Leukokinins are peptides having 20-25 amino acids. They are formed by acid proteases contained in leukocytes, cancer cells, and ascites fluids acting on a protein substrate known as leukokininogen. The leukokinins do not contain the bradykinin sequence in their molecule. The leukokinins are extremely potent (even more so than bradykinin) in causing increased vascular permeability and hypotensive blood pressure changes. The substrate from which leukokinins are cleaved, leukokininogen is 'not' a normal constituent of plasma, but is formed in certain pathological conditions in plasma or in pathological fluids from a 'proleukokininogen'. This conversion is the limiting step in the availability of leukokinins. While all white ceils so far tested contain cathepsins D-and E-like enzymes which act as leukokininogenases (form leukokinins), the white cells do 'not' contain kallikreins and consequently do not form bradykinin. The leukokinin system may represent the system which generates fluid accumulation in pathology such as ascites of neoplastic disease, arthritis and inflammation. Strong proof of this is seen in the experiments to be described in which an inhibitor of leukokinin formation, in vitro, 'Pepstatin' retards and even prevents ascites fluid accumulation in mice in vivo.

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Leukokinin-H, a pharmacologically active peptide, has been isolated from human ascites fluid following its generation in vitro at acid pH. The peptide has a molecular weight of approximately 2500. The partial sequence of Leu-AlaTyr-Thr-was obtained from the amino-terminal end. Arginine is the terminal amino acid at the carboxyl end.It was demonstrated that while cell-free ascites fluid generates leukokinin-H, the presence of neoplastic cells enhances the formation about 5 fold. A bradykinin-llke peptide was formed in the fluid following storage at a low temperature of 4~The presence of neoplastic cells, however, did not enhance this peptide formation.Procedures are described for the isolation of leukokinln-H by chromatography. The peptide was clearly differentiated from bradykinin, Lys-bradykinin and MetLys-bradyklnin by treatment of the leukoklnin and other kinins with fluorescamine and separation of the fluorescamlne peptides bygel electrophoresls. The pharmacology of leukokiuln-H isolated" from human ascites fluid is described and compared with bradykinin and leukoklnlns PMN and M. Like the other kinins, it is a potent agent in causing vascular permeability. Likewise it is a vasodepressor substance. Unlike bradykinin it has little spasmogenlc activity on the guinea pig ileum. Its pharmacological properties as well as other evidence cited indicates that it may play an important role as a permeability factor in ascites fluid accumulation of neoplastic etiology.

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