In addition to angiotensins and kinins, peptides such as substance P, VIP, enkephalins, neurotensin, somatostatin, etc., have significant vascular effects, and are present in the circulation and/or in nerves associated with gastrointestinal, renal and other blood vessels. The physiologic roles of these so-called """"""""brain/gut"""""""" peptides remain at an early stage of investigation, but could include modulation of regional blood flow and organ function. Further, significant evidence supports their involvement in the causes and/or symptomology of a variety of pathologic conditions. However, investigating the physiologic roles of these peptides is complicated by the fact that they have short half-lives in vivo, and their metabolites often have significant biologic activity. With few exceptions, e.i., vascular angiotensin I converting enzyme, little progress has been made in identifying specific vascular peptide-peptidase pathways of physiologic significance. Establishing the identity of such enzymes, and an ability of control their activities via inhibitors, is a promising avenue of approach to determining the physiologic roles of these endogenous peptides. The objectives of this proposal are to identify and charactrize enzymes within the vasculature and/or circulation which, by differential metabolism of vasoactive peptides, modulate vascular resistance, blood flow and local organ function. Biochemical studies will be conducted at the subcellular, cellular and vascular levels using purified vascular plasma membrane, cultured endothelium and smooth muscle, and isolated microvasculature. Analysis will include enzymatic and immunologic identification of specific peptide converting and degrading enzymes, TLC and HPLC analysis of peptide metabolism, and immunologic analysis of the relationship between the vascular and circulating forms of these enzymes. Further, as the enzymes modulating endogenous peptide levels are determined, inhibition studies will be conducted to investigate the role of these peptides in vivo. Such studies may eventually lead to development of drugs (inhibitors) which, via attenuation or potentiation of endogenous peptides, are of clinical value in the treatment of variety of pathologic conditions.
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