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These studies have indicated some quantitative aspects of the kallikrein kinin system in sepsis. While other investigators have noted the fall in plasma kininogen in patients with sepsis, e.g. Erdos and colleagues (23), this study has indicated that it is the fall in the LMWK that is significant in these patients. LMWK comprises of three-quarters of the total plasma kininogen and its consumption can lead to the production of 2.24 million picograms bradykinin/ml plasma. In health bradykinin concentration is of the order of 100-400 picograms/ml. It is not unreasonable to suggest therefore, that bradykinin levels are increased in acute disease and other investigators have shown this by direct assay of the peptide in such patients. The present study has shown that once bradykinin is generated in the circulation in terms of ng/ml, even with passage through the lung, systemic effects occur, namely reduction in TPR and a fall in CO and BP. Thus, bradykinin could be the humoral factor responsible for the hyperdynamic state and systemic hypotension in severe sepsis. It is apparent that metabolism of bradykinin involves more than simply clearance of the peptide. It appears that bradykinin can stimulate the production of other vasoactive mediators by the lung. The consumption of LMWK in sepsis indicates that it is not plasma kallikrein activity but rather non-specific kininogenase activity that is critical. This may be important not only from the viewpoint of kinin generation, but also because of the consumption of plasma protease inhibitors. A mechanism to control or inhibit such protease activity offers a possible therapeutic approach to circulatory failure in these patients.

Aprotinin, a protease inhibitor, has been used in a wide variety of pathophysiological states thought to be associated with an increase in protease activity. Opinion differ with respect to the success of the therapy. This paper proposes a rationale for the therapeutic action of aprotinin based on biochemical and physiological evidence. In the kallikrein-kinin system, in addition to kallikrein, other serine-esterases such as trypsin, plasmin, etc. can generate kinin production. In certain disease states such as pancreatitis there is not only an increase in serine-protease activity but frequently these enzymes reach parts of the organism where they are not found in health. Thus in such circumstances increased production of kinins can result. The consequences of increased kinin generation are discussed in light of work indicating their role in metabolic and circulatory homeostasis. Aprotinin is specifically a serine-esterase inhibitor. It is suggested that perhaps the most important action of this compound is as an inhibitor of the kallikrein-kinin system. On this basis a therapeutic regime in various disease states for the use of aprotinin, which allows for control of kinin generation, is suggested.