DIFFERENTIAL EFFECTS IN WHOLE ANIMALS 481 



It is not rhythmically contracting but it is not necessarily resting in the 

 sense of existing in its functionally lowest level. Some depolarization of 

 the cell membranes, due to damage or artificial conditions, may occur and 

 this may induce a partial contracture, or alter the metabolism in the ab- 

 sence of any contractile changes since ionic pumps may be more active 

 than in the idealized resting state. 



Cell Population in a Tissue Slice 



No tissue slice is composed entirely of a single type of cell. Whatever 

 else may be present, there are always vascular cells or connective tissue. 

 These cells contribute to the total metabolic processes to greater or lesser 

 degrees and occasionally introduce a different type of metabolism from that 

 of the principal cells being investigated. There is virtually nothing one 

 can do about this but to realize that it can cause deviations in kinetic be- 

 havior which make the calculation of inhibition constants more difficult. 

 In some cases a major fraction of the inhibitor-stable metabolism could 

 be due to a minority population of cells resistant to the inhibitor. The same 

 must apply to any tissue preparation and particularly to complex aggre- 

 gates of different cells such as one would find in an isolated intestinal seg- 

 ment. 



DIFFERENTIAL EFFECTS OF INHIBITORS IN WHOLE 



ANIMALS 



When an inhibitor is introduced into an animal it will, at proper dosage 

 ranges, affect some tissues more than others and, in rare instances, may 

 even act specifically on one type of cell. It is, indeed, this specificity which 

 is of primary importance in the development of compounds which will 

 depress or kill those abnormal or invasive cells responsible for much dis- 

 ease. The differential actions of inhibitors on tissues will be a fundamental 

 theme running through all the chapters devoted to the individual inhibitors. 

 The question to be considered now is: what are the reasons for the different 

 susceptibilities of tissues to inhibitors? 



Inhibitors are distributed inhomogeneously in the body, being concen- 

 trated in some tissues and deficient in others, and this is certainly one very 

 important reason for the differential effects usually observed. This has 

 been covered in the previous chapter. The distribution factor, however, 

 cannot by any means explain most cases of specificity and in some instances 

 it would appear that an inhibitor is quite equally distributed between tis- 

 sues resi^onding very differently. 



Each type of cell in the animal body has a characteristic pattern of 

 metabolism, probably distinct from every other type of cell, and for this 



