Comparison of glycyrrhetinic acid isoforms and carbenoxolone as inhibitorsof EDHF-type relaxations mediated via gap junctions

The vascular actions of the lipophilic gap junction inhibitors 18 alpha -gl ycyrrhetinic acid (18 alpha -GA), 18 beta -glycyrrhetinic acid (18 beta -GA ) and the water-soluble hemisuccinate derivative of 18 beta -GA, carbenoxol one, were investigated in preconstricted rings of rabbit superior mesenteri c artery. EDHF-type relaxations to acetylcholine (ACh), observed in the pre sence of 300 muM N-G-nitro-L-arginine methyl ester (L-NAME) and 10 muM indo methacin, were attenuated by preincubation with 18 alpha -GA (to 100 muM), 18 beta -GA (to 10 muM) or carbenoxolone (to 300 muM) in a concentration-de pendent fashion. By contrast, none of these agents affected responses to so dium nitroprusside, an exogeneous source of NO, and relaxations evoked by A Ch in the absence of L-NAME were attenuated by only similar to 20%. 18 alph a -GA exerted no direct effect on vessel tone, whereas 18 beta -GA and carb enoxolone caused relaxations which were maximal at similar to1 and similar to 10 mM, respectively. Relaxations to carbenoxolone were attenuated by end othelial denudation and by incubation with L-NAME, whereas those to 18 beta -GA were unaffected. In conclusion, all three agents inhibit EDHF-type rel axations evoked by ACh, providing further evidence for the involvement of g ap junctions in such responses. Unlike 18 alpha -GA, carbenoxolone and 18 b eta -GA possess intrinsic vasorelaxant activity which in the case of carben oxolone involves functional enhancement of NO activity in addition to direc t effects on vascular smooth muscle.