| Summary: | Acute hyperglycemia induces oxidative damage and inflammation, leading to vascular dysfunction. Ginsenoside Rb<sub>1</sub> (Rb<sub>1</sub>) is a major component of red ginseng with anti-diabetic, anti-oxidant and anti-inflammatory properties. Here, we investigated the beneficial effects and the underlying mechanisms of Rb<sub>1</sub> on hypercontraction induced by high glucose (HG) and endothelial dysfunction (ED). The isometric tension of aortic rings was measured by myography. The rings were treated with N<sup>G</sup>-nitro-L-arginine methyl ester (L-NAME) to induce chemical destruction of the endothelium, and Rb<sub>1</sub> was added after HG induction. The agonist-induced vasoconstriction was significantly higher in the aortic rings treated with L-NAME + HG50 than in those treated with HG50 or L-NAME (<i>p</i> = 0.011) alone. Rb<sub>1</sub> significantly reduced the hypercontraction in the aortic rings treated with L-NAME + HG50 (<i>p</i> = 0.004). The ATP-sensitive K<sup>+</sup> channel (K<sub>ATP</sub>) blocker glibenclamide tended to increase the Rb<sub>1</sub>-associated reduction in the agonist-induced vasoconstriction in the rings treated with L-NAME + HG50. The effect of Rb<sub>1</sub> in the aortic rings treated with L-NAME + HG50 resulted from a decrease in extracellular Ca<sup>2+</sup> influx through the receptor-operated Ca<sup>2+</sup> channel (ROCC, 10<sup>−6</sup>–10<sup>−4</sup> M CaCl<sub>2</sub>, <i>p</i> < 0.001; 10<sup>−3</sup>–2.5 × 10<sup>−3</sup> M CaCl<sub>2</sub>, <i>p</i> = 0.001) and the voltage-gated Ca<sup>2+</sup> channel (VGCC, 10<sup>−6</sup> M CaCl<sub>2</sub>, <i>p</i> = 0.003; 10<sup>−5</sup>–10<sup>−2</sup> M CaCl<sub>2</sub>, <i>p</i> < 0.001), whereas Rb<sub>1</sub> did not interfere with Ca<sup>2+</sup> release from the sarcoplasmic reticulum. In conclusion, we found that Rb<sub>1</sub> reduced hyper-vasoconstriction induced by HG and ED by inhibiting the ROCC and the VGCC, and possibly by activating the K<sub>ATP</sub> in rat aorta. This study provides further evidence that Rb<sub>1</sub> could be developed as a therapeutic target for ED in diabetes.
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