Blockade of gap junction coupling by glycyrrhetinic acids in guinea pig cochlear artery: A whole-cell voltage- and current-clamp study

Abstract

Background and purpose: Glycyrrhetinic acids (GAs) are widely used as gap junction blockers, but their efficacy and side effects have not been well determined. Experimental approach: Whole-cell electrical recordings were made from vascular smooth muscle cells (VSMCs) embedded in or dissociated from, guinea pig cochlear artery segments. Key results: 18β- & 18α-GA concentration-dependently increased membrane input resistance (R in) of in situ VSMCs, with a maximal input conductance (G in=1/R in) reduction of 92% & 77% and IC 50 of 2.0 & 4.4 μm, respectively. 18βGA (30 μM) resulted in a R in of 2.2 GΩ and C in of 12 pF, comparable to those of freshly dissociated VSMCs (3.1 GΩ & 6.1 pF). The GAs (≥30 μM) caused a depolarization in VSMCs in situ. In dispersed VSMCs, they both inhibited delayed rectifiers; 18βGA also activated a non-selective cation conductance while 18αGA inactivated a voltage-independent K +-conductance. ACh induced an outward current in VSMCs in situ at -40 mV, with a positive slope I/V relation and a reversal potential near E K. The ACh-induced current was attenuated by 18β- & 18αGA with an IC 50 of 4.3 & 7.8 μM, respectively. Conclusions and Implications: 18βGA blocked the vascular gap junctions, achieving a complete electrical isolation of the recorded VSMC at ≥30 μM while causing a mild depolarization by a complex conductance alteration. 18βGA suppressed the ACh-induced current in VSMC by blocking the myoendothelial gap junction and by a non-junctional action. 18αGA at 30-100 μM failed to fully block the gap junctions while exerting side actions. © 2007 Nature Publishing Group All rights reserved.