The general hypothesis to be tested in this proposal is that kinins formed in some areas of the brain, in pituitaries and in adrenal glands have an important role in the neuroendocrine regulation of cardiovascular homeostasis. In addition, we postulate that kallikrein can process polypeptide precursors to biologically active peptide hormones.
Our specific aims are geared to determine: 1) whether both kallinkrein and kininogen, the kinin precursor, are synthesized in the same regions of the brain, pituitary and adrenal medulla, and their cellular and subcellular localization; 2) to determine whether free kinins are present in discrete regions of the brain, pituitary and adrenal glands, and whether kinins are present in and can be released from synaptosomes; 3) to determine the effects of administration of competitive antagonists of kinins into the brain ventricles in the following situations: a) after changes in cardiovascular variables secondary to administration into the brain of kininase inhibitors; b) after hypertension induced by intraventricular administraiton of melittin; and c) after injections of the kinin antagonist into control rats, into SHR and into rats maintained on either a high, normal or low sodium diet; 4) to determine whether kinins can stimulate the release of peptide hormones from the adrenal medulla and anterior pituitary; and 5) to determine whether pituitary kallikrein and/or kallikrein-like enzymes purified by us can process neuropeptide hormones. Peptides released by these enzymes from precursor peptides will be identified and their sequences compared with that of related naturaly occurring peptides. These studies will help to determine whether the tissue kallikrein-kinin system contributes to the regulation of cardiovascular functions.
