Nitric Oxide, Human Diseases And the Herbal Products That Affect the Nitric Oxide Signal Pathways

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Clinical and Experimental Pharmacology and Physiology (2003) 30, 605–615

BRIEF REVIEW

NITRIC OXIDE, HUMAN DISEASES AND THE HERBAL PRODUCTS THAT AFFECT THE NITRIC OXIDE SIGNALLING PATHWAY
Francis I Achike* and Chiu-Yin Kwan†
*Clinical Sciences Section, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia and †Department of Medicine and Smooth Muscle Research Program, McMaster University, Hamilton, Ontario, Canada

SUMMARY
1. Nitric oxide (NO) is formed enzymatically from in the presence of nitric oxide synthase (NOS). Nitric oxide is generated constitutively in endothelial cells via sheer stress and blood-borne substances. Nitric oxide is also generated constitutively in neuronal cells and serves as a neurotransmitter and neuromodulator in non-adrenergic, non-cholinergic nerve endings. Furthermore, NO can also be formed via enzyme induction in many tissues in the presence of cytokines. 2. The ubiquitous presence of NO in the living body suggests that NO plays an important role in the maintenance of health. Being a free radical with vasodilatory properties, NO exerts dual effects on tissues and cells in various biological systems. At low concentrations, NO can dilate the blood vessels and improve the circulation, but at high concentrations it can cause circulatory shock and induce cell death. Thus, diseases can arise in the presence of the extreme ends of the physiological concentrations of NO. 3. The NO signalling pathway has, in recent years, become a target for new drug development. The high level of flavonoids, catechins, tannins and other polyphenolic compounds present in vegetables, fruits, soy, tea and even red wine (from grapes) is believed to contribute to their beneficial health effects. Some of these compounds induce NO formation from the endothelial cells to improve circulation and some suppress the induction of inducible NOS in inflammation and infection. 4. Many botanical medicinal herbs and drugs derived from these herbs have been shown to have effects on the NO signalling pathway. For example, the saponins from ginseng, ginsenosides, have been shown to relax blood vessels (probably contributing to the antifatigue and blood pressure-lowering effects of ginseng) and corpus cavernosum (thus, for the treatment of men suffering from erectile dysfunction; however, the legendary aphrodisiac effect of ginseng may be an overstatement). Many plant extracts or purified drugs derived from
L-arginine

Chinese medicinal herbs with proposed actions on NO pathways are also reviewed. Key words: endothelial cells, flavonoids, ginseng, inflammation, medicinal herbs, nitric oxide synthase, polyphenols, tea catechins, tetrandrine, vascular relaxation.

INTRODUCTION The yin and yang of nitric oxide
The existing knowledge on the role of nitric oxide (NO) in physiological and pathophysiological states has opened up a wide range of possibilities, especially in our understanding of the mechanisms of actions of drugs that modulate NO action. The enzyme nitric oxide synthase (NOS), constitutively or inductively, catalyses the production of NO in several biological systems. The constitutive NOS was found originally in neuronal tissues (referred to as ‘nNOS’ or type I NOS) and in vascular endothelium (referred to as ‘eNOS’ or type III NOS), whereas the type II NOS is the inducible enzyme that is activated by inflammation-mediating cytokines, as in Gram-negative endotoxic shock. Activation of type II NOS leads to the production of micromolar levels of NO, much higher than the level (nanomolar range) generated by the constitutive eNOS or nNOS. The high level of inducible NO is thought to be a major factor in the severe hypotension that characterizes the toxic shock syndrome. The nNOS conceivably contributes to the regulation of neuronal transmission, which, in turn, controls several other functions, such as cerebral vascular tone/calibre, thus influencing cerebral tissue perfusion and/or ischaemia. The eNOS represents a major physiological regulator of blood vessel tone, mediating the interaction between endothelium and the cellular components of blood.1,2 Endothelial cells (EC) release NO either spontaneously under the influence of physical, cellular and humoral factors2,3 or by induction under the influence of insult by pathogens. Most of the effects of NO, on smooth muscle cells, platelets and cardiac myocytes, are mediated through its activation of soluble guanylate cyclase,4,5 amplifying the production of cGMP.6,7 Nitric oxide is a reactive oxygen species (ROS) as well as a reactive nitrogen species. It carries a reactive lone pair electron that undergoes an oxidative process (e.g. with other ROS or superoxide anions) to form more active intermediates, such as peroxynitrite, which are capable of toxic nitrosylation and/or nitration of some amino acid residues of proteins such as tyrosine and cysteine. Thus, prolonged exposure to a large amount of NO (as in activation

Correspondence: Professor CY Kwan, Department of Medicine, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada. Email: [email protected] Received 13 August 2002; revision 12 December 2002; accepted 22 December 2002.

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List of abbreviations: EC GTN 5-HT IDDM L-NAME L-NOARG LPS Endothelial, cell Glyceryl trinitrate 5-Hydroxytrytamine Insulin-dependent diabetes mellitus NG-Nitro-L-arginine methyl ester NG-nitro-L-arginine Lipopolysaccharide

FI Achike and C-Y Kwan

NANC NO NOS PGH2 ROS SMC TXA2

Non-adrenergic, non-cholinergic Nitric oxide Nitric oxide synthase Prostaglandin H2 Reactive oxygen species Smooth muscle cell Thromboxane A2

of iNOS) inhibits the activity of several enzymes, such as aconitase, complexes I and II, cytochrome c oxidase and ribonucleotide reductase.8,9 As a result, NO could become cytotoxic or cytostatic. This, in part, is the basis for the pathophysiological functions of NO. Therefore, a proper control of NO homeostasis makes NO a useful signal (yang nature) in a given physiological event and excessive generation of NO renders NO cytotoxic (yin nature), leading to a pathophysiological state. Obviously, although a pharmacological intervention at the level of NO formation may serve as a therapeutic target in certain disease states, a proper dietary regimen aiming at a positive NO homeostasis may also serve as a preventive measure towards the management of health and diseases. Indeed, fruits, vegetables and functional botanical foods, including some medicinal herbs and their active components, have increasingly been discovered to possess anti-oxidant activity and exert their therapeutic effects, at least in part, by influencing NO metabolism. In the following sections, we reiterate the proposed roles of NO in several common human diseases and review some medicinal herbs whose therapeutic effects depend, at least in part, on the modulation of NO pathways. Although the primary focus of the present review is on NO-related mechanisms, it by no means excludes the importance of other pathophysiological mechanisms of diseases or the mechanisms of action of the herbal drugs under review.

arteries when NO formation is inhibited. Blood pressure homeostasis depends in part on basal NO release, which is diminished in hypertension.10–12 In both human and animal models, endotheliumdependent acetylcholine-induced relaxation is impaired during hypertension.13 This has been attributed to the presence of ROS, which impair the endothelial function and, therefore, inhibit NO production and/or inactivate NO whenever it is produced.14 It has been reported that the ROS is a product of endothelial COX.15 Treatment with anti-oxidants or free radical scavengers has been useful in restoring NO production16 and treatment with L-arginine, the substrate for NO synthesis, has been shown to have antihypertensive effects.17,18 It is conceivable that a potentially important goal in antihypertensive therapy is the restoration of endothelial function and this is not achieved by simply lowering the blood pressure.19,20 Bradykinin is one of the endogenous endothelium-based vasorelaxant agonists whose action is based on NO production. Bradykinin is degraded by angiotensin-converting enzyme (ACE). The promotion of the bradykinin effect by ACE inhibitors partly explains their successful use in the treatment of hypertension and atherosclerosis.5 Angiotensin-converting enzyme inhibitors have also been reported to upregulate eNOS expression21 and to have beneficial cardioprotective effects in myocardial ischaemia through the elevation of kinin.22,23

Diabetes NITRIC OXIDE AND HUMAN DISEASES Nitric oxide and cardiovascular diseases Hypertension
The contractile state of arteries is a major determinant of the peripheral resistance, which is elevated in sustained hypertension. Thus, an imbalance in vascular function in which contraction (yang nature) predominates over relaxation (yin nature) is thought to be a major pathophysiological feature of hypertension (yang dominant). Likewise, excessive vasorelaxation could contribute to the state of circulatory shock (yin dominant). At the tissue level, exaggerated vasoconstriction in hypertension may also be a result of an imbalance of the paracrine function of the vascular endothelium in which endothelium-derived contractile factors (yang element) predominate over those of the relaxant factors (yin element), whereas the excessive production of the yin element, such as NO, in septic shock, for example, results in overwhelming vasorelaxation over the vasoconstriction and causes hypotension. Nitric oxide is the main endothelium-derived relaxant factor, whereas the contracting factors include products of the cyclooxygenase (COX) metabolic pathway (thromboxane (TX) A2 and prostglandin (PG) H2). Endothelium-derived hyperpolarizing factor may also play a role in vasorelaxation, especially in small Although diabetes mellitus is an endocrine disorder, uncontrolled diabetes is frequently associated with cardiovascular complications, such as hypertension and artherosclerosis. Insulin-dependent diabetes mellitus (IDDM) arises from the destruction of pancreatic -cells and the subsequent failure to produce insulin. The destruction of the -cells has been attributed to the induction of iNOS in the -cells24 and the ensuing NO-mediated toxicity to which the -cells are reported to be particularly prone.25 Cytokines, such as interleukin (IL)-1 , have been implicated in the expression of the iNOS within these cells.26,27 Macrophages also infiltrate the islet cells in the early stages of IDDM and they secrete cytokines, which also promote iNOS expression. Hence, the use of a selective iNOS inhibitor in the management of IDDM is undergoing extensive research. It has been reported that low levels of NO promote insulin production10 and insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent.28 Diabetic angiopathies have been attributed to impaired endotheliumdependent relaxation, resulting, in part, from the glycosylation of cellular proteins, leading to the formation of products that directly inhibit NO and alter the pathway for NO synthesis.29 Acute inhibition of normal arteries with elevated glucose concentrations caused inhibition of normal relaxation to acetylcholine.This impairment was prevented by coincubation with an NO–aspirin analogue, NXC4016.30 In addition, chronic treatment with NXC4016

NO, human diseases and herbal products prevented the development of defective endothelium-dependent relaxation to acetylcholine. This protection did not occur as a result of any changes in blood glucose concentration or haemoglobin glycation.

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(L-NOARG) has been shown to be effective in reducing the severity of both GTN-induced and spontaneous migraine attacks.42

Neurodegenerative diseases
Parkinson’s and Alzheimer’s diseases are neurodegenerative conditions that have been associated with oxidative stress resulting from mitochondrial dysfunction and the production of ROS. The inhibitor of complex I of the mitochondrial respiratory chain induces Parkinson-like syndrome in primates and humans.43 As with stroke, the neuronal damage seems to have a component that is due to excessive NO generated from increased nNOS activity.44 Inducible NOS is implicated in Alzheimer’s disease because a component ( -amyloid peptide) of the characteristic amyloid plaque induces iNOS expression in astrocytes via the nuclear factor- B mechanism.45 Inducible NOS expression is high in demyelinated regions of brain tissues from post-mortem specimens.46,47 All these findings suggest a role for selective NOS inhibitors in the management of the neurodegenerative diseases. The NOS inhibitor 7-nitroindazole48 prevents the depletion of striatal dopamine and the loss of neurons in the substantia nigra, leading to improved motor and cognitive functions.49

Nitric oxide, insulin resistance and obesity
Inducible NOS is induced by inflammatory cytokines in skeletal muscle and fat (see also the section on NO and inflammation and infection) and chronic iNOS induction may cause muscle insulin resistance. Recently, it has been demonstrated that iNOS expression is increased in the muscle and fat of genetic and dietary models of obesity.31 Moreover, mice in which the gene encoding iNOS is disrupted (Nos2–/– mice) are protected from high fat-induced insulin resistance.31 Whereas both widl-type and Nos2–/– mice developed obesity on the high-fat diet, obese Nos2–/– mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo and normal insulin-stimulated glucose uptake in muscles. Inducible NOS induction in obese wild-type mice was associated with impairments in phosphatidylinositol 3-kinase and Akt activation by insulin in muslce. These defects were fully prevented in obese Nos2–/– mice.31 These findings provide genetic evidence that iNOS is involved in the development of muscle insulin resistance in dietinduced obesity, which is also a major risk factor for NO-mediated inflammatory atherosclerosis.32

Nitric oxide in inflammation and infection
There is a consensus that, in the acute phase of inflammation, eNOS plays a role of limiting the inflammatory process by inhibiting leucocyte activation,50 platelet aggregation51 and by inducing vasodilatation.52 Polymorphonuclear cells and resident macrophages express iNOS, which increases total NOS activity eightfold, of which more than 90% is attributable to iNOS. Arthritis is exacerbated in a rat arthritis model by L-arginine treatment,53 whereas elevated synovial fluid concentrations of nitrate and nitrites have been reported in patients with rheumatoid arthritis.54 In asthma and inflammatory bowel disease, excess iNOS-induced NO production has been established.55,56 All these findings suggest a role for NO in the inflammatory condition. Bacterial infection can lead to circulatory shock and hypotension is a characteristic feature of the septic shock syndrome. It is now known that increased NO production from increased iNOS activity is a contributory factor. Because iNOS activity is responsive to dexamethasone and aminoguanidine, these agents have been shown to prevent the drop in mean arterial pressure and PO2 in a rodent model of shock.57 Non-selective NOS inhibition attenuates the microvascular injuries associated with Escherichia coli lipopolysaccharide (LPS)-induced shock, in rodent models.58 In humans, the treatment of shock through NOS inhibition was first described in 1991; the hypotension was reversed by L-NOARG.59 Larger studies with L-NOARG have confirmed the benefits of haemodynamic stabilization in septic shock.60,61

Nitric oxide and neurological diseases Stroke
Stroke is brain ischaemia resulting from a thrombotic blockade or haemorrhage from a vessel supplying that part of the brain. This leads to neuronal death, a consequence of hypoxia and nutrient deficiency, all of which trigger metabolic changes (mainly glutamate release) summed up as excitotoxicity.33 Both the hypoxia and glutamate cause increased NO production, initially due to nNOS but later due to iNOS expression.34 It is thought that, in the early stages, NO from nNOS worsens brain damage whereas endothelial NO is protective. For this reason, non-selective NOS inhibitors have not been successful but, rather, worsen focal ischaemia in animal models,35,36 probably because of their vasoconstrictor effect. In contrast, the nNOS-specific inhibitor 7-itroindazole decreases infarct size.37 These findings suggest that selective nNOS inhibitors hold good prospects for the management of stroke. Expression of iNOS has also been implicated in the pathophysiology of stroke, with iNOS being expressed within 12 h (peak 48 h) of ischaemia in a rat model.38 Combined inhibition of iNOS and nNOS may constitute the therapeutic goal in stroke.

Migraine
A hypothesis is gradually emerging that suggests that migraine is due to a release of 5-hydroxytrytamine (5-HT) in key areas of the cerebral vasculature. The 5-HT acts on the 5-HT2B and 5-HT2C receptors to release NO from the endothelium and, possibly, from nitriergic nerves that regulate cerebrovascular blood flow.39 The NO, in turn, causes vasodilatation and sensory fibre activation/ sensitization, leading to the inflammatory like process that is characteristic of migraine.11 The NO donor glyceryl trinitrate (GTN) has been shown to elicit symptoms similar to spontaneous migraine episode40,41 and the NOS inhibitor NG-nitro-L-arginine

Nitric oxide and respiratory diseases Pulmonary hypertension
In either primary or secondary pulmonary hypertension, there is a decreased expression of pulmonary vascular eNOS.62 Whether this is a cause or effect of these conditions remains unclear. Inhaled NO has proved useful in preventing hypoxia-induced pulmonary hypertension in rats63 and in decreasing hypoxia-induced pulmonary hypertension and right ventricular dysfunction in humans.64,65

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FI Achike and C-Y Kwan health, not only for their carbohydrates, minerals, vitamins and fibres, but also for the presence of many anti-oxidant substances (e.g. polyphenols) that exert protective and beneficial effects on living cells. Polyphenolic substances are also present in some plant products (e.g. tea and soy), which are neither vegetables nor fruits, and are recreationally consumed in a large quantity. Many beneficial health effects of tea, especially the green tea (not oxidized via fermentation) have been reported and attributed to the tea flavonoids, catechins.76 Some herbal products (e.g. ginseng), in addition to being consumed as functional food, are also used for medicinal purposes. Herbal medicine, originally a part of some ancient cultures (e.g. Chinese traditional medicine), has now become a major part of the complementary medicine in our modern, economically affluent societies and herbal products are increasingly used by the American public, medically and recreationally.77 In this review, a few of the popular herbal products are discussed as examples of products that exert their effects, at least in part, on the NO signalling pathway.

Acute respiratory disease
Non-homogeneous injury of the lungs results in vasoconstriction and microvascular occlusion. These lead to ventilation/perfusion (V/Q) mismatch, intrapulmonary shunting, arterial hypoxaemia and pulmonary hypertension. Inhaled NO selectively improves the perfusion of ventilated alveoli, thus matching ventilation with perfusion. The improved perfusion would, in turn, enhance the diversion of blood from the less-ventilated alveoli to the well ventilated, thus reducing intrapulmonary shunting and the pulmonary hypertension.66 Several human studies with inhaled NO have been reported and it is generally suggested that, in the absence of sepsis, 60–80% of acute respiratory disease patients respond well to inhaled NO (< 20 p.p.m).66

Nitric oxide and gastrointestinal tract function
Nitric oxide is known to mediate the non-adrenergic, noncholinergic (NANC)-nerve controlled relaxation of the longitudinal and circular smooth muscles of the lower oesophageal sphincter, stomach, duodenum, small intestine and the internal anal sphincter.67,68 This action of NO is linked to the hyperpolarization of the tissues.69 Intestinal mucosal integrity may depend, in part, on endothelial NO, which enhances mucosal blood flow.70

Drinks and beverages from plants: Red wine and tea
Wine and tea are two very common and popular drinks derived from plants. In recent years, evidence has accumulated to suggest that long-term consumption of wine (from grapes), especially red wine, may have a protective effect against cardiovascular diseases due to its high content of polyphenolic compounds.78 These polyphenols originate from the skins, seeds and vine stems of the grapes, although some are formed during the process of vinification. The effects of short-term oral administration of red wine polyphenolic compounds on haemodynamic parameters and on vascular reactivity have been investigated in rats.78,79 Daily intragastric administration for 7 days of red wine polyphenolic compounds (20 mg/kg) in rats (5% glucose for control rats) produced a progressive decrease in systolic blood pressure. Aortas from rats treated with red wine polyphenolic compounds displayed increased endothelium-dependent relaxation to acetylcholine that was related to increased endothelial NO activity and involved a mechanism sensitive to superoxide anion scavengers. The endotheliumdependent NO-mediated relaxant effect of red wine was also observed in human coronary arteries.80 In addition, in the aorta, red wine polyphenolic compounds increased the expression of COX-2 and increased the release of endothelial TXA2,80 which compensated for the extra-endothelial NO-induced hyporeactivity in response to noradrenaline, resulting from enhanced iNOS expression. Tea, especially the non-fermented green tea, also contains a high level of polyphenols, termed tea catechins, the actions of which, like those of the grape polyphenols, may account for the general belief by Chinese people that ingestion of green tea following physical exertion has cardiotonic and antifatigue effects. The purified green tea catechin (–)epicatechin, caused both endothelium-dependent and -independent relaxation in rat mesenteric artery.81 NG-Nitro-L-arginine methyl ester (L-NAME; 100 mol/L) and methylene blue (10 mol/L) significantly attenuated (–)epicatechin-induced relaxation in endothelium-intact tissues. L-Arginine (1 mmol/L) partially antagonized the effect of L-NAME. (–)Epicatechin (100 mol/L) significantly increased the tissue content of cGMP and NG-nitro-L-arginine (100 mol/L) or removal of the endothelium abolished this increase. Iberiotoxin,

Nitric oxide and erectile dysfunction
Nitric oxide is a major physiological stimulus for relaxation of penile vasculature and trabecular smooth muscle, all essential for penile erection.71 Relaxation of the trabecular smooth muscle of the corpus cavernosa leads to a decreased vascular resistance and increased blood flow to the penis. Alongside the increased flow, venous outflow is reduced by the compression of the subtunical venules. The combination of increased inflow and decreased outflow causes penile engorgement and erection.71 Nitric oxide from the vascular endothelium of the sinusoids and from the NANC cavernosal nerves appears to mediate the vasodilatation.72,73 The new drug used for the treatment of erectile dysfunction, sildenafil, acts by potentiating the effect of NO by inhibiting the specific enzyme (phosphodiesterase V) that terminates the action of NOgenerated cGMP in the penile vasculature.74 A recent study in mice lacking nNOS and eNOS indicated that the nNOS isoform is required for sildenafil-induced facilitation of erectile responses in vivo.75 Although extensive efforts have been made to explore the roles of NO and its signalling pathways in the pathophysiological events in various disease states and, as reiterated above, increasing evidence has, indeed, emerged, it should be noted that other mechanisms unrelated to NO (thus, not discussed here) may also participate in a significant way.

HERBAL PRODUCTS THAT AFFECT NO
Plants are consumed not only as essential diet, but also as functional/recreational food supplements or as medicines. As part of complementary medicine, food therapy, whether for therapeutic or preventive purposes, is based on the principle of achieving a physiological level of homeostasis without the use of medicinal drugs. Indeed, many edible plants, such as vegetables and fruits, are of significant dietary importance for the maintenance of good

NO, human diseases and herbal products at 100 nmol/L, attenuated (–)epicatechin-induced relaxation in endothelium-intact arteries and this effect was absent in the presence of L-NAME.82 In clinical studies, Duffy et al.83 found that both short- (2 h) and long-term (4 week) tea consumption improved endothelium-dependent flow-mediated dilation of the brachial artery in 66 patients with proven coronary artery disease, whereas consumption of water had no effect. However, in another study,84 by comparing the acute and ambulatory blood pressure changes between two groups (group of tea drinkers vs group receiving caffeine), tea ingestion caused larger acute (after 30 min tea ingestion) increases in blood pressure than caffeine alone. However, any acute effects of tea on blood pressure did not translate into significant alterations in ambulatory blood pressure during regular tea consumption. It is interesting that two most abundant components of the four major green tea catechins could actually cause transient contraction in endothelium-denuded rat aorta, probably mediated by the hydroperoxide generated from catechins in solution.84 It is not known whether this transient vasoconstriction evoked by tea catechins is related to the transient rise in blood pressure. The health effects of tea remain inconclusive and require more detailed clinical investigation.

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Plants as health food: Ginseng roots
According to Chinese ancient medical writings, dried ginseng roots are commonly used as a tonic to invigorate the body (especially after physical exertion, during recovery from illness or in old age) and restore/enhance the ‘Qi’ (the vital energy), which then mobilizes the blood (improvement of blood flow). Ginseng has multiple actions, including blood sugar-lowering, antihypertensive, antiangina, antifatigue and anti-ageing effects, as a sexual, gastric, haematopoietic and immunological stimulant, in the improvement of memory and in the suppression of cough.85 In the East, ginseng roots are often taken culinarily as food or recreationally as herbal tea, whereas in the West, ginseng extracts are more commonly taken as supplements in the form of tablets or capsules. The ginseng plants cultivated in the Orient (e.g. China and Korea) and in North America (e.g. US and Canada) are different ginseng species and are referred to as Panax ginseng CA Meyer and Panax quinquefolius Linn, respectively. The close connection between NO and the actions of ginseng extracts and their active ingredients has increasingly been noted in recent years.86,87 The most active ingredients in ginseng roots are saponins, also referred to as ginsenosides. The ginsenosides do not elicit a non-selective lytic effect on living cells as do some other plant saponins88 and can modify cell membrane ion channels, including Ca2+ and K+ channels.89,90 The ginsenosides isolated from P. ginseng CA Meyer have been reported to cause vasodilation in an endothelium-dependent, NO-mediated manner in rabbit pulmonary vessels87 and rat aorta90 (via NO generation from eNOS) and to cause neurogenic NO-mediated relaxation in electrically stimulated monkey cerebral artery91 and rat mesenteric artery92 (via NO generation from nNOS). These vasodilatory actions of ginsenosides may account, in part, for the antihypertensive and memory improving effect of P. ginseng CA Meyer.93 Studies of P. quinquefolius Linn in relation to cellular NO production are very limited in the literature. In Chinese medicinal literature, P. ginseng CA Meyer is considered to be ‘warm’ (yang) nature, whereas P. quinquefolius Linn is of ‘cold’ (yin) nature.

Interestingly, the total saponins isolated from P. ginseng CA Meyer and P. quinquefolius Linn also displayed such a dichotomous relationship in their in vitro actions on vascular contractility, in that saponins from P. ginseng CA Meyer caused vasorelaxation whereas P. quinquefolius Linn did not relax, and even enhanced the contraction of, vascular tissues depending on the anatomical parts (leaves and stems versus roots) from which saponins were extracted.94 The lipid constituent of ginseng roots trilinolein, which is a triacylglycerol with linoleic acid as the only fatty acid residue in all three esterified positions of glycerol, has been shown to elicit potent endothelium-dependent, NO-mediated vasorelaxation (at concentrations ranging from 0.1 nmol/L to 1 mol/L) in rat aorta.94 Trilinolein also exerts antiplatelet aggregation via the NO-mediated generation of cGMP.95 Panax ginseng is popularly used to enhance stamina and relieve fatigue, as well as physical stress, probably through the enhancement of blood flow and the haematopoietic effects of the ginsenosides. In addition to the vascular effects mentioned above, ginsenosides from P. ginseng, namely Rb1 and Re, have been shown to significantly stimulate NOS activity concentration dependently in cardiac myocytes and to inhibit their peak shortening when stimulated to contract at 0.5 Hz.97 Pretreatment with the NOS inhibitor L-NAME abolished the effect of Rb1 and Re. The NO-mediated relaxant effect of ginsenosides also occurred in airway smooth muscle and the NO was generated predominantly from airway epithelium and acted on cGMP synthesis by the smooth muscle.98 This action may account for the coughsuppressing effect of P. ginseng. Not only do ginsenosides promote eNOS-mediated release of NO from vascular EC, they also enhance iNOS-mediated NO production in cultured porcine EC following 12 h incubation with the cultured cells.99 Nitric oxide-mediated signalling events also underlie the legendary claims of ginseng’s aphrodisiac effect in ancient Chinese medical writings. In a clinical study100 of patients with erectile dysfunction, changes in early detumescence and erectile parameters, such as penile rigidity and girth, libido and patient satisfaction were significantly higher in the group receiving ginseng than was observed in the placebo control group or the group treated with the 5-HT reuptake inhibitor trazodone. The overall therapeutic efficacies of the Korean red ginseng on erectile dysfunction were 60% for the ginseng group and 30% for the control groups.100 It has now been well documented in animal studies that the ginsenosides from P. ginseng roots relax rabbit corpus cavernosum smooth muscle by enhancing the release of NO from EC, as well as the perivascular nitrergic nerves, and that the relaxant effect of ginseng extract or the ginsenosides can be inhibited by NOS inhibitors.101–103 A purified saponin, namely Rg3, has been identified as being responsible for the endothelium-dependent, NO-mediated relaxation of rat aorta.104 The successful development of sildenafil (Viagra) for the effective treatment of erectile dysfunction also attests to the importance of the NO pathway as a theurapeutic target.74,75

Plants as medicine: Traditional Chinese herbal medicine
Traditionally in China, some medicinal herbs are ‘cooked’ together with other food items as a preventive measure in the maintenance

Table 1 Herbal drugs with nitric oxide-promoting effects

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Compounds/extracts 106 Whole animal (rat) Rat aorta Human EC 107 Whole animal (rat) Rat aorta 108 Rat mesenteric artery 109 Rat aorta Cultured EC 110 111 Rat aorta 112 Human EC line (ECV304) 113 Rat mesenteric artery Rat mesenteric artery Rat aortic SMC Pig coronary artery Bovine aortic EC 116 Rat aorta 117 Rat mesenteric artery Patch SMC and EC 118 114 115

Herb species (Chinese name) Traditional use/biological actions Tissues/cells Reference

Andrographolides

Andrographis paniculata (Chuan Xin Lian)

Aqueous extract

Artemisia verlotorum Lamottee

Aqueous extract

Crataegus monogyna or Hawthorn

Aqueous extract

A standardized extract

Aqueous extract

Danshinoate-B

Eucommia ulmiodis Oliv (Du Zhong) Ginkgo biloba L (Yin Xing Ye) Paeonia lactiflora Pallas (Bai Shao) Salvia miltiorriza (Dan Sheng)

Berberine

Coptis chinesis (Huang Lian)

FI Achike and C-Y Kwan

Gypenosides

Gynostemma pentaphyllum (Jiao Chiu Lan)

Methanol extract and haematoxylin

Casesalpinia sappan (Su Mu)

Rutaecarpine

Evodia rutaecarpa (Wu Shu Yu)

Used as an antihypertensive by Malaysians and as an antimicrobial by Chinese Lowers blood pressure in the rat Causes +E vasorelaxation Induces NO release and cGMP formation Used as an antihypertensive in Turkey Shows a transient hypotensive effect in the rat +E relaxation; elevated NO and cGMP due to muscarinic receptor agonism Used for circulatory disturbances +E relaxation, sensitive to L-NAME or methylene blue As an antihypertensive Induces +E relaxation sensitive to K+ channel blockers Used to improve cerebral blood flow Induces NO formation in EC, which is partially inhibited by K+ channel blockers Used to improve uterine blood flow and treat menstrual irregularity Induces +E, L-NAME-sensitive relaxation, which is mimicked by gallotannins Used to increase coronary blood flow Enhances NO release via increased expression of eNOS Used as an anti-arrhythmic agent Induces L-NAME-sensitive +E relaxation and inhibits caffeine contraction Partly responsible for +E relaxation and abolishes caffeine contraction Inhibits SMC growth Used for circulatory improvement Induces L-NAME-sensitive vasorelaxation Increases NO release Used to enhance blood flow and as an anti-inflammatory agent +E relaxation inhibited by L-NAME and enhanced by L-arginine with NO and cGMP formation Used as an antihypertensive and an anti-inflammatory agent +E relaxation sensitive to L-NAME and methylene blue Inhibits L-type Ca channels in SMC, but opens non-voltage-dependent cation channels in EC

+E, endothelium-dependent; SMC, smooth muscle cells; EC, endothelial cells; L-NAME, NG-nitro-L-arginine methyl ester; NO, nitric oxide; eNOS, endothelial nitric oxide synthase.

NO, human diseases and herbal products of good health. They are also taken as medicines for therapeutic purposes, usually in the form of a concentrated decoction or as alcoholic extracts. Prescribed Chinese herbal medicines almost always contain multiple herbs, each with its own therapeutic force directed at a specific energy channel, to collectively enhance the positive ‘Qi’ and expel the negative ‘Qi’ in order to restore the natural homeostasis in health.105 Therefore, the therapeutic effects of these herbal remedies are not based on the action of a single herb or a single active ingredient. This philosophy of herbal remedies has made the understanding of the use of traditional Chinese medicinal herbs very difficult. Some of the herbal extracts or purified active substances whose actions have been linked to the NO pathway are listed in Tables 1,2. It is interesting to note that herb products that are used to tonify the cardiovascular system or to remove blood stasis (which contributes to pain) appear to show vasodilatory effects via NO production from eNOS and, thus, generally improve circulation (Table 1). In contrast, those that are used to treat inflammation, infection or cancerous diseases appear to inhibit NO generation from iNOS (Table 2). It is likely that some biological effects of these herbs may be attributed to other activities unrelated to the NO pathway. For example, berberine, an isoquinoline derivative purified from Coptis chinesis (Huang Lian), which is a vasodilatory, anti-inflammatory and antimicrobial agent, exhibits a Ca2+ channel antagonistic effect and interacts with dopaminergic receptors as well -adrenoceptors.85,113,114 The prototype bisbenzylisoquinoline alkaloid tetrandrine is an antihypertensive and anti-inflammatory Chinese folk medicine. It is the most studied herbal drug with Ca2+ channel antagonistic activities underlying its vasodilatory and antihypertensive effect.119 Tetrandrine inhibits L-type Ca2+ channels, such as those in the vascular smooth muscle cells (SMC),120 as well as non-voltage-dependent Ca2+ channels, such as the non-selective cation channels in EC121 or the putative receptor-operated Ca2+ channels in the SMC.120,122 As a result of its inhibitory effect on Ca2+ channels, tetrandrine attenuates eNOS-mediated NO formation and release from the EC, thus reducing endothelium-dependent vasorelaxtion. However, this effect of tetrandrine may be of minimal physiological significance when compared with its predominant inhibitory effect on SMC and the resultant relaxation and reduction in arterial resistance. When tetrandrine is used as an anti-inflammatory agent, it has been shown to inhibit the expression of iNOS, thus reducing the excess pro-

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duction of NO during the inflammatory process.123 As shown in Table 2, other anti-inflammatory isoquinoline alkaloids, such as higenamine,124,125 and pyrazinal alkaloids, such as tetramethylpyrazine,126,127 also inhibit the expression of iNOS and the formation of inflammatory mediators. As noted earlier, many plant polyphenolic compounds cause endothelium-dependent vasorelaxation by directly activating the formation of NO from eNOS or some may enhance NO-mediated relaxation by scavenging the superoxide anions, which destroy NO. Some polyphenols, including flavonoids, tannins, lignans and catechins,134–141,143–145 also decrease the formation of NO by either direct scavenging of NO128 or by inhibiting the expression of iNOS (e.g. in the macrophages;129 see Table 2). This provides a logical basis for their immunostimulant and anti-inflammatory properties. Thus, these polyphenols have both the ‘yang’ nature (activate eNOS and increase physiological effects of NO) and the ‘yin’ nature (inhibit iNOS and decrease the pathological effects of NO). Such a coexistence of yin and yang activities has also been observed for andrographolide,106,130,131 radix Salviae miltiorryzae112,132,133 and Gingko biloba.110,137,138 There are also herbal extracts/drugs that enhance the production of NO via iNOS. These drugs148–152 are generally used as anticancer and antibacterial folk remedies. A classic example is the development of the antineoplastic agent paclitaxel (Taxol; Bristol Myers Squibb, New York, NY, USA) from the dried bark or leaf of Taxus chinesis or Taxus yunnanensis.81 Paclitaxel mimics the actions of LPS on murine macrophages by producing NO and tumour necrosis factor.153 Unlike LPS, which causes hyporeactivity and lowers blood pressure, Taxol increases the in vitro contractility of human blood vessels154 and could elevate blood pressure.155 In conclusion, we have discussed the roles of NO in the biological system and have highlighted its importance in cellular homeostasis and in the pathophysiology of human diseases. We have also, for the first time, reviewed extracts and drugs derived largely from traditional Chinese medicinal herbs, the pharmacological effects of which include the modulation of the NO pathway. However, it should be noted that although these herbs and their active chemical substances may act on the NO pathway in a way that seems to be consistent with the claimed therapeutic use, it does not mean that the NO pathway is the primary mechanism of the therapeutic action of the medicinal herb. Conceivably, some of

Table 2 Herbal drugs that inhibit the inducible nitric oxide synthase (iNOS) system by suppressing iNOS expression Drugs/extracts Tetrandrine and related alkaloids Higenamine Tetramethyl pyrazine Andrographolides Aqueous extract Baicalein, Wogonin Yomogin EGb 761 Quercetin Catechin Tannins Dehydrocostus lactone Methanol extract, honokiol and magnolol Aqueous extract Aqueous extract, sanquiin and proanthrocyanidin Species (Chinese name) Tetrandra Stephenia (Fen Fang Ji) Aconittum coreanum (Wu Tou) Ligusictum wallichii (Chuang Xiong) Andrographis paniculata (Chran Xin Lian) Salviae miltiorryzae (Dan Sheng) Scutellaria baicalensis (Huang Qin) Artemisia princeps Rampan (Ai Ye) Ginkgo biloba L (Yin Xing Ye) From many plant species; commercially available Camellia sinensis (Cha Ye) Melastoma dodecandrum Lour Saussurea lappa (Mu Xiang) Magnolia fargesii (Xin Yi) and M. obovata (Yu Lan) Dichroa febrifuga Lour (Chang Shan) Sanguisorbaeofficialis L (Di Yu) References 123 124, 125 126, 127 130, 131 132, 133 134, 135 136 137, 138 139 140 141 142 143, 144, 145 146 147

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these herbal extracts or drugs may elicit contributing modulating effects on ion channels, receptor function or enzyme activities unrelated to the NO pathway.

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