Relationship of Plasma Peptides to the Myocardial Depressant Factor in Hemorrhagic Shock in Cats

Abstract

The pathophysiological relationships of a myocardial depressant factor (MDF) present in the plasma of cats in hemorrhagic shock were studied. Aprotinin (Trasylol), an inhibitor of a variety of proteases including kallikrein and trypsin, prolonged survival of cats in postoligemic shock as well as prevented the appearance of MDF in the plasma. Trasylol did not alter the arterial blood pressure, venous pressure, or heart rate of these cats in shock, nor did it protect by exerting a positive inotropic effect. Trasylol was ineffective in preventing or reversing the negative inotropic effects of MDF in isolated cat papillary muscles. Column chromatography of plasma from control cats, from untreated shocked cats and from cats treated with Trasylol before shock showed six peptide peaks, designated A, B, C, D, E, and F in decreasing order of molecular weights. Peptides corresponding to peaks A, B, E, and F exhibited insignificant myocardial depressant activity. The peptide corresponding to peak C was present in control plasma and accounted for some of the small negative inotropic effect of control plasma. The peptide corresponding to peak D had a marked myocardial depressant effect which could account for all the activity of shock plasma. The molecular weight of this peptide was estimated to be 800 to 1000. This peptide is not bradykinin, but appears to be produced by a protease present in shock.ADDITIONAL KEY WORDS kallikrein papillary muscle Trasylol postoligemic shock bradykinin column chromatography toxic factor membrane ultrafiltration eledoisin proteases• Several investigators have reported that there is a substantial increase in the concentration of circulating peptides (1-4) or in proteolytic enzymes (2,5) in the plasma of animals in hemorrhagic shock. However, the role of these peptides in the pathogenesis of hemorrhagic shock is not clear (6)(7)(8)(9). Previous studies have shown that a myocardial depressant factor (MDF) present in the plasma of This investigation was supported by U. S. Public Health Service Crant HE-09924 from the National Heart Institute and by a grant from the American Heart Association. Dr. Lefer is an Established Investigator of the American Heart Association. Mr. Martin is a U. S. Public Health Service research trainee of the National Heart Institute (Crant HE-05661).Received August 16, 1969. Accepted for publication November 9, 1969. cats in postoligemic shock is a peptide having a molecular weight between 500 and 1000 (10). MDF accumulates in the plasma as postoligemic shock progresses, and exerts a depressant effect upon isolated heart muscle (11), upon systemic blood pressure in the intact cat (10), and upon the reticuloendothelial system (12). The purposes of this study were: (a) to determine whether MDF production could be inhibited by a protease inhibitor, and (b) to isolate MDF and determine some aspects of its chemical nature. Methods SHOCK PROCEDUREAdult cats of both sexes weighing between 2.4 and 3.1 kg were used for the shock experiments. All cats were isolated for ...

Beneficial action of new angiotensin-converting enzyme inhibitor (SQ 14,225) in hemorrhagic shock in cats.

“…21 This agent antagonizes a variety of proteases including trypsin, plasmin, and kallikrein. 22 Since aprotinin reduces bradykinin concentration as it protects in shock, 23 it thus renders less likely the bradykinin-potentiating effects of SQ 14,225 as being a significant component of its protective effect in hemorrhagic shock.…”

“…The reductions in lysosomal and proteolytic activities probably result from direct biochemical actions of SQ 14,225, since in vitro studies demonstrated lysosomal stabilization and general antiprotease actions. MDF is thought to be formed from a combination of the actions of lysosomal and zymogenic proteases within pancreatic acinar cells; 21 therefore, the lowered levels of this toxic peptide probably also are dependent on stabilization of lysosomal membranes and the antagonism of zymogenic proteases within pancreatic acinar cells.…”

Regional and Central Hemodynamics during Segmental Ischemia of the Small Intestine in the Rat

“…The erythrocyte volume fraction before and after 2 h of ischemia was almost the same, indicating that no large volume of plasma could have been lost to the extravascular space. Lefer and Martin [15] demonstrated that a myocardial depressant factor was released from ischemic splanchnic tissue and assumed this fac tor to be a polypeptide. Williams et al [27] observed a myocardial de pressant factor in dog plasma after occlusion of the arteries of a small in testinal segment.…”

Dissociation of Myocardial Contractility and Pump Performance in Hemorrhagic Shock

“…L efer et al [15] and L efer and M artin [16] have recently presented evidence which suggests that a low molecular weight protein breakdown product is elaborated during shock that is toxic to the myocardium. It has been hypothesized that this material is the result of the action of proteases released from ischemic pancreas on proteins in the blood.…”