. The fact that the transmembrane potential is around — 43 mv at 

 the lumenal surface and — 64 mv at the peritubular surface was interpreted 

 by Giebisch (1960) as indicating the greater Na+ permeability of the lu- 

 menal membrane. Mercurials could thus depress Na+ resorption by acting 

 in three ways: (1) inhibition of the Na+ pump, (2) decrease of the permeabi- 

 hty to Na+ of the lumenal membrane, or (3) increase of the permeability 

 to Na+ of the peritubular membrane. It has frequently been assumed that 

 the mercurials inhibit active transport directly but, as has been discussed 

 for other systems, it is possible that the primary effect is on the membrane 

 structure controlling permeability. The evidence from the changes in elec- 

 trical potentials brought about by chlormerodrin shows that both mem- 

 branes are affected (Giebisch, 1961). The potential across the peritubular 

 membrane is decreased to —25 mv and, since the transtubular potential 

 is simultaneously decreased to — 7 mv, it would seem that the lumenal 

 membrane potential is decreased to —18 mv. These changes can be in- 

 terpreted as due to increases in the Na+ permeability of both membranes, 

 but it is also possible to conclude that there is a general decrease in the 

 ionic permeability. Until information on the effects of mercurials on ion 

 fluxes is available, one cannot distinguish between these possibilities. The 

 results of Mudge (1951) on rabbit kidney slices point either to an increase 

 in permeability to Na+ and K+, or to an inhibition of active transport. 

 However, the relationship of these in vitro results to mercurial diuresis is 

 obscure, especially as Auditore and Holland (1956) found that diuresis can 

 be produced without appreciable loss of cell K+, although the latter can 

 occur with minimal toxic doses. That mercurials can alter ion permeabilities 

 without appreciably depressing active transport is demonstrated by studies 

 on other tissues, such as atria (page 945). Mercurials could conceivably 

 alter pore sizes by distorting membrane structure, or actually clog ion- 



