Activation of 11 beta-hydroxysteroid dehydrogenase by dehydroepiandrosterone sulphate as an anti-hypertensive agent in spontaneously hypertensive rats.
The anti-hypertensive properties of dehydroepiandrosterone sulphate (DHEAS) have been investigated by studying its effects on blood pressure, on serum concentrations of corticosterone and dehydrocorticosterone, and on 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) activity in spontaneously hypertensive rats (SHR). SHR were given intraperitoneal injections of DHEAS (10 mg day-1 for 70 days) from six to 16 weeks of age. The blood pressure-time curve was significantly (P < 0.05) suppressed immediately after administration of DHEAS. There was no difference between the heart rates of control and DHEAS groups. Serum concentrations of corticosterone and dehydrocorticosterone in the DHEAS group were significantly (P < 0.05) lower than those of the control group. The dehydrocorticosterone/corticosterone concentration ratio was, however, significantly (P < 0.05) higher in the DHEAS group, suggesting that treatment with DHEAS enhanced the overall interconversion of corticosterone to dehydrocorticosterone. The activity of 11 beta-HSD in specific organs of the DHEAS group was affected, characteristic changes being increases in the kidney (14-58%), decreases in the liver (11-27%) and no change in the testis. Direct addition of DHEAS to 11 beta-HSD preparations from the kidneys of control SHR had the same effect as that observed in the in-vivo experiments. The fall in serum corticosterone in the DHEAS group is considered to be related, at least partly, to increased activity of kidney 11 beta-HSD. The inverse correlation of kidney 11 beta-HSD activity with serum corticosterone and blood pressure (-r = 0.628, P < 0.01, and -r = 0.478, P < 0.05, respectively) suggest that DHEAS delayed the development of hypertension in SHR by selective promotion of kidney 11 beta-HSD activity which in turn resulted in lower serum concentrations of corticosterone and its minimal aldosterone-like activity.
Homma
M
M
Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Science, Japan.
Onodera
T
T
Hirabatake
M
M
Oka
K
K
Kanazawa
M
M
Miwa
T
T
Hayashi
T
T
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005938:Glucocorticoids / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D005938:Glucocorticoids; D019314:Dehydroepiandrosterone Sulfate; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D003345:Corticosterone