Significance of Splanchnic Proteases in the Production of a Toxic Factor in Hemorrhagic Shock

Abstract

The pathogenesis of circulatory shock has been previously associated with the plasma accumulation of a myocardial depressant factor (MDF). The plasma accumulation of MDF in cats subjected to hemorrhagic shock was associated with marked increases (P <0.01) in activities of plasma cathepsins A-B. The pH optima for three of the five cathepsins were in the range of 4.8-5.2, a pH range close to that found intracellularly during shock. Moreover, pancreatic and hepatic tissue from these cats exhibited significant decreases in total specific activities for these enzymes, compared with minimal changes in heart, duodenum and spleen. Decreases in total pancreatic cathepsin activities were associated with marked ultrastructural changes in pancreatic acinar cells primarily characterized by vacuolization of the lysosomes. Incubation of homogenates of splanchnic viscera of unshocked dogs revealed that significant concentrations of MDF were produced only in incubated pancreatic homogenates. Infusion of MDF in amounts half that produced by a cat pancreas into intact anesthetized cats yielded a significant circulatory depression indicated by a progressive decline in cardiac output and mean arterial blood pressure and a 54% decrease in cardiac work performance within 60 minutes. These data indicate that substantial amounts of lysosomal proteases are released during shock and that they operate in a suitable pH range to account for the production of quantities of MDF that are sufficient to induce a marked degree of cardiac depression.