Inhibition of endothelium-dependent vasorelaxation by extracellular K[sup +]: a novel controlling signal for vascular contractility.

The effects of extracellular K[sup +] on endothelium-dependent relaxation (EDR) and on intracellular Ca[sup 2+] concentration ([Ca[sup 2+]][sub i]) were examined in mouse aorta, mouse aorta endothelial cells (MAEC), and human umbilical vein endothelial cells (HUVEC). In mouse aortic rings precontracted with prostaglandin F[sub 2α] or norepinephrine, an increase in extracellular K[sup +] concentration ([K[sup +]][sub o]) from 6 to 12 mM inhibited EDR concentration dependently. In endothelial cells, an increase in [K[sup +]][sub o] inhibited the agonist-induced [Ca[sup 2+]][sub i] increase concentration dependently. Similar to K[sup +], Cs[sup +] also inhibited EDR and the increase in [Ca[sup 2+]][sub i] concentration dependently. In current-clamped HUVEC, increasing [K[sup +]][sub o] from 6 to 12 mM depolarized membrane potential from -32.8 ± 2.7 to -8.6 ± 4.9 mV (n = 8). In voltage-clamped HUVEC, depolarizing the holding potential from -50 to -25 mV decreased [Ca[sup 2+]][sub i] significantly from 0.95 ± 0.03 to 0.88 ± 0.03 µM (n = 11, P < 0.01) and further decreased [Ca[sup 2+]][sub i] to 0.47 ± 0.04 µM by depolarizing the holding potential from -25 to 0 mV (n = 11, P < 0.001). Tetraethylammonium (1 mM) inhibited EDR and the ATPinduced [Ca[sup 2+][sub i] increase in voltage-clamped MAEC. The intermediate-conductance Ca[sup 2+]-activated K[sup +] channel openers 1-ethyl-2benzimidazolinone, chlorozoxazone, and zoxazolamine reversed the K[sup +]-induced inhibition of EDR and increase in [Ca[sup 2+]][sub i]. The K[sup +]-induced inhibition of EDR and increase in [Ca[sup 2+]][sub i] was abolished by the Na[sup +]-K[sup +] pump inhibitor ouabain (10 µM). These results indicate that an increase of [K[sup +]][sub o] in the physiological range (6-12 mM) inhibits [Ca[sup 2+]][sub i] increase in endothelial cells and diminishes EDR by depolarizing the membrane potential, decreasing K[sup +] efflux, and activating the Na[sup +]-K[sup +] pump, thereby modulating the release of endothelium-derived vasoactive factors from endothelial cells and vasomotor tone. [ABSTRACT FROM AUTHOR]