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

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: 18 beta- & 18 alpha-GA concentration-dependently increased membrane input resistance (R-in) of in situ VSMCs, with a maximal input conductance (G(in) = 1/Rin) reduction of 92% & 77% and IC50 of 2.0 & 4.4 mu M, respectively. 18 beta GA (30 mu M) resulted in a R-in of 2.2G Omega and C-in of 12 pF, comparable to those of freshly dissociated VSMCs (3.1 G Omega & 6.1 pF). The GAs (>= 30 mu M) caused a depolarization in VSMCs in situ. In dispersed VSMCs, they both inhibited delayed rectifiers; 18bGA also activated a non-selective cation conductance while 18 alpha GA 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 EK- The ACh induced current was attenuated by 18 beta- & 18 alpha GA with an IC50 of 4.3 & 7.8 mu M, respectively. Conclusions and Implications: 18 beta GA blocked the vascular gap junctions, achieving a complete electrical isolation of the recorded VSMC at >= 30 mM while causing a mild depolarization by a complex conductance alteration. 18 beta GA suppressed the ACh-induced current in VSMC by blocking the myoendothelial gap junction and by a non-junctional action. 18 alpha GA at 30-100 mM failed to fully block the gap junctions while exerting side actions.