Direct and indirect effects of carbenoxolone on responses to glucocorticoids and noradrenaline in rat aorta.
BACKGROUND
In the kidney carbenoxolone impairs inactivation of glucocorticoids 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.


METHODS
Noradrenaline-induced vasoconstriction was measured in helical de-endothelialized rat aortic strips following 2-5 h exposure to one or more of: carbenoxolone, corticosterone, a mineralocorticoid-receptor antagonist (spironolactone) and a glucocorticoid- and progesterone-receptor antagonist (RU 38486).


RESULTS
Carbenoxolone potentiated noradrenaline-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-adrenalectomized rats were studied, carbenoxolone attenuated noradrenaline-induced vasoconstriction.


CONCLUSIONS
Carbenoxolone has a direct effect, independent of 11 beta-OHSD, which potentiates noradrenaline-induced vasoconstriction and might be mediated by activation of mineralocorticoid receptors. Carbenoxolone also has an indirect effect, attenuating noradrenaline-induced vasoconstriction dependent on corticosterone and, therefore, mediated by inhibition of 11 beta-OHSD. Although experiments with carbenoxolone must be interpreted with caution because of its direct effect, the present data confirm that 11 beta-OHSD modulates vascular sensitivity to glucocorticoids and noradrenaline. Therefore, 11 beta-OHSD activity might influence blood pressure by effects in both the kidney and the vasculature.
Walker
B R
BR
Department of Medicine, University of Edinburgh, Western General Hospital, UK.
Sang
K S
KS
Williams
B C
BC
Edwards
C R
CR
D000315:Adrenalectomy; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D002229:Carbenoxolone / Q000494:pharmacology*; D003345:Corticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000494:pharmacology; D014661:Vasoconstriction
D005938:Glucocorticoids; D013148:Spironolactone; D015735:Mifepristone; C003552:11-dehydrocorticosterone; D002229:Carbenoxolone; D003345:Corticosterone; D009638:Norepinephrine