(Hypertension. 1997;30:449.)
© 1997 American Heart Association, Inc.
Articles |
11ßOH-Progesterone Affects Vascular Glucocorticoid Metabolism and Contractile Response
From Rhode Island Hospital (A.S.B., R.B.B.), Roger Williams Medical Center (T.K.), Miriam Hospital (D.J.M.), and Brown University School of Medicine, Providence, RI.
Correspondence to Andrew S. Brem, MD, Division of Pediatric Nephrology, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903.
Abstract Vascular smooth muscle (VSM) contains a
bidirectional isoform of 11ß-hydroxysteroid dehydrogenase
(11ß-HSD), the enzyme that can metabolize endogenous
glucocorticoids to their respective 11-dehydro derivatives.
11ßOH-progesterone (11ßOH-P), a compound that can be produced in
vivo, is as potent or more potent than licorice derivatives in
inhibiting renal and hepatic 11ß-HSD. When studied in
homogenates prepared from primary cultures of rat VSM,
11ßOH-P and its derivative, 11-keto-progesterone (11-keto-P), proved
to be potent, directionally specific inhibitors of vascular
11ß-HSD. 11ßOH-P selectively inhibited the forward dehydrogenase
reaction
(corticosterone
11-dehydrocorticosterone),
whereas 11-keto-P selectively blocked the reverse oxidoreductase
reaction. To test the physiological effects,
vascular rings were prepared from rat aorta. Rings were incubated in
culture media containing either a submaximal concentration of
corticosterone (10 nmol/L),
11-dehydrocorticosterone (100 nmol/L),
11ßOH-P (1 µmol/L), 11-keto-P (1 µmol/L), or a
combination of glucocorticoid and inhibitor for 24 hours.
After the 24-hour incubation, rings were briefly stimulated
sequentially with phenylephrine (10 nmol/L to 1
µmol/L) and angiotensin II (1 µmol/L). The
immediate contractile response in rings incubated with both
corticosterone and 11ßOH-P was greater than in rings previously
incubated with either the corticosterone or 11ßOH-P alone (eg,
response to 100 nmol/L phenylephrine in milligrams of
force, mean±SE: corticosterone, 728±56, n=9; 11ßOH-P, 325±105,
n=4; both, 1132±122, n=8; corticosterone versus both,
P<.01). In contrast, the immediate contractile responses to
phenylephrine and to angiotensin II were
attenuated in rings exposed previously to both
11-dehydrocorticosterone and 11-keto-P.
Thus, 11ßOH-P and 11-keto-P (and possibly structurally similar
compounds) alter the vascular effects of glucocorticoids and may play a
role in glucocorticoid-induced hypertension.
Key Words: muscle, smooth, vascular • angiotensin • glucocorticoids • catecholamines • progesterone • metabolites
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