19-Nor-deoxycorticosterone (19-nor-DOC) is a potent mineralocorticoid which is excreted in excess is some forms of genetic, experimental, and human hypertension. Whether 19-nor-DOC is etiologic or just a marker for hypertension is unknown. Our laboratory, however, recently demonstrated that inhibition of 19- nor-DOC greatly modifies the elevation of blood pressure in some forms of genetic hypertension. 19-Nor-DOC production was inhibited by a suicide aromatase inhibitor which has been shown by us to inhibit adrenal mitochondrial 19-hydroxylase. Therefore, further studies of the possible significance of 19-nor-DOC in hypertension are warranted. This proposal has three main goals. First, to purify and characterize the 19-hydroxylase, which may e the rate-limiting enzyme for the 19-nor-DOC pathway. This enzyme will be characterized by two-dimensional gel electrophoresis, immunochemistry, spectrophotometric analysis, and enzyme kinetic studies. Second, to determine whether 19-hydroxylase is abnormal in 19-nor- DOC-related hypertension, including the spontaneously hypertensive rat (SHR), salt-sensitive hypertensive rat (S.JR), adrenal regeneration hypertension (ARH), and human hypertension. Particular attention will be paid to possible differences in 11 beta/18/19-hydroxylase activity, since this is a pivotal step in a number of biologically important steroid pathways including 19- nor-DOC. Third, to investigate the hypertensinogenic activity of 19-nor-DOC by selectively increasing or decreasing 19-nor-DOC production in rats. This will be done by infusing either 19-oic-DOC (precursor or specific 19-nor-DOC inhibitors. We have preliminary studies which support the expected success of this proposal. Purified 11 beta/18/19-hydroxylase has already been prepared by us, and we have found evidence of selective inhibition of 19-hydroxylation using a suicide aromatase inhibitor. Abnormal adrenal 11 beta/18/19- hydroxylation in the S/JR, SHR and ARH has been reported by us based on adrenal mitochondrial incubation and urinary steroid excretion data. Furthermore, using a specific 19-nor-DOC inhibitor which blocks adrenal 19-hydroxylase, we have been able to prevent the hypertension and greatly prolong survival in the SHR and S/JR. In conclusion, this project will improve our understanding of the mechanisms of adrenal steroidogenesis and will better define the pathophysiologic significance of 19-nor-DOC in hypertension.
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