11-BETA-OH-PROGESTERONE AFFECTS VASCULAR GLUCOCORTICOID METABOLISM AND CONTRACTILE RESPONSE

Vascular smooth muscle (VM) contains a bidirectional isoform of 11 bet a-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme that can meta bolize endogenous glucocorticoids to their respective Il-dehydro deriv atives. 11 beta OH-progesterone (11 beta OH-P), a compound that can be produced in vivo, is as potent or more potent than licorice derivativ es in inhibiting renal and hepatic 11 beta-HSD. When studied in homoge nates prepared from primary cultures of rat VSM, 11 beta OH-P and its derivative, 11-keto-progesterone (11-keto-P), proved to be potent, dir ectionally specific inhibitors of vascular 11 beta-HSD. 11 beta OH-P s electively inhibited the forward dehydrogenase reaction (corticosteron e-->11-dehydrocorticosterone), whereas 11-keto-P selectively blocked t he 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 corticos terone (10 nmol/L), -dehydrocorticosterone (100 nmol/L), 11 beta OH-P (1 mu mol/L), 11-keto-P (1 mu mol/L), or a combination of glucocortico id and inhibitor for 24 hours. After the 24-hour incubation, rings wer e briefly stimulated sequentially with phenylephrine (10 nmol/L to 1 m u mol/L) and angiotensin II (1 mu mol/L). The immediate contractile re sponse in rings incubated with both corticosterone and 11 beta OH-P wa s greater than in rings previously incubated with either the corticost erone or 11 beta OH-P alone (eg, response to 100 nmol/L phenylephrine in milligrams of force, mean+/-SE: corticosterone, 728+/-56, n=9; 11 b eta OH-P, 325+/-105, n=4; both, 1132+/-122, n=8; corticosterone versus both, P<.01). In contrast, the immediate contractile responses to phe nylephrine and to angiotensin II were attenuated in rings exposed prev iously to both 11-dehydrocorticosterone and 11-keto-P. Thus, 11 beta O H-P and 11-keto-P (and possibly structurally similar compounds) alter the vascular effects of glucocorticoids and may play a role in glucoco rticoid-induced hypertension.