464 9. INHIBITION IN CELLS AND TISSUES 



throlines that are not chelating agents, or of compounds structurally related 

 in other ways, may allow establishing a correlation between the effect on 

 the cell and the chelating activity. The lack of a demonstrable effect on the 

 over-all metabolism of the cell or tissue is not sufficient evidence for a 

 nonenzymic effect because the action may be localized and that fraction 

 of the total metabolism affected could be insignificant. Also one cannot 

 be certain that he is measuring the right thing to show the metabolic 

 effect if it does exist. 



Dependency of the Functional Activity on the Level of High-Energy Bonds 



The cell function may require an available source of energy in the form 

 of ATP or other high-energy nucleotides. These nucleotides, furthermore, 

 are often in equilibrium with a store of creatine phosphate. The function 

 may remain relatively unchanged until the ATP drops below a certain 

 level due to an inhibitor and some ATP may be furnished through phosphor- 

 ylation of ADP by the creatine phosphate. A cell function requiring little 

 energy can thus continue for some time after the fundamental energy- 

 supplying reactions are blocked or uncoupled. The function may also be 

 dependent on conditions established by ATP or other energy sources. 

 These conditions may be fairly stable and persist for a long time after 

 ATP formation is stopjied. The conduction of nerve impulses or ameboid 

 movement during periods of metabolic failure would be examples. In the 

 former case, it it basically due to the fact that the ion pumps have estab- 

 lished concentration differences and potential differences at the mem- 

 brane; each impulse requires so little ion movement that the potential 

 drops only slowly when the pumps cease activity. The degree of functional 

 inhibition in these cases clearly bears no relationship to the interference 

 with metabolism. 



The more actively a cell functions, the more rapidly will it deplete its 

 store of energy and suffer depression from an inhibitor. Thus nerve tissue 

 or a heart will fail more rapidly in the presence of an inhibitor if it is stim- 

 ulated rapidly so that impulses or contractions are more frequent. The 

 functional activity is therefore dependent not only on the rate at which 

 energy is supplied but also on the rate at which it is utilized. Most cells 

 perform several functions (we may consider syntheses and growth as func- 

 tions here for convenience) and some may require ^nore energy than others. 

 In this case, an inhibitor can more or less selectively depress certain func- 

 tions. Generally the function requiring the most energy will be dejjressed 

 more readily than the rest. It might be erroneously concluded that this 

 function only was dependent on the particular metabolic phase inhibited, 

 whereas all the processes might depend on the same enzymic reactions but 

 to different degrees. Let us for the moment assume that all the functions 

 draw energy from a common pool and are not siDccifically related to indi- 



