Kinins are potent vasoactive peptides which have been implicated in many pathologic conditions including inflammation, shock and hypertension. Kallidin and bradykinin act through B2 kinin receptors and are rapidly degraded in vivo by angiotensin converting enzyme (ACE). In addition, carboxypeptidase N (CPN), converts kallidin and bradykinin to their respective des(Arg)kinin metabolites, des(Arg10)kallidin and des(Arg9)bradykinin. These des(Arg)kinin metabolites are potent agonists of B1 kinin receptors which are induced in inflammatory and stress conditions. However, despite the potent cardiovascular actions of kinins and des(Arg)kinins, it is now known that ACE and CPN account for less than half of the degradation of B2 kinins in vivo, and do not participate at all in the degradation of B1 des(Arg)kinins. In the past, establishing clear relationships between kinins and cardiovascular disease has been hampered by the lack of effective antagonists. However, a first generation of both B2 and B1 kinin antagonists have recently been developed which support the existence of multiple kinin receptors, and a significant role for endogenous kinins in pathologic processes. Nevertheless, these antagonists have relatively low potencies, short durations of action and, at the high doses normally required, non-specific (non-receptor) mediated effects. Both the potency and receptor specificity problems of these analog have now been shown to be directly related to rapid in vivo metabolism by enzymes other than ACE. Thus, as yet unidentified enzymes are involved in the metabolism of both the naturally occurring kinins/des(Arg)kinins, and their antagonists. The present study will identify the blood and vascular enzymes which, in addition to ACE, control the levels of the naturally occurring B2 and B1 kinins in vivo. In addition, after determining how identified enzymes degrade existing kinin antagonists, these studies will develop new analog which, through resistance to multiple kinin-metabolizing enzymes, are more potent, longer acting and specific.
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