Comparison of Glycyrrhetinic Acid Isoforms and Carbenoxolone as Inhibitors of EDHF-Type Relaxations Mediated via Gap Junctions

The vascular actions of the lipophilic gap junction inhibitors 18α-glycyrrhetinic acid (18α-GA), 18β-glycyrrhetinic acid (18β-GA) and the water-soluble hemisuccinate derivative of 18β-GA, carbenoxolone, were investigated in preconstricted rings of rabbit superior mesenteric artery. EDHF-type relaxations to acetylcholine (ACh), observed in the presence of 300 µM NG -nitro-L-arginine methyl ester (L-NAME) and 10 µM indomethacin, were attenuated by preincubation with 18α-GA (to 100 µM), 18β-GA (to 10 µM) or carbenoxolone (to 300 µM) in a concentration-dependent fashion. By contrast, none of these agents affected responses to sodium nitroprusside, an exogeneous source of NO, and relaxations evoked by ACh in the absence of L-NAME were attenuated by only -20%. 18α-GA exerted no direct effect on vessel tone, whereas 18β-GA and carbenoxolone caused relaxations which were maximal at ∼1 and ∼10 mM, respectively. Relaxations to carbenoxolone were attenuated by endothelial denudation and by incubation with L-NAME, whereas those to 18β-GA were unaffected. In conclusion, all three agents inhibit EDHF-type relaxations evoked by ACh, providing further evidence for the involvement of gap junctions in such responses. Unlike 18β-GA, carbenoxolone and 18β-GA possess intrinsic vasorelaxant activity which in the case of carbenoxolone involves functional enhancement of NO activity in addition to direct effects on vascular smooth muscle.