Ginseng has, as an adaptogen, been credited with the ability to normalise both high and low blood pressure conditions. Therefore it would appear to be potentially useful in the treatment of hypertension, a condition of high blood pressure predisposing to strokes and heart attacks and associated with old age. Certainly it had been valued for the treatment of impaired circulation and the sedative effect lowering the blood pressure was well-known. Early workers in the 1920's and 1930's using rats, dogs and rabbits as test animals established that the effects were dose dependent, smaller doses causing an increase and larger doses a lasting decrease in blood pressure (Hou, 1978).
Lee et al. (1981) examined the effects of ethereal, ethanolic and aqueous P. ginseng extracts on cardiovascular function in dogs after intravenous injection (40 mg/kg). The ether extract caused significant decrease of heart rate and central venous pressure, the ethanol extract significant decrease of heart rate and mean arterial pressure and the aqueous extract significant decrease of cardiac output, stroke volume and central venous pressure but the total peripheral resistance was markedly increased.
Using intravenous injections of total ginsenosides in dogs, Chen et al. (1982) confirmed that the peak value of left ventricular pressure and the arterial systolic pressure were rapidly decreased. Heart rate and renal arterial blood flow decreased although renal vasoresistance was significantly increased. This vasoconstrictory effect of ginsenosides was not blocked by a-adrenoreceptor blocking or serotonin receptor blocking agents. Other workers reported that the cardiovascular responses to the stem and leaf saponins were similar to those observed with the root saponins (Pan et al., 1985). Pan and Li (1991) also noted that, in mice, ginseng flower saponins as well as root saponins at appropriate oral dosage could raise the level of myocardial cyclic adenosine monophosphate (cAMP), an intracellular hormonal mediator. Flower saponins also affected myocardial cyclic guanosine monophosphate (cGMP) at suitable dose levels, the ratio cAMP/cGMP in mice increasing progressively at dosages of 50, 25 and 12.5 mg/kg.
Several Chinese workers have indicated that various ginseng saponins can reduce the size of myocardial infarction, the area of dead tissue developed after coronary occlusion has obstructed the blood flow to the cardiac muscles or myocardium. Experimentally this can be achieved by ligation of the left descending coronary artery (ca 40 min) and subsequent reperfusion (ca 120 min). In various animals (dogs, guinea pigs, rats and mice) Chen et al. (1981) observed that ginsenosides increased myocardial tolerance to hypoxia (oxygen deficiency), a decrease in myocardial oxygen consumption apparently occurring during hypoxia. The survival times for mice given ginseng extract intraperitoneally and subjected to hypoxia were prolonged (Lu et al., 1987). Ginsenosides have also been reported by other workers to protect mice against metabolic disturbances and myocardial damage associated with severe anoxia and anoxaemia (lack of oxygen in the tissues) (Yunxiang and Xiu, 1987). Myocardial necrosis can be also induced with isoproterenol (isoprenaline) and changes in the electrocardiogram and serum creatine phosphokinase, lactic dehydrogenase and y-glutamyl-transferase levels can be normalised with ginsenosides from ginseng root, stem, leaf and fruit. Such actions are comparable to those of propranalol, a heart sympathetic stimulation inhibitor used in the treatment of cardiac arrhythmias associated with heart disease (Chen et al., 1986).
P. notoginseng saponins (50 mg/L and 100 mg/L) slowed the breakdown of adenosine triphosphate (ATP) in cultured chick embryo neurons after 2 hours of hypoxia and stimulated the restoration of ATP during 30 min reoxygenation. The saponins (100 mg/L), whether administered at the commencement of hypoxia or after induction of hypoxia, also reduced the release of creatine kinase (Jiang et al., 1995). Ginsenosides improved the survival rate of cultured rat hippocampal neurons under anoxic conditions, reducing the efflux of K+ and lactate dehydrogenase (Wang et al., 1995). Similar conditions probably apply to myocardial neurons. Chan et al. (1997) confirmed the myocardial protective effect in the rat heart of the naturally occurring triacylglycerol trilinolein isolated from ginseng. Pretreatment of isolated cardiomyocytes with trilinolein at the low concentration of 10-9 M reduced the 45Ca2+ influx caused by hypoxia/ normoxia by 34 per cent. When the isolated perfused rat heart was subjected to 1 hr global hypoxaemia without reperfusion it was observed that pretreatment with 10-7 M trilinolein for 15 min reduced by 37 per cent the size of the infarct or dead tissue area caused by stagnation of the blood circulation. Determination of superoxide dismutase-mRNA by Northern blot analysis in the in vivo heart that had undergone 30 min ischaemia (hypoxic reduction of blood supply) followed by 10 min reperfusion indicated that pretreatment with 10-7 M trilinolein resulted in a synergistic action with antioxidant systems preventing a rise in superoxide dismutase-mRNA. It can therefore be concluded that ginsengs operate by inhibition of 45Ca2+ influx, by restoration of high energy phosphates during reoxygenation and by improvement of antioxidant activity.
The individual saponin glycosides were shewn to act in different ways. Ginsenosides Rg, Rg1 and total flower saponins were recorded as cardiac performance improvers whilst ginsenosides-Rb and total leaf saponins had the opposite effect. Negative chronotropic effects (retardation of the rapidity of the periodically-recurring phenomena e.g. heart beat) and negative inotropic effects (not modifying the force or speed of contraction of the cardiac muscle) in vitro have been demonstrated for ginseng saponins; the mechanism of action resembles that of verapimil (5-[N-(3,4-dimethoxyphenethyl)-methylamino]-2-(3,4-dimethoxyphenyl)-2-iso-propyl-valeronitrile hydrochloride), a drug reducing the work load on the heart by reducing the oxygen requirements of the myocardium and decreasing peripheral resistance and used for angina pectoris treatment (Wu and Chen, 1988). However in vitro experiments had also indicated an increase in coronary blood flow together with a positive inotropic effect (Lei et al., 1986).
Ginseng saponins Rc and Rd provided some antiarrhythymic action against aconitine- and barium chloride-induced arrhythmias in rats and adrenaline-induced arrhythmias in rabbits. The mode of action resembled that of amiodarone and prompted prolonged RR, PR and QTC intervals on the electrocardiogram (Li and Zhang, 1988).
P. notoginseng saponins (12.5 and 25 |g/mL) and ginsenosides Rb1 (10 |g/ mL) and Rg1 (10 |g/mL) decreased cardiac creatine phosphokinase release, reduced myocardial Ca++ accumulation, reduced malondialdehyde production and blocked reduction of superoxide dismutase activity in isolated rat hearts with global ischemia and reperfusion. Therefore P. notoginseng saponins and the ginsenosides Rb1
and Rg1 tend to prevent cardiac ischemia by inhibition of lipid peroxidation (Li et al., 1990). Panaxadiol and panaxatriol saponins were shewn to dose-dependently decrease the action potentials of normal cultured myocardial cells suggesting selective Ca++ channel blockade and to protect against free radical oxidative damage induced by xanthine and xanthine oxidase (Zhong et al., 1991). Ginsenosides of group Rb but not Rg possess Ca++ antagonist activity and a protective effect on experimental myocardial infarction in rabbits. Arrhythmias induced by reperfusion were prevented by panaxatriol pretreatment at 5 or 50 pg/mL. Panaxatriol saponins inhibited the release of creatine phosphokinase and lactate dehydrogenase as well as malondialdehyde production from ischaemic reperfused hearts at 50 pg/mL. There was also action on superoxide dismutase at 5 and 50 pg/mL, action probably due to inhibition of free radical accumulation and lipid peroxidation (Li et al., 1992a). Total P. quinquefolium saponins (90-180 mg/kg i.p.) administered to rats having the myocardium damaged by injury to the left anterior descending coronary artery were also shewn to protect the myocardium with an anti-ischaemic action probably related to a decrease in free fatty acid levels and an elevation of lactate dehydrogenase activity. The total saponins may also have produced a Ca++ channel blocking effect (Jin and Lu, 1992).
Investigating the effect of 11 ginsenosides on the action potentials induced by microelectrodes on cultured cardiomyocytes Jiang et al. (1993) noted that ginsenosides reduced the amplitude, ginsenosides Rg2, Rg1 and Re in decreasing order being the most effective and similar in action to the Ca++ channel blocker nimodipine. Ginsenosides Rd, Rf and Ro had no effect on action potential and the protopanaxatriol-derived ginsenosides Re, Rg1, Rg2 and Rh 1 were more potent than protopanaxadiol-derived ginsenosides Rb1, Rb2, Rb 3 and Rc. Therefore the Ca++ channel blocking action of the triols is greater than that of the diols. Significantly ginsenoside Re was patented in 1995 as a treatment for cardiac arrhythmia (see Chapter 9).
Further work on the protective action on myocardial ischaemia and reperfusion injury of saponins from P. notoginseng and P. japonicus and of isolated gypenosides indicated that all possessed some effectiveness, the first two named acting by prevention of Ca++ overload and the gypenosides acting by anti-lipid peroxidation (Ha et al., 1994). It is clear that some ginseng constituents are antioxidants restricting lipid peroxidation, others are less effective or ineffective and some inconsistencies are undoubtedly due to the variations in qualitative and quantitative chemical composition of the plant materials or saponin mixtures used. Hence the importance of standardised experimental materials.
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