COMPOUND 48/80 ON RAT 



depend on a direct interaction between the histamine-liberator and some 

 component of the tissues themselves. This is evident, since the tissue which 

 first loses histamine and loses it in greater amount is the tissue with which 

 the liberator first comes into contact (Feldberg and Talesnik, 1953). After intra- 

 peritoneal injection of compound 48 80 the mesentery and omentum promptly 

 release their histamine, followed in due course by the subcutaneous tissue and 

 ears. But when the experimental conditions are altered and the liberator is 

 injected direct into an artery leading to another area, the ear, the loss of 

 histamine is almost entirely confined to that tissue. Thus we may infer that 

 the clue to the action of compound 48 80 as a liberator of histamine will be 

 found in the tissues and not in the blood. 



The mast cell as the target for compound 48 80 



So far as present evidence goes, the mast cell is the first component of a living 

 tissue to react to a local concentration of compound 48 80. Topical applica- 

 tion on to a serous surface by means of intraperitoneal injection is followed 

 by rapid dissolution of the subserous mast cells. Moreover, the mast cells 

 and the histamine disappear together. Later, as the cells regenerate, the 

 histamine content of the tissue again increases. This is well shown in the 

 "chronic dosage' experiment, in which there is partial restoration of mast cells 

 in the subcutis but not in the ear, the histamine values running parallel with the 

 mast-cell status of each. The disruptive effect of compound 48/80 on the mast 

 cells has even been observed in tissue spreads in vitro (Mota et a/, 1953), 

 a finding which I have confirmed. Norton (1954) was able to utilize the 

 phenomenon for assaying batches of compound 48 80: she also confirmed 

 the protective action of the antihistamines, as described by me for the 

 diamidines (Norton and de Beer, 1955). All the evidence therefore points 

 to the mast cell as the component of a tissue on which compound 48 80 acts 

 to release histamine. 



Dosage effect of compound 48 80 on the mast cells 



Intraperitoneal injection of compound 48 80 produces an almost explosive 

 destruction of the abdominal mast cells, and in the ear subjected to intra- 

 arterial injection there is again evidence of direct damage. On the other hand, 

 examination of tissues at some distance from the site of injection (the sub- 

 cutaneous tissues and the ear tissues of rats injected intraperitoneally) reveals 

 a slower and lesser effect on the mast cells. In these distant sites the cells 

 become swollen and their granules lose their affinity for basic dyes ('ghost' 

 cells) until at length they are no longer recognizable as mast cells. 



The phenomena of the recovery phase also differ. Thus the peritoneal mast 

 cells are slowly restored through the development of new cells from small 



107 



