PHYSIOLOGY AND BIOCHEMISTRY OF SHOCK 435 



1 0. The Question of Proteolysis and Release of Histamine 

 in Shock Produced by Proteolytic Enzymes and in Ana- 

 phylaxis 



A number of investigators have pointed out a parallelism between 

 the effects of an antigen in a previously sensitized animal and those 

 of trypsin in similar animals without the necessity of sensitization. 

 These effects, release of histamine and heparin from the tissues by the 

 injection of trypsin, the phenomenon of desensitization, the inhibition 

 of smooth muscle contraction by arginine and histidine are considered 

 restricted to anaphylactic experiments and significant. As in ana- 

 phylactic shock, proteolytic enzymes produce: (a) failure of blood 

 to clot, perhaps due to release of heparin; (b) less conspicuous, but 

 nevertheless significant, is the brief period of increased clotting which 

 precedes the failure of blood to clot, and which may be due to the 

 conversion of prothrombin to thrombin. When trypsin is injected into 

 the intact animal it is believed there is sufficient time for such an effect 

 to occur before the tissue release of heparin obscures the accel- 

 erated clotting (Rocha e Silva, 1943). Tagnon, et ah (1945) found 

 intravascular clots by post-mortem examinations of dogs after the in- 

 jection of 2 mg. of trypsin/kg. Mirsky and Freis (1944) reported a 

 similar finding. 



Dragstedt and Wells (1944) reported a parallelism between the 

 pharmacological activity and enzyme activity of trypsin. The inactiva- 

 tion of trypsin by acid, heat, and serum inhibitor produced an equal 

 decrease in proteolytic potency and pharmacological activity. As they 

 pointed out, however, the pharmacological effects are not the con- 

 sequence of gross or obvious digestion of either blood or tissues. 

 Intravenous injection of trypsin produces its dramatic effects upon the 

 circulation within fifteen to twenty seconds. The contraction of an 

 isolated intestinal strip occurs within one to three seconds. The libera- 

 tion of histamine from rabbit blood cells to plasma occurs promptly and 

 before any morphological evidence of digestion is present. It may be 

 pointed out, however, that our chemical methods of in vitro quantita- 

 tive measurement may be too crude to permit the measurement of 

 proteolytic effects associated with the above processes. Mirsky and Freis 

 (1944) report that intraperitoneal injection of trypsin causes extensive 



