458 9. INHIBITION IN CELLS AND TISSUES 



or various invertebrates. Liver tissue made anoxic by clamping the he- 

 patic artery for short times shows a reduced respiration and ability to 

 deaminate amino acids (Wilhelmi et al., 1944a, b). A period of 5 min of 

 anoxia depressed the respiration 10% and 10 min of anoxia r. duced it 

 58%; reduction of deamination and uptake of amino acids occurred si- 

 multaneously. Brain cortex slices (Wilhelmi et al., 1944c) and heart slices 

 (Webb et al., 1949a) subjected for short periods to anoxia show progres- 

 sive failure of respiration. The mechanisms involved in these effects are 

 not known, but it is established that chemical and structural changes 

 — alterations in ionic or nucleotide concentrations, swelling, vacuolization, 

 and chromatolysis — can occur rapidly in cells deprived of oxygen. What 

 is to be emphasized is that in oxygen deficiency we have evidence of the 

 disturbances that may occur in dynamic equilibria and visible proof that 

 energy is required for cell maintenance, as well as for growth and function, 

 and in the case of anoxia there is no question but that the primary effect 

 is metabolic depression, whereas inhibitors could be supposed to act in 

 other nonmetabolic ways. Furthermore, we see that in many cells, parti- 

 cularly the most active, this dynamic equilibrium does not require much 

 time to be irreparably damaged. The possibility of such changes taking 

 place during the action of an inhibitor on cells should be kept in mind at 

 all times, since in experiments of duration exceeding a few minutes one may 

 be measuring secondary and tertiary effects. In cells, and especially in 

 whole organisms, the primary action of an inhibitor may progressively 

 produce a series of secondary changes, radiating out to encompass even- 

 tually processes and tissues not even in contact with the inhibitor. A heavy 

 metal is able by acting specifically on the enzymes involved in renal tu- 

 bular transport to produce biochemical and functional changes in the brain 

 mediated through the altered composition of the blood. Such phenomena 

 are obvious but there are many relationships more subtle and less under- 

 stood. Each time an inhibitor acts on a living cell there is the possibility 

 that in some way protein synthesis is depressed and that the resultant 

 alteration in intracellular enzyme concentration will derange all manner 

 of metabolic processes. These phenomena are not so much related to the 

 properties of an inhibitor as to the inherently complex characteristics of 

 cells and organisms. The type of response will, to some extent, depend on 

 the nature of the inhibitor; it will depend even more, in most cases, on the 

 potentialities of the living system to respond. 



THE CONCEPT OF PACEMAKERS IN METABOLISM 



The concentrations of the various metabolic intermediates in the normal 

 cell are generally low and this lack of accumulation indicates that in most 

 instances the rates are limited not by enzyme activity but by the availa- 

 bility of substrate. Some enzymes are known to be present in excess of the 



