466 9. INHIBITION IN CELLS AND TISSUES 



of in terms of competition between functional processes for energy and 

 the relative depressions will reflect to some extent the competitive abilities. 

 Of course, in the living cell, although this simplified picture may be valid 

 generally, it is probable that some functions are specifically and spatially 

 related to enzyme sytems of different types. One of the most interesting 

 problems in nerve and muscle physiology is whether the excitatory events 

 at the membrane are dependent on enzyme reactions within the membrane, 

 as opposed to the total cell metabolism, and if inhibitors can modify the 

 electrical behavior of the membrane, and secondarily the cell function, 

 by acting on these enzymes of the membrane. It might be expected that 

 all types of oxidative or phosphorylative inhibition would produce the 

 same effects upon membrane behavior if this behavior were dependent 

 only on a source of ATP from the bulk of the cell or from the mitochondria. 

 However, the effects of different inhibitors are not the same on resting and 

 action potentials and this might be taken as indirect evidence for enzymic 

 processes at the membrane (Webb and Hollander, 1959). 



Inhibition of an Enzyme System Forming an Agonist 



An enzyme inhibitor may alter tissue function by reducing the formation 

 or inactivation of some substance that is produced by the tissue, this sub- 

 stance itself controlling the tissue function. Such a substance may be termed 

 an agonist, in conformity with pharmacological nomenclature (Furchgott, 

 1955), which implies that the substance acts on the responsive cells, either 

 to stimulate or depress them. The agonist could be formed by the cells 

 under investigation or it could arise in other types of cells present in the 

 preparation. In the latter situation, the agonist may either produce its 

 effect by reacting with receptors at the surface of the responding cells, or 

 it may have to enter into the membrane to react, or it may have to pass 

 through the membrane into the interior of the cell. The enzyme inactivat- 

 ing the agonist may likewise be situated spatially either outside, within the 

 membrane, or inside the cell. Finally, the agonist may simply diffuse away 

 from the region where it is produced and where it acts. These processes 

 may be represented diagramatically as: 



diffusion 



Xj -> Xj ... -> A -|- R -> effect on cell 

 I E,. 

 inactivation 



where X^ and Xg are precursors of the agonist, Ey represents the enzymes 

 involved in its formation, R is the receptor group with which it must react 

 to affect the cell, and E, is the enzyme inactivating the agonist. The action 

 of an enzyme inhibitor on either Ey, E,, or R will modify the functional ac- 



