MITOCHONDRIA, CELLS, AND TISSUES 577 



pressions (such as 12-74) must be modified in this manner to include the 

 hydrogen ion concentration is such cases. Several instances where the pH 

 affects the rate of inliibition have been reported (e.g., with the nitrophenols, 

 malonate, iodoacetate, and cyanide) but discussion of these will be post- 

 poned to Chapter 14 where the effects of pH on inhibition will be considered 

 in greater detail. 



(C) The state of the membrane as related to functional activity. It is well 

 known that the permeability properties of cell membranes are changed 

 during the fluctuations in electric potential associated with excitation or 

 activity in muscle, nerve, and gland cells. It is likely that most cells have 

 an electric potential across their membranes, as a result of differences in 

 ion concentrations between the cytoplasm and the external medium, and 

 that this potential varies in response to many influences that play upon 

 the cells. The penetration of any ionic inhibitor into a cell will be affected 

 by the distribution of charge across the membrane, not only because of the 

 purely electrostatic effects but perhaps due to the variations in membrane 

 structure brought about by the changes in potential. Inasmuch as excita- 

 tion of cells generally involves a depolarization of their membranes, it is 

 probable that the permeability to inhibitors would depend on the level of 

 activity or the fraction of the time that the membrane is depolarized. One 

 might expect, therefore, that functionally active tissue would be inhibited 

 more rapidly than resting tissue when the inhibitors are ionic, and perhaps 

 even when they are not ionic. If cellular metabolism or secondary activities 

 are measured, it would be difficult to separate such an effect from the pos- 

 sibly altered susceptibility of the metabolism or fimction itself, but if 

 the inhibition of a particular enzyme could be followed, it would be possible 

 to test this hypothesis. In any event, the role of fluctuating permeabilities 

 to inhibitors should not be overlooked. 



(D) Nonenzymic material and protecting substances. The binding of the 

 inhil)itor to nonenzymic substances in a cellular or tissue preparation will 

 lower the effective inhibitor concentration and slow the rate of inhibition. 

 Substances that readily combine with the inhibitor may actually prevent 

 the development of the inhibition completely, as may be observed in the 

 protection afforded by sulfhydryl compounds, such as dimercaprol (BAL), 

 against inhibition by arsenicals. Since cellular preparations contain much 

 material capable of reacting with most inhibitors, this must often be a 

 distorting factor in the kinetics of inhibition. 



(E) Metabolism of the inhibitor. Rapid inactivation of the inhibitor by 

 the enzyme systems of the cell is another factor that can reduce the effective 

 concentration within the cell. The kinetics of such systems have been dis- 

 cussed in Chapter 8 and the effective concentrations of inhibitor were there 



