DIRECT AND INDIRECT EFFECTS OF CARBENOXOLONE ON RESPONSES TO GLUCOCORTICOIDS AND NORADRENALINE IN RAT AORTA

Background: In the kidney carbenoxolone impairs inactivation of glucoc orticoids and facilitates their access to mineralocorticoid receptors by inhibiting 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD). 11 beta-OHSD is also expressed in vascular smooth muscle, and, in humans, carbenoxolone potentiates vasoconstrictor sensitivity to cortisol and noradrenaline. Objective: To establish in vitro whether the vascular effects of carbenoxolone are mediated by inhibition of 11 beta-OHSD. M ethods: Noradrenaline-induced vasoconstriction was measured in helical de-endothelialized rat aortic strips following 2-5h exposure to one o r more of: carbenoxolone, corticosterone, a mineralocorticoid-receptor antagonist (spironolactone) and a glucocorticoid- and progesterone-re ceptor antagonist (RU 38486). Results: Carbenoxolone potentiated norad renaline-induced vasoconstriction in aortae from adrenalectomized rats , an effect which was prevented by spironolactone but not by RU 38486. By contrast, when corticosterone was added or when aortae from non-ad renalectomized rats were studied, carbenoxolone attenuated noradrenali ne-induced vasoconstriction. Conclusions: Carbenoxolone has a direct e ffect, independent of 11 beta-OHSD, which potentiates noradrenaline-in duced vasoconstriction and might be mediated by activation of mineralo corticoid receptors. Carbenoxolone also has an indirect effect, attenu ating noradrenaline-induced vasoconstriction dependent on corticostero ne and, therefore, mediated by inhibition of 11 beta-OHSD. Although ex periments with carbenoxolone must be interpreted with caution because of its direct effect, the present data confirm that 11 beta-OHSD modul ates vascular sensitivity to glucocorticoids and noradrenaline. Theref ore, 11 beta-OHSD activity might influence blood pressure by effects i n both the kidney and the vasculature.