CARBENOXOLONE DAMAGES ENDOTHELIUM AND ENHANCES VASOCONSTRICTOR ACTIONIN AORTIC RINGS

Carbenoxolone causes hypertension indirectly by inhibition of 11 beta- hydroxysteroid dehydrogenase and consequent elevation of intracellular glucocorticoid levels and enhancement of vasoconstrictor action. We p erformed the present study to determine whether carbenoxolone also enh ances vascular tone directly by mechanisms independent of glucocortico ids and other systemic influences. Exposure of rat aortic rings to 10 to 100 mu mol/L carbenoxolone in aerated Krebs-Henseleit buffer for 24 hours resulted in concentration-dependent increases in angiotensin II (Ang II) (100 nmol/L)-stimulated contractions and significant shiftin g of the phenylephrine cumulative contraction curve to the left but no t increases in KCl (120 mmol/L)-stimulated contractions. Maximal enhan cement of Ang II contraction was 39%. In contrast, brief (15-minute) e xposure to 100 mu mol/L carbenoxolone did not alter Ang II contraction s. Mechanical denudation of the endothelium obviated enhancement of An g II contractions by carbenoxolone, suggesting interaction of carbenox olone with the endothelium. Endothelium-dependent relaxation of precon tracted rings to acetylcholine of ATP was reduced by more than 90% by 24-hour pretreatment with 100 mu mol/L carbenoxolone but not with 100 mu mol/L deoxycorticosterone acetate (a mineralocorticoid) or 100 mu m ol/L glycyrrhizic acid (a natural 11 beta-hydroxysteroid dehydrogenase inhibitor). Vascular smooth muscle relaxation with sodium nitroprussi de was not inhibited by carbenoxolone. Incubation of cultured endothel ial cells with 100 mu mol/L carbenoxolone for 24 hours did not inhibit nitric oxide synthase activity, as measured by conversion of [H-3]L-c itrulline. Electron micrography demonstrated that endothelial cell ult rastructure but not vascular smooth muscle cell ultrastructure was abn ormal after incubation of rings for 24 hours with 100 mu mol/L carbeno xolone. These studies suggest that carbenoxolone concentrations higher than 10 mu mol/L enhance vasoconstrictor action via selective toxicit y to the endothelium and elimination of endothelium-dependent relaxati on.