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.
Chaytor
A T
AT
Department of Diagnostic Radiology, Wales Heart Research Institute, University of Wales College of Medicine, Cardiff, UK.
Marsh
W L
WL
Hutcheson
I R
IR
Griffith
T M
TM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology*; D002229:Carbenoxolone / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007536:Isomerism; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D001685:Biological Factors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; C119129:18alpha-glycyrrhetinic acid; D009599:Nitroprusside; D010656:Phenylephrine; D002229:Carbenoxolone; D000109:Acetylcholine; D006034:Glycyrrhetinic Acid; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin