Previous reports have shown that ginseng saponins, the active ingredients of Panax ginseng, induce relaxation of hormone- or high K(+)-induced blood vessel contraction. We recently demonstrated that 20(R)- and 20(S)-ginsenoside Rg(3) epimers regulate ion channel activities in a stereospecific manner. Here, we examined whether ginsenoside Rg(3) epimers also exhibit differential effects on swine coronary artery contractions induced by high K(+) or 5-HT. We found that treatment with 20(S)- but not 20(R)-ginsenoside Rg(3) caused a potent concentration-dependent, endothelium-independent relaxation of coronary artery contraction induced by 25 mM KCl. However, treatment with both 20(S)- and 20(R)-ginsenoside Rg(3) induced a significant, concentration-dependent relaxation of 3 microM 5-HT-induced coronary artery contractions in intact samples, while only 20(S)-ginsenoside Rg(3) inhibited coronary artery contraction in endothelium-denuded arteries. 20(S)- but not 20(R)-ginsenoside Rg(3) inhibited L-type Ca(2+) channel currents in a dose- and voltage-dependent manner. These results indicate that 20(S)- and 20(R)-ginsenoside Rg(3) epimers might exhibit stereospecific relaxation effects on swine coronary artery contractions caused by high K(+) and 5-HT receptor activation.