and The Roswell Park Memorial Znstitute Buffalo, N.Y.The role of proteolytic enzymes in the pathogenesis of shock has been the subject of many studies. Evidence of enhanced proteolytic activity has been noted in shock caused by traumala surgery,' burns,2S8-l0 hemorrhage,lsJ4 endotoxin,15-18 and anaphylaxi~.l~-~~ The literature on this subject has been reviewed recently.28*2BThe following scheme (FIGURE 1 ) highlights, in perhaps an oversimplified and disproportionate manner, the possible involvement of proteases in the physiologic changes characterizing shock. The stimulus, whether mechanical, thermal, immunologic, bacterial or neural, may activate and release intraand extra-cellular enzymes as trypsin, chymotrypsin, plasmin, kallikrein, and cathepsin directly, or indirectly through effects on the coagulation system. These enzymes then may initiate vascular and hemodynamic changes directly by proteolytic action on (a) circulating coagulative proteins as fibrinogen and prothrombin, (b) vascular fibrin substrates, or indirectly by forming vasoactive breakdown products and mediators from specific precursor substrates. The stimulus also may initiate the shock through the action of local humoral factors released by as yet unknown, nonproteolytic mechanisms. Reduced tissue blood flow and resulting hypoxia may act as a secondary stimulus and establish a vicious cycle leading to death. Some of the mediators involved may be seen in FIGURE 2.In this study, proteinase inhibitors were used as pharmacologic aids in evaluating the possible role played by proteolytic enzymes in experimental shock caused by trauma, burn, and anaphylaxis. Detailed physiologic and biochemical analyses were possible only in the canine anaphylaxis model system. In the other shock systems, mortality was adopted as the criterion for drug effect.
Traumatic Shock in RatsTraumatic shock was produced in rats by the method of Noble and C01lip.~~ Sherman albino female rats ranging in weight from 120-125 grams were used. Initial experiments revealed female rats to respond more uniformly to this form of shock than male rats. Since small variations in weight were noted to influence significantly the response, animals were weighed both in the evening before and on the day of the experiment. Food and water consumption were checked and animals not showing normal intake were excluded, because short periods of fasting were also shown to affect response to Noble-Collip shock.Rats anesthetized lightly with diethyl ether and their limbs taped together were placed one by one into each of four drums so designed that, when rotated, the animals were thrown against two opposing triangular projections within the drums (FIGURE 3). Control animals (saline-treated) and drug-treated animals were placed into opposite drums rotated by the same axle. The four drums were
