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African Journal of Traditional, Complementary and Alternative Medicines, Vol. 8, No. 2, 2011, pp. 104-127 INSIGHTS INTO THE MONOMERS AND SINGLE DRUGS OF CHINESE HERBAL MEDICINE ON MYOCARDIAL PRESERVATION Shi-Min Yuan* and Hua Jing Department of Cardiothoracic Surgery, Jinling Hospital, School of Clinical Medicine, Nanjing University, Nanjing 210002, Jiangsu Province, People’s Republic of China. E-mail: shi_min_yuan@yahoo.com Code Number: tc11014 AbstractChinese herbal drugs have been proved to be effective agents in myocardial protectionby preventing ischemia-reperfusion injury. The underlying mechanisms as to how these agentswork were however poorly elucidated. Studies on the monomers or on the single drugs havehighlighted the possible rationales, leading to a better understanding of the pharmaceutical effects of the active parts of the herbs. These agents have been found to be structure-sensitive while they play the role of a protective ingredient. Polysaccharidesof Chinese herbal medicine have pharmaceutical effects in immune modulation, anti-inflammation, anti-virus, anti-tumor, anti-aging mechanisms, with an anti-oxidativeeffectbeing a commonlyrecognizedmechanism.Saponinsare prone toalleviate calcium overload.As bioflavonoids commonly contain active phenolic hydroxy group, they have good anti-oxidant property. Those containing effective lignanoids and essential oils can result in a reduced nitric oxide secretion of the endothelial cells and an increased intercellular cell adhesion molecule-1 expression. Alkaloids may resist free radical injuries. Most importantly, modern in-depth research revealed that myocardial infarction is typically associated with apoptosis,and herbal medicine containing carbohydrates and glycosides showed cardioprotective effects by way of inhibiting apoptosis of myocytes. As a supplement to cardioplegia, some Chineseherbal drugs have become especially valuable in myocardial protection in open heart surgery by preserving metabolic energy. In conclusion, the classification of Chinese herbal medicinemade according to their main active ingredients has facilitated the expression of their functioning mechanisms. Chinese herbal drugs play an important role in cardioprotection via many different mechanisms, the most recent and important finding being the inhibition of apoptosis. Key Words: apoptosis; Chinese herbal drugs; myocardial ischemias. Introduction Several theories, including calcium overload, oxygen free radicals, infiltration of granular leukocytes, complement participation, enzymatic effects, apoptosis, and gene expression disorder, etc., have been popularly recognized as the fundamental mechanisms of myocardial injury due to ischemia-reperfusion(Wang and He, 2004. Alternative strategies with the purpose of myocardial preservation therefore start with alleviation of calcium overload, maintenance of homeostasis of the cellular membrane, inhibition of nitric oxide (NO) delivery, and prevention of apoptosis. Recent studies discovered coagulable cytolysis around the ischemic myocardial infarction zone without presence of infiltration of inflammatory cells, a phenomenon similar to the morphological changes of apoptosis. Accordingly, an agreement was reached that myocardial infarction was typically associated with apoptosis. In a rabbit model of ischemia-reperfusion injury, scattered apoptotic cells positive for terminal deoxynucleotidyl transferase dUTP nick end-labeling were present in the ischemic region 1 hr after ischemia, peaked at 3 hrs, and decreased thereafter, whereas no apoptotic cells were found in the normal myocardium. Furthermore, apoptotic cells began to appear in the ischemic margin 1 hr after ischemia, and the number of the apoptotic cells increased with time and peaked at 5 hrs after ischemia, suggesting apoptosis may be a main feature of myocardial ischemia (Hu et al., 2001). It was shown that growth factors may inhibit the development of apoptosis and hence alleviate the apoptosis of myocytes caused by ischemia-reperfusion injury. Like the growth factors, Chinese herbal drugs have gained a popular recognition in terms of myocardial preservation by apoptotic inhibition (Zhang et al., 2007). Chinese herbal medicine was usually categorized with respect to Chinese medicinal property or the natural character. With the introduction of modern scientific technologies, novel classifications were introduced for Chinese medicine, such as drug effect, medicinal portion, botanical, zoological, mineralogical, and chemical ingredient classifications. Of them, the classification referring to the pertinent major active ingredients contained in Chinese medicine is apparently convenient for the expression of their effective mechanisms. In recent years, studies on these active ingredients of Chinese herbal drugs have become attractive, leading to an in-depth understanding of the medicinal properties. These ingredients were grouped into four classes: alkloids, flavonoids, saponins and others including coumarins and lignanoids, that are related to vascular endothelial functions (Shi and Yan, 2005). As for myocardial preservation, more components can be involved, such as carbohydrates, glycosides, amino acids, peptides, proteins and enzymes.\ Chinese herbal medicine 1. Carbohydrates 1.1 Astragalus mongholicus Radixes of Astragalus mongholicus Bge and Astragalus membranaceus Bge are quality products of Astragalus mongholicus. The main components of Astragalus mongholicus include Astragaloside, Astragalus polysaccharides, and flavonoids, etc. (Huo, 2007). Total flavonoids of Astragulus could prevent the decrease of the NO concentration. Concomitantly, total flavonoids of Astragulus and Astragaloside A work as inotropic agents by way of increasing cAMP contents of the myocardium, and inhibiting the activity of the Na+-K+-ATPase on the myocardial cellular membrane, while Astragalosides act as free radical scavengers. Astragaloside IV is a leading active ingradient with inotropic effect, not only improvingheart function of the experimental rats, but also avoiding an increase of the oxygenconsumption of the myocardium (Fang, 2004). Total flavonoids of Astragulus may inhibit the increase of the intracellular calcium concentration induced by isoproterenol hydrochloride, indicating a calcium antagonism ofthetotalflavonoids of Astragulus by relievingthe calcium overload of the sarcoplasmic reticulum (Meng et al., 2004). Anincreased superoxide dismutase(SOD) and decreased malondialdehyde (MDA) and creatine phosphokinase (CPK) activities wereassociated with the introduction of Astragalus mongholicus (Li et al., 2003). Additionally, similar results for Astragalus mongholicus have been noted in patients with angina pectoris (Li and He, 2003). Pretreatment with Astragalus membranaceus significantly attenuated thedaunorubicin-induced increases of reactive oxygen species, apoptosis and the secretions of lactate dehydrogenase (LDH) in cultured neonatal cardiomyocytes of Sprague Dawley rats (Luo et al., 2009). Astragalus mongholicus at a concentration of 100 g/L or 1000 g/L could reduce the apoptotic rateby 34.96% and 37.02%, respectively.The upgradingofthe reperfusioninjury salvage kinase (RISK), including PI3K-AKT and p42/44 [extracellular regulated protein kinase (ERK)1/2] could be the initiating way of Astragalus mongholicusin to regulate myocardialapoptosis. The mitogen-activated protein kinase signaling pathways have also been found tobe under the modulation of Astragalus mongholicus in the in vitro rabbit ischemia-reperfusioninjury and cultured myocyte hypoxia-reoxygenation models (Song et al. 2008). 1.2 Lycium bararum polysaccharides. The botanical source of Lycium bararum polysaccharides is the dry mature fruit of the Solanaceae plant Lycium barbarum L. When Lycium Bararum Polysaccharide Extract was givenvia gastric lavage or intraperitoneal injection to the animals, both lysozyme and SOD activities and NO secretion were increased by resting macrophages, with the former drug route having a better effect (Zhou et al., 2000). Lycium Bararum Polysaccharides can promote theactivities of glutathione peroxidase (GSH-Px) and SOD of the senile rats induced byD-galactose, and can further scavenge the free radicals (Chen and Chen, 2005). When freeradical injuried myocytes induced by xanthine/xanthine oxidase system were treated by Lycium Bararum Polysaccharides (12.5 μg/mL), the myocardial ultrastructures remained almost normal (Yang et al., 2001). 1.3 Tremella fucifamis Berte, or, Tremella fuciformispolysaccharide. Tremella fucifamis Berte is a polysaccharide with free radical scavenging and anti-lipid peroxidation effects. It is prepared and extracted from Tremella fucifamis bysubmerged cultures. Tremella polysaccharide can protect cardiomyocytes by suppressing theapoptosis induced by oxidative damage in vitro. The results suggested that Tremella tremella polysaccharide had dose-related anti-apoptotic and anti-oxidative effects on cardiomyocytes in D-galactose induced aging mice (Qu et al., 2009). 1.4 Saussures involucrate The chemical ingredients isolated from Saussures involucrate has been proved to be complex, including flavonoids, alkaloids, and polysaccharides, etc. The half-scavenging concentration ofpolysaccharide of Saussurea was 22.0μg/mL,withwhich the oxygenconsumption of the mice could be reduced, and the swimming time of the animal increased. Both hispidulin and acacetin that were isolated from Saussures involucrate were capable of scavenging freeradicals with anti-lipid peroxidation effect. The total alkaloids of Saussures involucrate were able to decrease the permeability of the cutaneous vessels of the rabbit, leading toa vascular contraction of the rabbit ear, which may be blocked by α-antagonist regilin. Moreover, the total alkaloids of Saussures involucrate could cause slowdown of the heart rate or even heart arrest of the in vitro rabbit heart (Yuan et al., 2004). 1.5 Polysaccharide Krestin Coriolus versicolor polysaccharide is an abstract of the dry carpophore of Polyporus Varlus (PERS) Fr. Luo et al. (2002) administered the canine model of ischemia-reperfusioninjury with oral Polysaccharide Krestin 150 mg/kg daily two days prior to operation. Theyfound that these animals had better left ventricular ejection fraction and lower plasma MDAcontents during early reperfusion (5- 120 mins). 2. Glycosides 2.1. Phenolic glycoside Paeonol. Paeonol is a main active ingredient of Cynanchum paniculatum (Bge.) Kitag. Paeonol can decrease the cholesterol/phospholipid ratio of the mitochondrial membrane, andimprove membranous Ca2+-ATPase activity, membrane lipid fluidity and myocardial free fattyacid of the myocardial ischemia-reperfusion injury model in mice (Zhang and Zhang, 1994).Tang and Shi (1990) observed the Ca2+ influx in neonatal mice myocytes, a remarkable decrease in beating rate of the myocytes, and an inhibition of the Ca2+ uptake in both fast and slow phases with 50-400 μg/mL paeonol. At a dose of 400 μg/mL, it showed a similar effect on the calcium uptake in cultured myocardial cells to verapamil at 10 μmol/L. 2.2. Anthraglycosides and Quinones 2.2.1 Danshensu Salvianic acid A and Tanshinone Danshensu Salvianic acid A showed its protective effect on myocardial mitochondria of the ischemia-reperfusion injury mice by scavenging O- and OH-. Working as a free radical scavenger to eradicate O-2, OH- and H2O2, sodium tanshinone IIA sulfonate (5 mg/kg) was ableto decrease the products of MDA in the myocardium and lessened the delivery of CPK. Itillustrated that as a free radical scavenger tanshinone was even superior to verapamil interms of myocardial protection in the in vitro mouse heart model. Experimental studiesdisclosed that intravenous injection of sodium tanshinone IIA sulfonate in the caninemyocardial ischemia-reperfusion injury model may lead to decreased myocardial oxygen consumption byloweringleft ventricularwallstress, and broughtabout a decreased myocardial infarcted area with an effect comparable to dipyridamole. Tanshinone IIA may protect cultured PC12 cells from all injury models including hypoxia, hypoglucose, oxidant injury, calciumoverload, NO neurotoxicity, and glutamic acid injury, especially was good for the ischemic and calcium overload injuries (He et al., 2001). In the myocardial infarction rats, sodiumtanshinone IIA sulfonate significantly reduced the infarct sizes, the blood LDH level, and the number of apoptotic cardiomyocytes in the infarcted hearts (Yang et al., 2008a).Protective mechanisms of tanshinone were evidenced to be mediated by increased scavenging of oxygen free radicals, prevention of lipid peroxidation and upregulation of the Bcl-2/Bax ratio (Fu et al., 2007a). Tanshinone IIA may inhibit the increasing sizes of the myocytes,the synthetic rate of the myocardial protein, and the apoptotic rate induced by angiotensinII, thereby decreasing the expression of the apoptotic gene Fas mRNA (Feng and Zheng, 2006). Tanshinone IIA (2 mmol/L) markedly attenuated adriamycin-induced reactive oxygen species production, and prevented the adriamycin-mediated reduction of the Bcl-2/Bax ratio asevidenced by the Western blot assay (Gao et al., 2008). 2.2.2 Polygonum multiflorumPolygonum multiflorum is the dry radix of Polygonum multiflorum Thunb. Polygonum multiflorum can improve SOD activity of the myocytes, scavenge free radicals and inhibit lipid peroxidation. Polygonum multiflorum may significantlyimprove the stability of the lysosomal membrane, protect the membranal structureof the myocardium, and stabilize the cellular membrane (Jin and Jin, 2006). Experiemntal studies revealed that Polygonum multiflorum inhibited 52.1 ± 7.3% of the oxygen consumption and 50.9 ± 5.3% of MDA production (Hong et al., 1994). Itsability to enhance myocardial anti-oxidant status under the conditions of ischemiareperfusion-induced oxidative stress has been proved (Yim et al, 2000). Tetrahydroxystilbene-glucoside, one of the effective ingredients of Polygonum multiflorum, was tested in terms of its protective effect on rat myocardial ultrastructure. Tetrahydroxystilbene-glucoside even in a low dose could remarkably decrease the expression of transforming growth factor-β1 of myocardial cytoplasm, indicating a possible inhibition onthe transforming growth factor.Lower MDA levels and inducible nitric oxide synthase (iNOS) activities of the myocytes were seenin the rats administered with tetrahydroxystilbene-glucoside (Tang, 2006). 2.3. Flavonoids and Flavonoid glycosides 2.3.1 Ginkgo biloba extract (Egb761) Egb761 is composed of flavonoids, terpenoids, phenolic compound, and aminoacids, etc. Liebgott et al. (2000) reported two main components of Egb761, flavonoidglycosides and terpenoid, may coordinate scavenging free radicals and prevent peroxidation injury. Tosaki et al. (1994) found EGb761 at a dose of 50 mg/kg or100 mg/kg may significantly improve coronary flow, aortic flow, left ventricular developed pressure, and the first derivative of left ventricular developed pressure(dp/dt max). EGb761 can increase SOD activity of the cytosol, prevent mitochondrial lipid peroxidation, maintainthe Ca2+-ATPaseactivity ofthe mitochondrial membrane, and improve Ca2+ transport of the ischemic myocardium (Li et al., 2007a). Shen andZhou (1995) found that treatment (10 mg/kg, injected into the coronary artery) resulted in significant inhibition of the lipid peroxidation and preservation of total and CuZn-SOD levels in both plasma and the myocardium during and at the endof reperfusion. Both tissue type plasminogen activator (t-PA) decrease andplasminogen activator inhibitor-1 (PAI-1) increase mediated byischemia-reperfusionwere significantly suppressed by EGb761. Egb761canapparently alleviate the accumulation of Na+ and Ca2+ and the loss of K+ and Mg2+ in the ischemia-reperfusion myocardium (Deng et al., 2006). EGb761 could inhibit influxof excellular calcium of myocardium of neonatal rats (Zhang et al., 2000). Egb761along with its monomer Quercetin dihydrate may inhibit myocyte hypertrophy, totalprotein and diameter increment, induced by angiotensin II, which could therebypromote SOD activity and decrease MDA content (Wu and Gu, 2006). Egb761 has shownan antagonistic action on platelet-activating factor, a key point of myocardial injury (Zhang and Gao, 2008). Expressions of p-ERK1/2, p-JNK and p-P38 mediatedby angiotensin II increased significantly and Quercetin could apparently inhibitthese expressions probably by the ROS/JNK signaling pathway. In the Egb761-treatedrats, apoptosis of the cardiomyocytes decreased significantly, suggesting theprotective effects of Egb761 on rat cardiomyocytes against apoptosis (Yu et al., 2007). EGb761 could typically inhibit NO release, decrease the expression of iNOS mRNA (Varga et al. 1999), and promote Bcl-2 and Bcl-xL gene expressions of rabbitmyocytes (Zhang et al., 2005a). 2.3.2 Bamboo Leaves The active ingredients of the bamboo leaves include abundant flavanoids,polysaccharides, and trace elements, etc., with antiseptic and anti-oxidantproperties (He and Yue, 2008). The Bamboo Leave Extract may increase coronary flowof the in vitro guinea pig heart, counteract T wave changes induced by pituitrin, and decrease the area of themyocardialinfarcted area (Fuet al., 2006). Experiments proved that the bamboo leave flavonoid was comparable to Egb761 in terms of the content of the flavonoid as well as the capacity of anti-free radicals (Zhang etal. 2002a). The bamboo leave flavonoid may reduce the occurrence of myocardial apoptosis, and inhibit the expression of Bax, Cyt-c and caspase-3, but not of Bcl-2 (Fu et al., 2007b). 2.3.3 Baicalin Baicalin is a flavonoid compound extracted from Scutellaria baicalensis Georgi. Baicalin significantly improved the SOD activityofthe hypoxic myocytes of neonatal Sprague-Dawley rats at a concentration of 0.1-10 μg/mL, inhibited MDA production at a concentration of 1 μg/mL, and inhibited NO secretion at a concentration of 10 μg/mL (Liu et al., 2003a). When baicalin 10-40 mg/kg was given to the rats 5mins before ligation of the coronary artery, the post-infarction heart function improved with decreased MDA content and increased SOD activity (Liu et al., 2003a).Woo et al. (2005) proposed that the cardioprotective effect of baicalin may notbe due to its anti-oxidant effect, because they observed an adverse rather than a protective effect when baicalin was present during hypoxia. Pretreatment ofneonatal rat cardiomyocytes with baicalin up to 10 μmol reduced LDH deliverysignificantly, while pretreatment with baicalin up to 100 μmol was ineffective. In the rat model, baicalin may improve CPK and LDH contents as well as myocardialultrastructure (Ouyang et al., 2006). The protective effects of baicalin on heartinjury of rats with severe acute pancreatitis led to better results in the ratmortality, pathological changes of heart, NF-κB, P-selectin, Bax, Bcl-2, andcaspase-3 protein expression levels (Xiping et al., 2007). 2.3.4 Carthamin yellow More than 60 chemical components have been isolated from the safflower including flavonoids, lignins, and acetylenics, etc. Carthamin yellow (also named saffloryellow) and hydroxysaffloryellow A are the main effective components. Carthamin yellow significantly reduced the LDH and MDA levels, and alleviated free radical damage (Zhang et al., 2003a). Effective ingredients of Safflower caninfluence immune system, block platelet-activating factor receptors, increase NO level and eradicate free radicals. Saffloryellow can inhibit Na+-K+-ATPase activityand increase cAMP content of the myocardium during ischemia-reperfusion (Cheng et al., 2000). Piao et al. (2002) found that in the coronary perfusion experiments in rats intraperitoneal injection ofCarthamin yellow 0.8-1.25 g/kgcouldremarkablyimprove the ischemic electrocardiographic changes induced by isoproterenol,reflecting an antagonistic action on the adrenergic receptors. Mo et al. (1995) found that Carthamin yellow Extract (5-500 mg/mL) blocked calcium influx inducedby noradrenaline and hyperkalemic solution, showing a dose-effect relationship similar to but weaker than that of verapamil. Safflower injection preserved ratheart displayed improved ultrastructures compared with the control, with higher SOD activity and lower MDA content (Zhang and Shi, 2003). Carthamus tinctorius extract was associated with a decreased apoptotic index, decreased expression of Bax, and upregulation of Bcl-2 (Chen and Zheng, 2006). 2.3.5 Erigeron breviscapus (Vant.) Hand-Mazz It is the whole plant of Compositae erigeron breviscapus (Vant.) Hand. Mazz. Components extracted and differentiated from the Erigeron breviscapus (Vant.)Hand-Mazz include flavonoids, caffeate, and phenolic acids,etc. Ofthem,flavonoidshad strong non-competitive inhibiting effect on protein kinase C, thereby alleviating ischemic injury (Zhou et al., 2002a). The effective ingredient Erigeron is an inhibitor of protein kinase C, which participates in ischemic neuron injury,and plays an important role in the cellular signaling pathways of neuron apoptosis (Lei et al., 2002). Erigeron could promote myocardial SOD, and decrease myeloperoxidaseactivities, by which accumulation of free radicals in the myocardium could be decreased and myocardial injury induced by isoproterenol was alleviated. Blockage of the calcium channel of the myocytes with a decrease of calcium influxwas observed when Erigeron was used. Erigeron alsodisplayedits effectsinpromotingSOD, nitric oxide synthase (NOS) and NO levels in the hypoxic rat model (Mao et al., 2004). Zhou et al. (2002b) noted Erigeron was useful in regressing leftventricular remodeling by improving cardiomyocyte hypertrophy, and decreasing collagen volume fraction in spontaneous hypertensive rats. Erigeron could significantly decrease the number and percentage of apoptotic nuclei of the myocardium, and upregulate the expression of apoptosis-inhibiting gene Bcl-2 mRNA(Liu and Chen, 2004). In male Sprague-Dawley rats, the myocardial infarct size wassignificantly reduced by scutellarin (15 and 50 mg/kg), an active molecule existingin Erigeron breviscapus (Vant.) Hand. Mazz, but not by breviscapine (5 to 50 mg/kg);and the anti-myocardial infarction effect of scutellarin was dose-dependent. Compared with the control group, scutellarin (50 mg/kg) remarkably reduced themyocardium cell apoptosis in myocardial myocardial infarction rats (Lin et al., 2007). 2.3.6 Puerarin Puerarinisan isoflavone extracted andisolated from thedry roots of the legume PuerariaLobata (Willd) Ohwi. Puerarin could significantly decrease theCPK deliveryof the myocardium. The heat shock protein 70 expression was much higher in rats receiving Puerarin compared to those subjected to ischemia-reperfusion (Tang etal., 2007). A significant decrease in MDA, NO and NOS levels and the leakage of LDH, and a rise in SOD activity occurred in the Puerarin Group (Yan et al., 2005).Puerarin may also regulate plasma endothelin and NO contents, hence improving theNO/endothelin ratio (Wang and He, 2004). In the rat hearts pretreated with 0.24mmol/L Puerarin for 5 mins, a significant inhibition of Ca2+-induced mitochondrial swelling was observed (Yang et al. 2008b). In the mitochondria isolated from therat hearts pretreated with 0.24 mmol/L Puerarin for 5 mins, a significant inhibition of Ca2+-induced swelling was observed, and this inhibition was attenuated by5-hydroxydecanoate (Gao et al., 2005). Puerarin showed a decrease in apoptosis ofthe ischemia-reperfusion myocardium in rats, where the apoptotic cells weresignificantly reduced during the reperfusion period. Experimental studies showed thatitinhibited cellular apoptosis during myocardialischemia-reperfusion injury,increased the expression of Bcl-2, and decreased the expression of Bax (Yan et al.,2005). Puerarin (120 mg/kg/day, intraperitoneal injection) could increase serumnitrite concentration in rats with myocardial ischemia, and induce transcriptionalor protein level expressions or activation of endothelial NOS, and the Akt/protein kinase B phosphorylation (Zhang et al., 2008a). 2.3.7 Total flavonoids of hawthorn leaves Total flavonoids of hawthorn leaves could alleviate arrhythmias, delay the arrest time, and decrease LDH delivery and MDA contents, and increase intracellularSOD activity and NO content of the myocytes of the ischemia-hypoxia model in 3-daySprague-Dawley neonatal rats (Ye etal.,2005). Flavonoids of hawthorn leaves (12.5,25.0, and 50.0 mg/kg) could alleviate ST segment changes of the rat heart due toischemia-reperfusion injury (Min et al., 2007). 2.3.8 Portulaca oleracea L. Portulaca oleracea L.isthewholeplantofpurslane of thefamily Portulacaceae. Portulaca oleracea L. contains n23 fatty acids, anti-oxidants, amino acids, and trace elements, which are effective cardiovascular components. Total flavonoidsof Portulaca oleracea L. showed inhibiting actions on pyrogallol autoxidation ina direct dose-effect relationship (Lu et al., 2004). 2.4. Saponins 2.4.1 Raidix ophiopogonis Raidix ophiopogonisisa liliaceous plants, andthe product currently available commercially in our country is the radix of Ophiopogon japonicus (Thunb.) Ker-Gawl. Acting as nourishing yin, and promoting fluid production, it has been found to have multiple pharmaceutical effects including two-way regulations of blood glucose and immunologic function, antibiosis, anti-cancer, and in particular cardiovascular effects. Ophiopogon polysaccharide and Ophiopogonin (60 g raw material/kg, via gastric lavage) could increase myocardial nutrient flow in a dose-effect relationship (Zhou et al., 2003). Ophiopogcnin may act on the Na+- and Ca2+-channels to decrease the influx of these ions, and it was effective to remarkably increasethe reduced expression of Bcl-2 gene, and alleviate calcium overload in the subject and thereby treat the peroxide-induced condition (Zhang et al., 2003b). 2.4.2 Ginsenosides Radix Ginseng is from Panax Ginseng, a herbaceous plant of the Araliaceae . The chemical components include ginsenosides, ginseng polysaccharides, and activepeptides, etc. Ginsenosides can limit myocardial infarction size, regulatemetabolism of arachidonic acid, and increase the 6-Keto-PGFlα/TXB2 ratio (Li et al.,2006). Theoptimal concentration of ginsenosides for myocardial protection was 20-80 mg/L, however, this drug may show a harmful effect on the myocardium when the concentration was 160 mg/L (Chen et al., 1994). Yuan et al. (1997) obtained a similar result in a cardiac concordant xenotransplantation rat model where the properconcentration of the drug was 40 mg/L; whereas the protective effect diminishedand it may jeopardize the myocardium when the concentration was 320 mg/L. Theydemonstrated that the Rb component may predominate at a lower concentration, while the harmful component may function instead at a higher concentration. Zhang et al. (1998) found that ginsenosides Rb1, Rb2 and Rb3 worked as both anti-oxidant andcalcium channel blockage by protecting myocytes from apoptosis duringischemia-reperfusion. Both Rb1 and Re significantly stimulated the NOS activity in a concentration-dependent manner. It demonstrated a direct depressant action of ginsenosides on cardiomyocyte contraction, which may be mediated in part throughthe increased NO production (Scott et al., 2001). The typical apoptotic features in the rat myocardium with ischemia-reperfusion injury could be improved with theuse of ginsenosides while the intracellular expression of Bcl-2 gene was significantly increased (Zhou and Xu, 2001). In the rat ischemia-reperfusion injury model, ginsenoside Rb, lavage for consecutive 7 days may reduce serum enzymaticactivities and MDA content, while increasing, SOD and GSH-Px activities, andjustifying the PGI2/TXA2 ratio (Qu et al., 2007). 2.4.3 Panax quinquefolium L. Panax quinquefolium L. is a perennial persistent root herb of the Araliaceae. Its bioactive materials are saponins, polysaccharides, flavonoids, essential oilsand trace elements, etc. Panax quinquefolium total saponins (30, 100, and 300 μg/mL)could decrease the delivery of aspartate aminotransferase, CPK and LDH in theisolated rat heart Langendorff model (Cao et al., 2003). Intraduodenal administration of ginsenosides from the leaves and stems of Panax quinquefolium to the myocardial ischemic models of dog and rabbit led to a reduced infarction area, reduced serum levels of free fatty acid and MDA, decreased LDH, CPK and aspartate aminotransferase, and an increased SOD activity (Ding et al., 2002). Ata concentration of 1.5 mg/mL, it may inhibit the increase of the intracellularcalcium comparable to the effect of verapamil (0.5 μmol/L) (Guan et al., 2004). Panax quinquefolium total saponins could decrease the left ventricular load, anddecrease myocardial oxygen consumption, and increase the blood supply to theischemic myocardium (Liu et al., 2001). Panax quinquefolium buffered significantlythe changes in the ventricular weight and cardiac coefficient of the ventricular remodeling rats, and improved the arterial pressure, and the left ventricular enddiastolic pressures. Panax quinquefolium also inhibited the thickening of the cardiac muscle fibers and improved myocardial interstitial edema, showing sameeffects as angiotensin converting enzyme inhibitor benazepril (Ju et al. 2007).Panax quinquefolium could significantly improve the endothelial function and prevent from ventricular remodeling post-myocardial infarction, regulate the lipidmetabolism and increase the PGI2/TXA2 ratio (Fan et al., 2009). Improved expressions of vascular endothelial growth factor and basic fibroblast growth factor in theinfarcted myocytes, with increasing vasogenesis in the ischemic region have beenshown in the panax quinquefolius saponin-treated rats (Wang et al., 2007a). The use of panax quinquefolium correlated with a significant reduction in apoptosis in rats after acute myocardial infarction, and a downregulation of Fas and anupregulation of Bcl-2 protein expressions in rats (Yin et al., 2005). 2.4.4 Notoginseng Saponins. Notoginseng is the radix of Ranax Notoginseng (Burk) F. H. Chen, a perennial herbaceous plant. The main active component of Notoginseng is Panax Notoginseng saponins. Li et al. (1990) found that Panax notoginseng saponins reduced the infarcted area, and decreased CPK release of the myocardium of rats with coronaryartery ligation and recannalization. Panax Notoginseng saponins could improve the Ca2+ pump activity on the membranes of myocardial sarcoplasmic reticulum, reduce myocardial intracellular Ca2+, and inhibit left ventricular remodeling(Deng, 2007). Pretreatment with Panax Notoginseng saponins significantly protected the mice from doxorubicin-induced cardiotoxicity as evidenced from improved ventricular contractile function, lower levels of serum LDH, CPK and CK-MB, minimal morphological changes in the hearts, and normalization of myocardial SOD, GSH-Pxand catalase activities (Liu et al., 2008). Notoginseng saponins significantlyimproved myocardial NO level and constitutive NOS activity , lowered collagencontent and iNOS activity, and inhibited cardiac hypertrophy in the myocardial hypertrophy rat model induced by isoproterenol (Zhou et al., 2006). Inhibited tumornecrosis factor (TNF)-α delivery, NF-κB activation and neutrophil infiltration and decreased ICAM-1 expression were seen with Notoginseng saponins pretreatment (Gu et al., 2005; Tang et al., 2003). Notoginseng saponins had an apparent inhibitoryeffect on cellular apoptosis induced by angiotensin II. Notoginseng saponins (50 mg/L) showed a remarkably decreased myocardial apoptotic rate and a more alleviated calcium overload comparing to Angiotensin II Group (Chen et al., 2005). TheNotoginseng saponins-administered endothelial cells showed a much lower apoptotic rate, with downregulation of Fas expression and upregulation of Bcl-2 (Lǚ and Liang, 2005). 2.4.5 Gross saponins from Tribulus terrestris Gross saponins from Tribulus terrestris could decrease the apoptotic rate atany dose, but a large dose may upregulate, while a small dose may downregulate Bcl-2 expression. Besides, it may significantlydecrease the TNF-α and interleukin (IL)-1β contents with obvious NF-κB p65 nucleus translocation at any dose in an Sprague-Dawley neonatal rat model of myocardial ischemia-reperfusion injury (Yin et al., 2006). It may also promote δPKC and εPKC expressions in neonatal rat model of hypoxia (Sun et al., 2008). 2.4.6 Sasanquasaponin (SQS) Sasanquasaponin is a mixed saponin extracted from the dregs after oil extract of the seeds of the Theaceae plant Camellia oleifera Abel. Sasanquasaponin has shown its anti-Na+-Ca2+ overload effect by decreasing Mg2+, and increasing Na+ and Ca2+ contents, and decreasing the Na+-K+-ATPase and Ca2+-Mg2+-ATPase activities of the mitochondria of rat myocardial ischemia model (Li et al., 2007b). It reduced LDH release and increased the cell viability in a dose-dependent manner up to 10 μmol and concomitantly decreased MDA and oxidized glutathione contents, while significantly increased the activities of SOD (Chen et al., 2007). By using an NOdelivery antagonist, the pretreating effect of Sasanquasaponin was weakened or abolished, suggesting that this agent may work at least partly by activating NOSand inducing the formation of NO and adenosine (Huang et al., 2001). 2.4.7 Gypenosides Gypenosides are saponins derived from Herba Gynostemmatis, the dry whole plant of Gynostemma pentaphyllum (Thunb.) Mak. of Cucurbitaceae family. Experimentsrevealed that Gypenosides may reduce myocardial MDA content, and inhibit thedelivery of serum CPK and plasma endothelin in the rat model of myocardialischemia-reperfusion injury, and remarkably increase myocardial SOD and plasma NOlevels, balancing the NO/endothelin ratio (Zheng et al., 2002). The cardioprotective effect of Gypenosides may also depend on calcium overload amelioration and abnormal excitement inhibition (Qi and Zhang, 2003). Moreover, Gypenosides inhibited c-fos gene expression in a dose-dependent manner with decreasing concentrations, whileit showed no influence on sis gene expression (Qi and Zhang, 2003). Tanner et al.(1999) found that the extract of Gynostemma pentaphyllum at 0.1-100 µg/mL elicited concentration-dependent vasorelaxation of porcine coronary rings that was antagonized by the NOS inhibitor N(G)-nitro-l-arginine methyl ester. Indomethacinhad no significant effect on Gynostemma pentaphyllum-induced relaxation. The results demonstrated that the extracts of Gynostemma pentaphyllum directly stimulated NO release, but not the prostanoid production. The expression of TNF-α was significantly increased in the Ischemia-Reperfusion Group (Zheng and Zheng, 2007). Compared with the Hypoxia-Reoxygenation Groups, the positive expressionindex of Fas/FasL proteins were significantly lower in groups with different doses of total flavones of Gynostemma pentaphyllum (Thunb) Mak., suggesting thatthe totalflavonoids could protect the myocardium against hypoxia-reoxygenation injury bydecreasing the production of TNF-α, downregulating the protein expression of Fas/FasL genes, and inhibiting myocyte apoptosis (Li et al., 2007c). 2.4.8 Dioscin Dioscin exists extensivelyin Dioscoreaceae, Liliaceae, and the legumeplants. It can be used for the purposes of eliminating phlegm, desensitization, anti-inflammation, anti-tumor, protection against myocardial ischemia, decreasingblood viscosity, reducing platelet aggregation, and decreasing triacylglycerol, etc. (Zhao et al., 2008). Dioscin could alleviate calcium overload of theexperimentally hypoxic myocytes (Liu et al., 2004a). In the rat models of myocardialischemia-reperfusion injury, either a high dose dioscin (300 mL/kg/day) or a low dose dioscin (150 mL/kg/day) may lead to a smaller myocardial infarction size andbetter cardiac function comparing to the control (Zhao et al., 2008). The in vitro Sprague-Dawley neonatal rat model of myocyte hypoxia showed decreased LDH (4.534 ± 0.872 U/L), cardiac Troponin I (0.682 ± 0.091 μg/mL) levels and a decreased intracellular free calcium concentration (479.99 ± 57.94 nmol/L) when treated with dioscin. Experiments also revealed that dioscin alleviated the calcium overload of the hypoxic myocytes by enhancing the expression of calcium pump SERCA2 on the sarcoplasmic reticulum (Liu et al., 2004b). High dose of dioscin (100 mL/L) resulted in a higher SOD activity, and lower MDA and NO contents comparing to the normal control and the hypoxia/reoxygenation groups (Ni et al., 2007). 2.4.9 Total saponins of Semen Ziziphi spinosae Total saponins of Semen Ziziphi spinosae are a kind of effective components extracted from Chinese medicine obtained from the seed of Ziziphus spinosa Hu. These agents had shown blood pressure lowering, anti-arrhythmic and anti-ischemic effects. In the anoxia-reoxygenation model of cultured neonatal rat myocytes, total saponins of Semen Ziziphi spinosae could markedly and dose-dependently decrease MDA content, elevate SOD activity and increase membrane fluidity, proving an effect ofanti-peroxidation induced by anoxia-reoxygenation (Wan et al., 1995). In culturedneonatal rat myocytes, the increase of LDH release from the damaged myocardial cellsinduced by oxygen-glucose deprivation, ehlorpromazine or mitomycin C could beattenuated by Ziziphi spinosae (33 μg/mL) (Chen et al., 1990). Compared with thecontrol, the experimental group treated with Semen Ziziphi spinosae showed significantly smaller myocardial infarcted area, and significantly decreased STsegment and T wave on electrocardiogram (Zhang et al., 2005b). 2.4.10 Paeoniflorin Paeoniflorin is extractable from the radix of Paeonia albifolra Pall. Paeoniflorin can inhibit platelet aggregation, dilate coronary arteries, increasecoronary flow, and protect acute myocardial ischemia. However, the exact cardiovascular mechanisms of Paeoniflorin remain unclear. Paeoniflorin showed an interdiction to L-type calcium channels in the isolated rat myocytes for patch clampresearch, but lack of frequency-dependent inhibition (Zhang et al., 2003c).High-dose ofPaeoniflorin remarkably decreasedthe hazard index, lowered myocardialCPK and LDH, and reduced the apoptotic index (Zhang et al., 2008b. Both paeoniflorin and paeonol, two main active compounds of the Paeonia albiflora Pallas, were shownto lead to a reduced myocardial infarct size in rats through protection fromapoptosis (Nizamutdinova et al., 2008). 2.4.11 Hyperin Hyperin is a common component of many Chinese herbal drugs. Hyperin (12.5,25 mg/kg/day × 3, intraperitoneal injection) decreased rat myocardial infarcted area, inhibited serum CPK and LDH elevation, and promoted myocardial SOD content (Li et al., 2001a). Hyperin (25, 50 mg/kg) had obvious protective effect on rat myocardial apoptosis 3.5 hrs after reperfusion, and Hyperin (0.5-50.0 μmol/L) mayreduce the apoptosis formation in rat myocyte with hypoxia-reoxygenation (Li etal., 2002a), and inhibit dose-dependently LDH delivery and calcium overload in the myocytes (Li et al., 2001a). Hyperin at 12.5 μg/mL, 50 or 12.5 μg/mL, and 50 μg/mL, 50 or 12.5 μg/mL was found to have a protective effect on myocardial injury caused by adriamycin, by mitomycin, by oxygen-glucose deprivation or by hypoxia-reoxygenation (Xu et al., 2000). 2.4.12 Acanthopanax Senticosus Saponins or Acanthopanax senticosides Radix Acanthopanacis Senticosi is an Araliaceae plant, with a botanical name of Eleutherococcus senticosus (Ruper.et Maxim.) Maxim., containing eleutherosides A~G, I, K, L, and M. Acanthopanacis Senticosi could improve T wave elevation and decreaseofheart rateinthe rabbitmyocardial ischemiamodelsubjectedtopituitrin injection, and promote regeneration of the surface cells. In such a model, ratmyocardial ischemia was significantly improved with a preserved SOD activity and a reduced MDA production. Acanthopanacis Senticosi could markedly increasecalmodulin content, suggesting that a nucleic acid system pathway might be followedby Acanthopanacis Senticosi in improving heart function (Wang and Juan, 2005). Treatment with Acanthopanax senticosus significantly improved the survival rate of mice. Acanthopanax senticosus pretreatment inhibited the elevation of TNF-α,and decreased the iNOS level in serum and liver, and inhibited the NO overproduction(Lin et al., 2008). Total saponins from the leaves of Acanthopanax Senticosus could weaken the contractility of isolated Wistar rat heart in a significant dose-dependent manner, in accordance with what was noted in a weakened excitation-contraction coupling. Acanthopanax senticosides Sb (50-200 mg/L) was found to decrease action potential of cultured Wistar rat myocytes, which couldbe reversed by Ca2+ 80 mg/L, showing a similar calcium channel blocking effect tonimodipine (Zhan et al., 1995). 2.5. Coumarin 2.5.1 Andrographis paniculata Andrographis paniculata is the dry aerial part of the Acanthaceae plant Androp raphis paniculata (Buri. f.) Nees. Present studies on Andrographis paniculata concentrate on Andrographolide and the flavonoid component API0134. This flavonoid component API0134 could improve canine heart function, decrease the extent ofmyocardial infarcted area, alleviate the extent of myocardial injury, and decrease the occurrence of arrhythmias. Meanwhile, it could promote the production of prostaglandin, raise the PGI2/TXA2 ratio, and inhibit the granulocyte from producing free radicals. API0134 had an extensive scavenging function on H2O2, O2-, and ·OH,and inhibited the induced aggregation of human-washed platelets. ProphylacticAPI0134 for 4 and 8 weeks significantly raised NO and cGMP contents and SOD activity, and decreased endothelin and lipid hydroperoxide contents (Zhang et al., 2002b),and maintain the NO/endothelin balance (Wang et al., 2003). API0134 (50 mg/kg, i.v.) in rabbits may raisethe cAMP level, slightly increase cGMP, alleviate degranulation and decrease cytoplasmic calcium concentration (Wu et al., 2002). Alleviation ofcalcium overload by API0134 may also be contributable to the effect of promotingNa+-K+-ATPase and Ca2+-ATPase activities on the cellular membrane of the myocardium. The cardioprotective effect of andrographolide was in a time-dependent manner with upregulation of glutathione (Woo et al., 2008). Andrographolide may dose-dependently upregulate ICAM-1 expression induced by TNF-α, and inhibit apoptosis. Andrographolide could inhibit cytochrome C from entering into thecytoplasm and eliminate mitochondrial potential energy, thereby preventing fromactivations of caspase-3 and -9, and inhibiting the mitochondrial pathway ofapoptosis. Andrographolide may induce the activationof ananti-apoptotic signaling protein kinase Akt and phosphorylation of the pro-apoptotic molecule BAD (Liu etal., 2003b). 2.5.2 Praeruptorin C Praeruptorin C is an effective component extracted from Peucedanum praeruptorum Dunn., with effects of vascular dilation, myocardial contractile inhibition, and myocardial compliance improvement. Praeruptorin C can inhibitmyocardial LDH delivery, increase intracellular SOD concentration in the neonatal rat model of myocyte damage (Zheng et al., 2007). Intraperitoneal injection of praeruptorin C can alleviate myocardial ischemia-reperfusion injury, promote coronary flow recovery, prevent the decrease of left ventricular systolic pressureand the dp/dt max, and inhibit CPK delivery, with similar effects to nifedipine (Yang et al., 1992). The Na+-Ca2+ exchanger mRNA level was much lower in neonatal rat myocytes with praeruptorin C pretreatment than that of the Ischemia-Reperfusion Group (Xi et al., 2008). Praeruptorin C showed predominant pharmacological actions of lowering blood pressure and dilating the coronary arteries with a possible mechanism of calcium antagonism (Kong et al., 2002). Comparing with the Hypoxia-Reoxygenation Group, the LDH value, intracellular calcium fluorescence intensity level, and cellular apoptotic index were remarkably decreased (Chen andZhu, 2007). 3. Lignanoids 3.1 Fructus schisandrae chinensis The effective components of Fructus schisandrae chinensis are lignanoids, essential oils, organic acids, and polysaccharides, etc., with lignanoids being the most important one, contained 19.2% in the fruits. Schisandra chinensis Baill Extractum had a strong protective effect on hypoxic or ischemic injury in animals.It significantly extended the survival time of the animals in the condition ofconstant pressure and hypoxia, and significantly improved the T wave changes onelectrocardiogram induced by pituitrin (Lin et al., 1998). The protective effects of this agentwereexperimentally observedasto increase SODactivity oferythrocyte, markedly lowered the lipid hydroperoxide content of the venous blood, and lessen the myocardial infarct extent (Guo et al., 2006). 4. Essential oils 4.1 Radix angelica sinensis Radix angelica sinensis is the dry root of Angelica Sinensis (Oliv.) Diels,a spignel plant. Radix angelica sinensis has antagonistic effects on oxidized lowdensity lipoprotein thereby leading to a reduced NO secretion of the endothelial cells and an increased ICAM-1 expression. The possible mechanism may be associated with the cholinergic receptor. Radix Angelica sinensis injection was proved to havea myocardial protective effect by way of calcium influx blockage similar to thatof verapamil. Radix Angelica sinensis extract may improve anti-oxidant capacity,activate ERK signaling transduction pathway, and enhance the expression of endothelial NOS. Radix angelica sinensis could upregulate the expression of Bcl-2 and downregulate the expression of Bax, causing a decreased Bax/Bcl-2 ratio, sothat apoptosis of the myocytes could be inhibited, and left ventricular function and ventricular remodeling improved (Shangguan et al., 2008). Radix angelica sinensis injection could effectively inhibit myocardial hypertrophy induced byangiotensin II (Yu et al., 2006). In the Radix angelica sinensis injection treated rats, the expression of P57kip2 protein was strong (Feng et al., 2008b), whereasthe expression of cyclin-dependent kinase-2 protein in the myocytes was weak, suggesting that Radix angelica sinensis may have an impact of positive cell-cycle regulating agent (Feng et al., 2008a). 4.2 Rhizoma Chuanxiong Rhizoma Chuanxiong is the dry rhizome of Ligusticum Chuanxiong Hort, a spignel plant. Chuanxiong-pathalide A can increase coronary flow and myocardialcontractility, and can significantly improve the delivery of LDH, MDA and SOD inan isolated rat heart model of ischemia-reperfusion injury. Increased NO and NOS activities were observed in culture solution of the Chuanxiong-pathalide A Group,associated with a reduced endothelin activity, an increased iNOS mRNA, and a decreased endothelin mRNA expression (Gao et al., 2007). Ligustrazine, with achemical name of tetramethylpyrazie (TMP), is the key component of Chinese herbRhizoma Chuanxiong.Ligustrazineobviously alleviated the degenerationand necrosis,and reduced the infiltration of inflammatory cells of the ischemic myocardium ofrat ischemia-reperfusion model (Li et al., 2004). The mechanisms were surmised tobe the inhibition of the mitochondrial calcium overload, and the decrease of themitochondrial NOS activity. Ligustrazine injection, containing 25 mg/mL of the drug, promoted the syntheses of proteins and RNA of the myocardium with oxygen-glucose deprivation,and enhanced the expressionofconstitutiveNOS mRNA(Tanetal., 2006).To strengthen the expression of NOS gene was hence regarded as the main strategyof the prevention and treatment of oxygen-glucose deprivation. Moreover,ischemia-reperfusion may induce myocyte apoptosis and upregulate c-fos geneexpression of the myocardium (Li et al., 2000, hence Ligustrazine might have playeda protective role by attenuating c-fos gene expression and apoptosis (Yi et al.,1995). 5. Alkaloids 5.1 Leonurus japonicus Houtt Leonurus japonicus Houtt was found to have a good effect on myocardialischemia-reperfusion injury by protecting anti-oxidation system. relieving lipid peroxidation, protecting myocardial ATPase, and alleviating calcium overload (Zhaoet al., 2004). In experimental rats, Leonurus Japonicus injection 0.8 mg/100 g body weight was given intravenously immediately after the ligation of the left anterior descending coronary artery, resulted in an elevated SOD activity, reduced MDA, LDH and CPK contents, decreased arrhythmic rates and better morphological changes ofthe myocardium (Shang et al., 2007). 5.2 Tetrandrine Tetrandrine mainly exists in the root of Stephania tetrandra S. Moore, aperennial woody liana. Tetrandrine has calcium antagonism and strong non-specific anti-inflammatory effects, and can effectively prevent the inflammatory reaction during myocardial ischemia-reperfusion. Deng et al. (1993) found that tetrandrinepredominently inhibited the isolated rat heart from delivering LDH and proteins from the myocardium with calcium overload, reduced myocardial infarcted size andled to declined inflammatory parameters, such as IL-1, TNF-α, platelet-activatingfactor, and myeloperoxidase, etc. Guan et al. (1998) obtained similar results incanine models. They observed that the myocardial infarct size was much smaller and IL-6, TNF-α, and myeloperoxidase levels were much lower in the Tetrandrine Group than the control. At 32 μmol/L, it showed negative inotropic action on the isolatedcat papillary muscle, inhibiting the contractility induced by adrenalin, and theincrease of ±dp/dt max (Jiang et al., 2002). The negative inotropic action wasfrequency- and voltage-dependent, and could be reversed by external calciumsupplement. Tetrandrine could decrease the activity of the Ca2+-ATPase of the endoplasmic reticulum, compatable to nifedipine. Tetrandrine pretreatment could reduce the production of TNF-α and inhibit the activation of NF-κB during myocardialischemia (Wang et al., 2007b). In the Tetrandrine Group, the LDH activity and MDAcontent decreased and SOD activity increased (Chen et al., 1998). Tetrandrine pretreatment remarkably lessened myocardial ischemia-reperfusion injury.Comparing with sham,tetrandrine had much less apoptotic myocytes, anda much smaller apoptotic index (Chang et al., 2006a). Zhang et al. (2003d) found a much lowerapoptotic rate (mean 3.2%) in the Tetrandrine Group of Sprague-Dawley neonatal rat model of myocardial ischemia-reperfusion. 5.3 Berberine Berberine is an isoquinoline alkaloid found in such plants as Berberis,goldenseal (Hydrastis canadensis), and Coptis chinensis. Berberine could decrease calcium influx, stabilize the cellular membrane, and prevent cell necrosis.Berberine had positive inotropic action and improved heart functionofheart failurepatients (Cui, 2006). In mice Langendorff heart perfusion model, berberine 0.5mmol/L added into modified Euro-Collins led to a better left ventricular peak systolic pressure and dp/dt max results and less myocardial water content comparingto the control (Luo et al., 2000). The administration of berberin (5, 10 and 20mg/kg, respectively) and positive control drug-Captopril(45 mg/kg) for consecutive 10 weeks had relieving effects on hydroxyproline content and interstitial collagenvolume fraction in the rat model with hypertrophic cardiomyopathy induced bypressure-overload, indicating that berberin may relieve the ventricular remodelingthrough inhibiting the fibrosis of myocardial interstitium (Hong et al., 2006). 6. Amino acids, peptides, proteins and enzymes 6.1. Cordyceps sinensis Cordyceps sinensis is abbreviated as worm grass. It is a complex incorporating a stroma of fungi from paecilomyces and the cadaver of its host Hepialidae Hepialus armoricanus. Natural Cordyceps sinensis contains25% protein, 8.4% fat,18.5%fibre, 29% carbohydrate and 4.1% aldosterone-stimulating hormone. Besides these compounds there are uridine, 2,4-Dichloropyrimidine, adenine, adenosine, mannitol, ergosterol and stearic acid, etc. Cordyceps sinensis contains a lot of polysaccharides, accounting for 3%-8% of the total dry weight. In the cultured Cordyceps sinensis, polysaccharides are secreted from the mycelium. Chiou et al.(2000) discovered that Cordyceps sinensis-induced vasorelaxation was mediated by the endothelium possibly by stimulating the release of NO and endothelium-derivedhyperpolarizing factor in a dose-dependent manner. Cordyceps sinensis extracts could promote NOS activity, and produce biological effects like NO production andcoronary arterydilation, exceptfor thatthey may decrease myocardialinfarct size, inhibit serum CK-MB and LDH elevation, improve SOD activity and decrease MDA content (Liu et al., 1999). Liu et al. (1999) tested 20% solution of the ethanol extractsof Cordyceps sinensis 100 mL at a concentration of 0.2 mL drug solution in one litreof Krebs-Henseleit-Bicarbonate solution in the Langendorff rat heart model, and found that the extracts improved myocardial metabolism and attenuated myocardialdamage by decreasing myocardial MDA contents and preserving myocardial ATP, ADP and AMP. Yamaguchi et al. (2000) found that the water extracts of the fruiting bodies of cultured Cordyceps sinensis significantly suppressed the increased serum lipidperoxide level but not other lipid levels in a dose-dependent manner in theatherosclerotic mice. Such preparations could decrease the calcium concentrationof the normal myocytes as well, and therefore alleviate calcium overload of the hypoxia-reoxygenation myocytes (Yu et al., 1998). 7. Other 7.1. Allicin Allicin is a kind of anti-bacterial substance in the squamous bulb of Allium sativum L. Allicin could improve the left ventricular dp/dt max, left ventricularsystolic pressure, left ventricular end diastolic pressure and endothelin valuesof the rabbit with acute ischemia-reperfusion injury (Liao et al., 2001). Allicincould promote SOD and GSH-Px activities, reduce plasma endothelin level, balance endothelin and NO, and thus improving vascular endothelial function (Li et al.,2001b; Li et al., 2002b). Allicin was more resistant to apoptosis of cultured hypoxia/reoxygenation myocytes of the neonatal rat (Shi et al., 2006). Discussion Chinese herbal medicine consists of complex chemical components, showing relationships with their bioactivities. Active ingredients were defined as ingredients of herbal medicines with therapeutic activity, where one or morechemical agents from a single or compound drugs should be over 50% (80%, if in aform of injection) of the total extracts (Sun, 2004). The main effective components include carbohydrates, glycosides, lignanoids, alkaloids, amino acids, peptides, proteins and enzymes. Clinical observations in patients with coronary heart disease and angina pectoris showed cardioprotective effects of preparations of some Chinese herbal drugs, such as Radix puerariae, Ginkgo biloba L., Radix salivae miltiorrhizae,Astragalus membranaceus Bge, Radix acanthopanacis semticosi, Chuanxiong rhizome,Allii sativi,and Notopterygium incisium, etc. (Hu and Yan, 2002). Besides, myocardial ischemia-reperfusion experiments were made in animals by coronary artery occlusion (ligation, balloon compression, or thromboembolism), drug induction (pituitrin- or ergometrine-induced coronary arterial spasm, or isopreterenolincreased myocardial oxygen uptake), or invitro (the Langendorff reperfusionmodel, or isolated heart, myocardial slices or cultutured myocytes subjected to ischemia) (Ni, 2004). The exact mechanisms of the therapeutic effects of Chinese medicine remain unclear(Ho andJie, 2007).However, modern studies revealed thatthe possiblecardioprotective mechanisms of the herbal agents were multifactorial, includingimproving haemodynamic haemorrheology, modulating vasoactive substance andcalcium balance, protecting chondrosome, inhibiting apoptosis, clearing free radicals, and promoting vasogenesis (Zhang et al., 2007). A polysaccharide is class of relatively complex, high-molecular weight carbohydrates consisting of long-chains of serial monosaccharides joined togetherby the glycosidic bonds. It exists extensively in the cellular membrane of animalsand the cellular wall of the plants and microorganisms. Polysaccharides of Chinese medicine have been noted to have a lot of pharmaceutical effects such as immune modulations, anti-inflamation, anti-virus, anti-tumor and anti-aging, etc., with the anti-oxidative effect being the basis of the above properties. Nowadays, polysaccharides from more than a hundred Chinese herbal drugs including Lycium chinensis, Coriolus versicolor, Ganoderma lucidum, garlic, Radix astragali,Cordyceps sinensis, gingko, and Notoginseng, etc., have been proved to have an anti-oxidant effect (Xin and Liu, 2000). The cardiovascular effects of cardiac glycoside containing medicinal herbs weredetected bytraditional Chinese physicians at the beginningofthe firstcentury, and were proved to have potential inotropic and electrophysiological actions (Lu, 1987). Salvia miltiorrhiza, Panax notoginseng, hawthorn and Polygonum multiflorum Thunb are four medicinal herbs commonly used in traditional Chinese medicine and have previously been shown to provide cardiovascular protection and to bephysiologically activeonhumanvascularendothelial cells.TheactionsofPolygonum multiflorum Thunb and hawthorn to reduce apoptosis, and of Salvia miltiorrhiza and Panax notoginseng to inhibit the adhesion molecule expression may help protect the endothelial function and inhibit atherogenesis (Ling et al., 2008). Radix Salviae miltiorrhizae is officially listed in the Chinese Pharmacopoeia used for angina pectoris, and has been tested in clinical trials of ischemic diseases such asangina, heart attack and stroke (Xu et al., 2007). Experiments on myocardial ischemia-reperfusion injury in the isolated rat hearts illustrated the cardioprotective effects of purified Salvia miltiorrhiza extract perfused at aconstant flow of 7-9 mL/min via the aorta (Chang et al., 2006b). Therapeutic treatment with salvianolic acids significantly reduced doxorubicin-induced toxicity, including elevationofbody weight and theheart weight/tibia length ratio,decrease of CPK, improvement of electrocardiogram and heart vacuolation (Jiang et al., 2008). Saponins are an important class of natural products with bioactivity. Saponins are composed of dioscingenin, glucose, uronic acid, and other organic acids. Inthe saponin molecule, there are many hydroxide radicals with big polarity.Furthermore, saponins usually share common physicochemical properties and similarbioactivities, such as an anti-platelet aggregation effect. Recent studies showedthat saponins commonly have significant anti-oxidant effect, playing an important role in protection against many pathophysiological phenomena including senility,atherosclerosis, and ischemia-reperfusion injury (Xu et al., 2004). The cardioprotectiveeffect of saponins restonprotection from myocardial damagecaused by chemical or physical injury. For example, astragaloside can protect culturedneonatal rat myocytes from damage caused by free radicals and mitomycin C, whereas gypenosides can protect the contractility of the endotoxin-shocked guinea pig papillary muscle and rat myocardium. Sasanguasaponin can improve myocardialcontractility, decrease the production of CPK and myocardial calcium content, andenhance cellular Na+-K+-ATPase and mitochondrial Ca+-ATPase activities (Fan and Liao, 2003). Flavonoids regulate cardiovascularfunction by wayof their general characters of anti-oxidation and inflammatory inhibition. As bioflavonoids commonly contain active phenolic hydroxy group, they have good anti-oxidant property. Flavonoids can inhibit the oxidative modification of low density lipoprotein induced by Fe2+ and Cu2+, and reduce the production of oxidized low density lipoprotein. They canalso increase myocardial SOD and GSH-Px activities, decrease the capillarybrittleness and permeability, and improve the microcirculation and rheology.Flavonoids mayhave an inhibitory effect onthe expression of the adhering receptors. Its anti-inflammatory property maybeassociated with theinhibition of lipoxygenaseduring the biosynthesis of prostaglandin (Lan et al. 2005). Alkaloids are widely distributed in the plant kingdom, in the families ofDicotyledoneae, such as Ranunculaceae, Menispermaceae, Papaveraceae, Solanaceae,Apocynaceae , and Rutaceae, etc., and Monocotyledoneae and lower plants as well.Alkaloids are always strongly active, being major active ingredients of Chineseherbal medicine (Feng and Shang, 2009). The main pharmaceutical applications of polysaccharides are improvement ofimmunity, those of phenolic compounds are anti-senility while those of alkaloidsare anti-tumor, inhibition of cardiovascular and digestive systems, and as ananalgesic and an antipyretic. Left ventricular function improvement, isotropiceffect, and free radical scavenging and anti-oxidant activities have been thought to be what the alkaloids contribute to myocardial preservation (Feng and Shang,2009). Alkaloids may also inhibit platelet aggregation of the rabbit, decrease the myocardial contractility of the rabbit and guinea pig, reduce blood pressure and inhibit respiration. Some alkaloids showed a muscarinic effect and a nicotinic excitation (Yan et al., 2000). Chinese medicinal monomers, such as Ligustrazine (Zhou, 2000), Radix angelica sinensis (Zhou, 2000), Puerarin (Deng et al., 2005), and Allicin (Li et al., 2001b), etc., may realize their cardioprotective effects by increasing plasma endothelinlevel, and decreasing the NO production. However, some monomers may show two-way regulations on the NO production according to their impact positions, dosage,concentration, and duration of action. For instance, Ligustrazine may induce the expression of NOS mRNA in oxygen-glucose deprivation myocytes, and increase NO production; meanwhile Ligustrazine can inhibit the expression of NOS and its genes and decrease NO production and therefore inhibit the formation of pulmonaryhypertension and pulmonary vessel remodeling (Xu et al., 2001). Calcium overload and free radicals are the main factors responsible for ischemia-reperfusion injury (Bagchi et al., 1997). Panax notoginseng saponins canimprove the calcium pump activity of the sarcoplasmic reticulum membrane of themyocardium, and decrease the intracellular calcium. Allicin, liquorice, Rhizoma chuanxiong, and Radix acanthopanacis senticosi can function as calcium influx antagonists. The anti-oxidant property of Chinese herbal medicine display activities such as inhibiting the production of free radicals duringischemia-reperfusion, inhibiting lipid peroxidation induced by free radicals, protecting myocardial SOD activity, and counteracting damage by exogenous freeradicals. The ability to decrease myocyte apoptosis, and to effectively block the pathways of myocyte apoptosis have become valuable cardioprotective methods ofChinese medicine. Astragalus can inhibit myocyte apoptosis of rabbit during ischemia-reperfusion period, and so could puerarin when it was was used as suplementin cardioplegia. The mechanism of Egb761 to inhibit myocardial apoptosis may beprobably associated with Ginkgolide B, which may promote endogenous anti-oxidantactivity, prevent cellular membrane from damage from active oxygen, and alleviatecalcium overload by counteracting platelet-activating factor and inhibiting lipidperoxidation caused by free radicals. Moreover, TNF-α may play an important partduring the activation of the neutrophilic granulocytes. By this way, vascualrdysfunction and myocardial damage develop. Despite the appearance of many cytokines after myocardial ischemia, elevation of the TNF-α expression can only be apparent during reperfusion (Hansson, 1993;Herskowitz et al., 1995). In addition, IL-6 and-1 mayimpacton themyocytes and vascularendothelial cells, inducing the production of ICAM and prompting the adherence of the neutrophils and further ischemia-reperfusion injury. Puerarin can inhibit the increase of IL-6 secretionand oversecretion of IL-6 by hypoxic myocardium (Zhu et al. 2001). In cardiac surgery, intermittent infusion of cold cardioplegia remains themain cardioprotective method, by which the myocardial metabolic rate can be decreased and myocardial endurance tohypoxia increased. Clinical studyillustratedthat the crystalloid cardioplegic solution containing puerarine (2 mg/kg) led tomuch less lactate and MDA contents, CPK and CK-MB delivery, and much bettermyocardial ultrastructure in comparison to the control in cardiac surgical patients (Yue and Hu, 1996). Cardioplegic infusion with ginsenosides (80 mg/L) or panaxadiolsaponins (40 mg/L) as a supplement in rat heterotopic cardiac abdominal transplantation model obtained a higher myocardial GSH-Px activity, and lower lipid hydroperoxide content and mitochondrial score relative to the control (Yuan et al., 2003). Liu et al. (1998) reported St. Thomas II cold cardioplegia containingginsenosides 80 mg/L was used in a transplanted rat heart after global ischemiafor 60 mins and reperfusion for 30 mins. The SOD activity in the myocardium treatedwithginsenosides wassignificantly higher, whereas theMDA and oxygenfree radicals in the myocardium were markedly lower than that of the control, illustrating thatginsenosides as a supplement of cardioplegia may decrease toxicity of oxygen freeradicals. Infusion of St. Thomas’s Hospital solution plus Egb761 2.5 mL/kg led toan insignificant changes of MDA content before, during and after aortic clamping,indicating that Egb761 markedly reduce the production of lipid peroxide during reperfusion, which may be associated with its natural anti-peroxidate property, well-preserved myocardial energy and reduced production of hypoxanthine andxanthine (Deng and Yu, 1999). In general, the classification of Chinese herbal medicine according to the main effective ingredients facilitated the expression of their functioning ways,which were proved to be structure-sensitive. Chinese herbal drugs play an important role in cardioprotection from many different mechanisms, with the most recent andimportant finding being the inhibition of apoptosis. Further studies on Chineseherbal medicine in cardioprotective mechanisms are needed in order to find alternative ways for the clinical management of ischemia-reperfusion injury. References
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