In the spontaneously hypertensive rat (SHR) numerous studies show evidence of abnormal pituitary-adrenal function. While significant alterations in adrenal corticosteroid secretion appear to exist during the onset of hypertension, available data fail to clarify whether excessive production of mineralocorticoids is pathogenic in SHR. The steroids progesterone (P), deoxycorticosterone (DOC) and androstenedione (AND) have been shown to undergo oxidation at the C-19 methyl group to 19-hydroxylated (19-OH) and demethylated (19-nor) products which may be involved in salt and water retention. Studies in this laboratory indicate that microsomal and mitochondrial fractions prepared from the kidneys of normotensive rats exhibit a NADPH-dependent conversion of progesterone to DOC, 19-OHP and 19-nor P. In addition, major differences were observed in the formation of DOC and 19-OHP in renal microsomes from male and female animals. We propose to study in SHR the biosynthetis pathways in the kidney which have been implicated in the formation of these hypertensinogenic steroid products. The hypothesis to be tested is that the development of hypertension in SHR is related to the capacity of renal tissue to convert adrenal and gonadal steroids to 21-OH, 19-OH and 19-nor products which have mineralocorticoid activity. SHR and Wistar-Kyoto control animals will be studied in prehypertensive and early stages of established hypertension. In vitro studies will measure 1) 21-hydroxylation of P, 2) 19-hydroxylation of P, DOC and AND, and 3) 19-demethylation of P, DOC and AND in renal subcelluar fractions. Concurrent studies will measure 21-, 11Beta- and 18-hydroxylase activities in adrenal homogenates, as well as determine if 19-hydroxylation occurs in this tissue. This approach will be used to evaluate the capacity of the adrenal gland to provide the precursors for the kidney to generate 19-nor steroids in SHR. A second line of investigation will examine the role of gonadal and adrenal steroids on the hormonal regulation of renal mineralocorticoid synthesis. The overall objective is to evaluate the biosynthetic potential of the kidney for in situ synthesis of steroid hormone products which enhance sodium retention. These studies will enable us to assess the potential involvement of an adrenal/gonadal-kidney interaction in steroid hormone synthesis in the pathophysiology of spontaneous hypertension.
| Salhab, A S; Applewhite, J; Couch, M W et al. (1987) Extraction of omega- and omega-1-hydroxylauric acids with ethyl acetate results in formation of acetoxy products. Drug Metab Dispos 15:233-6 |
