2-Aminoethoxydiphenyl borate blocks electrical coupling and inhibits voltage-gated K+ channels in guinea pig arteriole cells

Ma KT, Guan BC, Yang YQ, Nuttall AL, Jiang ZG. 2-Aminoethoxydiphenyl borate blocks electrical coupling and inhibits voltage-gated K+ channels in guinea pig arteriole cells. Am J Physiol Heart Circ Physiol 300: H335-H346, 2011. First published October 29, 2010; doi: 10.1152/ajpheart.00737.2010.-2-Aminoethoxydiphenyl borate (2-APB) analogs are potentially better vascular gap junction blockers than others widely used, but they remain to be characterized. Using whole cell and intracellular recording techniques, we studied the actions of 2-APB and its potent analog diphenylborinic anhydride (DPBA) on vascular smooth muscle cells (VSMCs) and endothelial cells in situ of or dissociated from arteriolar segments of the cochlear spiral modiolar artery, brain artery, and mesenteric artery. We found that both 2-APB and DPBA reversibly suppressed the input conductance (G(input)) of in situ VSMCs (IC50 approximate to 4-8 mu M). Complete electrical isolation of the recorded VSMC was achieved at 100 mu M. A similar gap junction blockade was observed in endothelial cell tubules of the spiral modiolar artery. Similar to the action of 18 beta-glycyrrhetinic acid (18 beta-GA), 2-APB and DPBA depolarized VSMCs. In dissociated VSMCs, 2-APB and DPBA inhibited the delayed rectifier K+ current (I-K) with an IC50 of similar to 120 mu M in the three vessels but with no significant effect on Ginput or the current-voltage relation between -140 and -40 mV. 2-APB inhibition of I-K was more pronounced at potentials of <= 20 mV than at +40 mV and more marked on the fast component than on the slow component, which was mimicked by 4-aminopyridine but not by tetraethylammonium, nitrendipine, or charybdotoxin. In contrast, 18 beta-GA caused a linear inhibition of I-K between 0 to +40 mV, which was similar to the action of tetraethylammonium or charybdotoxin. Finally, the 2-APB-induced inhibition of electrical coupling and I-K was not affected by the inositol 1,4,5-trisphosphate receptor antagonist xestospongin C. We conclude that 2-APB analogs are a class of potent and reversible vascular gap junction blockers with a weak side effect of voltage-gated K+ channel inhibition. They could be gap junction blockers superior to 18 beta-GA only when Ca2+-actived K+ channel inhibition by the latter is a concern but inositol 1,4,5-trisphosphate receptor and voltage-gated K+ channel inhibitions are not.