PLASMA PROTEASE AND KININ RELEASE WITH SPECIAL REFERENCE TO PLASMIN

Earlier studies have indicated that bradykinin can be released in human plasma by a spontaneously activated protease after acid-heat treatment to destroy kininase and protease inhibitors.1-3 During those studies the similarity between the acid-heat stability of plasminogen and bradykininogen, as well as the generation of plasmin simultaneously with the release of bradykinin from human denatured plasma, was noted.2 The peptide released during certain experimental conditions was shown to be identical with bradykinin by N-terminal end-group determination, the amino acid proportions, and the biological activity, when compared with synthetic bradykinin. Similar results were obtained after activation in human plasma with streptokinase3 and urokinase.4 Preliminary results indicated that a mixture of plasma kinins might have been formed. The presence of PTHarginine5.6 in an end-group assay showed that bradykinin was present. The fact that activation of the endogenous protease or the fibrinolytic system released bradykinin suggests a related mechanism of pathological plasma-kinin release observed in various states such as liver cirrhosis, carcinoid syndrome, anaphylactic shock, and inflarnmati~n,~-l~ which are also noted for an increased fibrinolytic activity.11J2 While it is possible to show kinin release with plasmin or the activation of fibrinolysis in vitro, the demonstration appears to be more difficult to achieve in vivo under physiological conditions. Back,lsJ4 however, was able to demonstrate a transient hypotensive reaction, presumably due to a release of vasoactive peptides by intravenous (i.v.) injection of human plasmin in the dog, which could be abolished by the administration of the pancreatic trypsin inhibitor (TrasyloF) .l4 It appears possible that the physiological and pathological bradykinin release proceeds through different pathways, and that release of plasma kinin by plasmin may occur mainly in pathological conditions. It is already well known that the kininogen is subject to the action of various proteases such as trypsin, snake venom proteases, plasma protease, bacterial proteaseP et cetera. It should further be noted that in many cases investigating the actions of these so-called kininogenins16 or kininogenases, analyses of the peptides split off have not been included. The present studies deal with the possible participation of the fibrinolysin system in the release of plasma kinins such as those found in the pathophysiological system that exists in the postmortem human plasma in cases of sudden death.17 In this type of plasma, the proteins have been subjected to at least two of the endogenous proteolytic activation processes, and were incoagulable because of the lack of fibrinogen or a defective coagulation mechanism.18 The results reported here concern the bradykininogen level in the postmortem human plasma, which was found to be decreased but not exhausted, despite strong proteolysis of the blood-coagulation process followed by complete lysis of the clots. At the same time it was noted that peptide split products deriving from the plasma protease reaction may play an important role in potentiating the action of bradykinin under pathophysiological conditions.