We have recently discovered a new protein which exhibits potent vasoconstrictor activity when applied to isolated vascular rings. We demonstrated that it is an enzyme belonging to the kallikrein family of serine proteases. The gene for this protein has been identified and the nucleotide sequence of its mRNA is available. We named the substance submandibular enzymatic vasoconstrictor (SEV) because it was isolated from the rat submandibular gland and requires enzymatic activity to contract arterial rings. We found that the mRNA for SEV is present in arteries, cultured vascular smooth muscle cells and kidney. When injected into rats, SEV caused a marked increase in blood pressure. We propose to test the general hypothesis that SEV participates in the regulation of vascular resistance and renal function. Furthermore, an unknown member of the kallikrein family is present in the vascular pole of the glomerulus, where it may play a role in the regulation of glomerular function. To further our understanding of the physio pathological role of these new kallikrein- related enzymes, we propose: I): to localize SEV and its mRNA in tissue using the polymerase chain reaction, in situ hybridization, immunohistochemistry and RIA. In addition, we will determine whether vascular tissue contains binding sites for SEV and whether SEV releases a vasoconstrictor peptide(s); II): to determine: a) whether SEV is released as an endocrine and/or exocrine hormone. We will study release of SEV into the salivary and urinary compartments of the submandibular gland and kidney, and in the venous effluent of these organs, respectively, b) the factor(s) that regulate tissue concentration and release of SEV and mRNA levels. III): to determine the effects of acute administration of SEV on blood pressure, cardiac output and renal function, and whether blockade of endogenous SEV with Fab fragments of monoclonal antibodies alters any of these parameters. IV): To identify, purify and characterize the kallikrein-related protein expressed in the vascular pole of the glomerulus.
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