Effects of licorice derivatives on vascular smooth muscle function

Vascular smooth muscle contains a bidirectional form of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) which can inactivate (dehydrogenase) endogenous circulating glucocorticoids (GCs) or activate (oxo-reductase) 11-dehydro-metabolites by their conversion back to the parent steroid. Enzyme direction in vascular smooth muscle (VSM) has potential physiological consequences since GCs may enhance the response to known vasoconstrictors. We determined that carbenoxolone is a competitive inhibitor of 11beta-HSD contained in VSM cells with a lower Ki for forward dehydrogenase reaction (0.02 microM) compared to the oxo-reductase reaction (0.41 microM). To test whether changes in enzyme directional activity can affect the contractile response, aortae from adrenally intact Sprague Dawley rats were removed and sectioned into 2.5 mm rings. Rings were incubated with corticosterone 10 nM plus carbenoxolone (CBX) 10 microM (a concentration well above the Ki for both the dehydrogenase and oxo-reductase reaction) for 24 hrs. These rings showed an enhanced dose dependent contractile response to phenylephrine (PE) 0.01 microM(-1) microM and to angiotensin II 1 microM compared to rings incubated with corticosterone alone, CBX alone, or controls: [e.g. response to PE 1 microM in mg of contractile force, mean +/- SE: corticosterone plus CBX 1495 +/- 162 (n=10) vs corticosterone 1039 +/- 64 (n=9), p<0.05]. Aortic rings preincubated with 11-dehydrocorticosterone 10(-7)M and CBX 10 microM displayed a decreased contractile response compared to 11-dehydrocorticosterone alone. Thus in situ glucocorticoid metabolism is important in mediating the constrictor responses of vascular tissue.