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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 18alpha-glycyrrhetinic acid (18alpha-GA), 18beta-glycyrrhetinic acid (18beta-GA) and the water-soluble hemisuccinate derivative of 18beta-GA, carbenoxolone, were investigated in preconstricted rings of rabbit superior mesenteric artery. EDHF-type relaxations to acetylcholine (ACh), observed in the presence of 300 microM NG-nitro-L-arginine methyl ester (L-NAME) and 10 microM indomethacin, were attenuated by preincubation with 18alpha-GA (to 100 microM), 18A-GA (to 10 microM) or carbenoxolone (to 300 microM) 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 approximately 20%. 18alpha-GA exerted no direct effect on vessel tone, whereas 18beta-GA and carbenoxolone caused relaxations which were maximal at approximately 1 and approximately 10 mM, respectively. Relaxations to carbenoxolone were attenuated by endothelial denudation and by incubation with L-NAME, whereas those to 18beta-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 18alpha-GA, carbenoxolone and 18beta-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.