The ginsenoside Rg₃ evokes endothelium-independent relaxation in rat aortic rings: role of K⁺ channels

Abstract

The purpose of the present study was to characterize the mechanism underlying the direct relaxing activity of ginsenosides on vascular smooth muscle. The total ginsenoside mixture, ginsenosides from either the protopanaxadiol group or the protopanaxatriol group, and the ginsenoside Rg₃ from the protopanaxatriol group caused a concentration-dependent relaxation of rat aortic rings without endothelium contracted with 25×10⁻³ M KCl but affected only minimally those contracted with 60×10⁻³ M KCl. Ginsenoside Rg₃ was the most potent relaxing agonist. Relaxations elicited by ginsenoside Rg₃ were markedly reduced by tetraethylammonium, a blocker of non-selective K⁺ channels, but not by glibenclamide, a blocker of ATP-sensitive K⁺ channels. Ginsenoside Rg₃ significantly inhibited Ca²⁺-induced concentration–contraction curves and the ${}^{45}\text{Ca}{}^{\mathrm{2+}}$ influx in aortic rings incubated with 25×10⁻³ M KCl whereas these responses were not affected in rings incubated with 60×10⁻³ M KCl. Ginsenoside Rg₃ caused a time- and concentration-dependent efflux of ${}^{86}\text{Rb}$ from aortic rings that was inhibited by tetraethylammonium but not by glibenclamide. These findings indicate that ginsenoside Rg₃ is a potent inhibitor of vascular smooth muscle tone and that this effect seems to be due to an inhibition of Ca²⁺ influx and stimulation of K⁺ efflux, possibly via activation of tetraethylammonium-sensitive K⁺ channels.

Introduction

Administration of ginsenosides, a mixture of saponin extracted from Panax ginseng, decreases blood pressure in both hypertensive patients and experimental animals (Sohn et al., 1980; Kim et al., 1994). The antihypertensive effect of ginsenosides may be due, at least in part, to their ability to inhibit vascular tone. Indeed, ginsenosides concentration dependently relax isolated rabbit pulmonary arteries contracted with prostaglandin F_2a (Chen et al., 1984) and isolated rabbit and rat aorta contracted with phenylephrine (Kim et al., 1994). The inhibitory effect of ginsenosides requires the presence of a functional endothelium and is mediated by an increased formation of endothelium-derived nitric oxide (Kim et al., 1994). Studies examining the effect of various purified ginsenosides on vascular tone identified ginsenoside Rg₃, a triterpene glycoside which chemically belongs to the protopanaxadiol ginsenoside group, as the most potent vasodilator (Kim et al., 1998). Since the endothelium-dependent nitric oxide-mediated relaxation in response to ginsenoside Rg₃ in rat aorta was prevented by tetraethylammonium, a blocker of non-selective K⁺ channels, but not by glibenclamide, an ATP-sensitive K⁺ channel blocker, activation of tetraethylammonium-sensitive K⁺ channels seems to be implicated in the formation of nitric oxide in endothelial cells. Recently, we found that, in addition to the endothelium-dependent relaxation, ginsenoside Rg₃ also inhibited the tone of aortic rings without endothelium contracted with 25×10⁻³ M KCl whereas only a small relaxation was found in rings contracted with phenylephrine (Kim et al., 1998). The purpose of the present study was to characterize the mechanisms underlying the direct relaxing effect of ginsenoside Rg₃ on the blood vessel wall.