Studies on Hageman Factor, Plasmin and Kallikrein

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It is well known that plasma kinins which appear during inflammation or antigen-antibody reactions are formed by action of proteases such as plasmin and kallikrein. These plasmin and kallikrein originate from plasminogen and kallikreinogen, inactive precursors found in blood. It has been suggested that these are activated by Hageman factor in blood, by which activation plasminogen and kallikreinogen are successively converted into plasmin and kallikrein, resulting in formation of these latters form kinins from kininogen, respectively. However, there is no evidence indicating existence of such activation systems except kinin formation by kallikrein. Although many investigators have reported kinin formation by plasmin, no direct evidence have been demonstrated. We reported last year at this symposium that plasmin could convert directly kininogen into kinins. In 1964, Vogt suggested that plasmin might form kinins indirectly, through the mediation of its formation of kallikrein from kallikreinogen.<BR>At this symposium, we tried to confirm his hypothesis and also examined whether or not the activated Hageman factor could convert plasminogen and kallikreinogen into plasmin and kallikrein, respectively. It was demonstrated that human plasmin and kallikrein was successfully separated by column chromatography on DEAE Sephadex A-50. Then, conversion of kallikreinogen into kallikrein by plasmin was examined by means of this column chromatography. However, we could not obtain any evidence showing the existence of such conversion. We also tried to confirm the above result by using purified kallikreinogen. The purification was carried out in accordance with the following procedures. Euglobulin fraction separated from human plasma was suspended in 0.03M EDTA solution, stirred overnight at 4°C and centrifuged. The resulting supernatant contained kallikreinogen and the precipitate included most of plasminogen. Then, plasmin was made to act on the kallikreinogen purified by these procedures and conversion of kallikreinogen into kallikrein by plasmin was examined. No evidence, however, was obtained indicating that plasmin converted kallikreinogen into kallikrein.<BR>Activated Hageman factor was purified by the Schoenmakers' method to investigate whether or not the activated Hageman factor can convert plasminogen and kallikreinogen into plasmin and kallikrein, respectively. Activity was measured by means of caseinolysis in case of activation of plasminogen and of TAMe activity in case of activation of kallikreinogen. It was clarified that the Hageman factor could convert kallikreinogen into kallikrein, but not plasminogen into plasmin.<BR>Finally, we succeeded in synthesis of a kallikrein inhibitor, that is, δ-guanidino valeric acid hexyl ester. This substance inhibited plasmin as well as kallikrein.
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Studies on Hageman Factor, Plasmin and Kallikrein

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