Natural plant products in treatment of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a severe disease characterized by progressive remodeling of distal pulmonary arteries and persistent elevation of pulmonary vascular resistance (PVR), which leads to right ventricular dysfunction, heart failure, and eventually death. Although treatment responsiveness for this disease is improving, it continues to be a life-threatening condition. With the clinical efficacy of natural plant products being fully confirmed by years of practice, more and more recognition and attention have been obtained from the international pharmaceutical industry. Moreover, studies over the past decades have demonstrated that drugs derived from natural plants show unique advantages and broad application prospects in PAH treatment, not to mention the historical application of Chinese traditional medicine in cardiopulmonary diseases. In this review, we focus on summarizing natural plant compounds with therapeutic properties in PAH, according to the extracts, fractions, and pure compounds from plants into categories, hoping it to be helpful for basic research and clinical application.

Keywords

pulmonary arterial hypertension natural products traditional Chinese medicine treatment pulmonary vascular resistance

Pulmonary arterial hypertension (PAH) is a severe disease characterized by progressive pulmonary vascular remodeling^1–3 and an increase in pulmonary vascular resistance (PVR), which may lead to right ventricular dysfunction, heart failure, and death.^4–6 In addition, the prognosis of PAH is still poor and the mortality rate is highly comparable to cancer. Although treatment strategies for this pulmonary vascular disease are improving, it still represents a life-threatening disorder.

There are several drugs available in clinic, such as inhaled nitric oxide (NO), prostacyclin drugs, endothelin receptor antagonists, Phosphodiesterase type 5 inhibitor, and the latest developed soluble guanylate cyclase stimulator.^7–10 Unfortunately, current therapeutics for PAH are limited; most are designed to reduce pulmonary arterial resistance by inducing vasodilatation. The progressive vascular remodeling is still hardly to be reversed. Thus, there is an urgent need for novel therapies.

Historically, natural products from plants and animals were the source of virtually all medicinal preparations. More recently, natural products have been developed as new medicines in clinical practice after convincing clinical trials, particularly as vascular disease treatment agents (Table 1). Furthermore, the utilization of natural products or natural product structures plays an extremely significant role in the drug discovery and development process. A detailed analysis of new medicines approved by the U.S. Food and Drug Administration during 1981–2010 revealed that 34% of those medicines based on small molecules were natural products or direct derivatives of natural products, including the stains, tubulin-binding anticancer drugs, and immunosuppressants.^11,12 Furthermore, because of the increasing high cost and lengthy development process of chemical drugs, the natural products industry, characterized by “naturopathy,” is thought to become the most promising industry in the global pharmaceutical industry. Interestingly, studies over the past decades have demonstrated that drugs derived from natural plants show unique advantages and broad application prospects in PAH treatment, not to mention the historical application of traditional Chinese medicine (TCM) in cardiopulmonary diseases. Experimental and clinical research revealed that natural products can ameliorate the symptoms and improve prognosis of PAH. Additionally, some natural products selectively improve the pulmonary circulation without affecting systemic arterial pressure. In this review, we will summarize the current knowledge about the natural plant compounds with the potential and promising therapeutic properties in the field of PAH, according to the extracts, fractions, and pure compounds from plants into categories, hoping it will provide useful information for future basic research and clinical application (Table 2).

Table 1.

Natural plants for any vascular disease.

Vascular disease	Natural plants	Efficacy	Reference
Atherosclerosis	Ginkgo biloba leaf	• Reduce atherosclerotic nanoplaque formation and size, suppress atherosclerotic lesion development • Reduce intima-media ratio, decrease proliferation and migration of VSMCs, and induce greater apoptosis • Improve glucose homeostasis and circulating adiponectin levels, attenuate the expression of connexin 43 protein and the concentrations of plasma Homo sapiens C-reactive protein	^144–147
	Salvia miltiorrhiza Bunge	• Inhibit atherosclerotic lesion formation in aorta • Lower cholesterol and inhibit low density lipoprotein oxidative modification • Downregulate protein expression and activities of matrix metalloproteinase-2 and matrix metalloproteinase-9 through inhibiting nicotinamide adenine dinucleotide phosphate oxidase 4-mediated reactive oxygen species generation	^148–151
	Green tea	• Protect apolipoprotein E^−/− mice from atherosclerosis through the Jagged 1/Notch pathway • Attenuates atherosclerotic lesion formation and development through decreasing macrophage cholesterol content and MCP-1 expression in macrophages • Reduce total cholesterol, triglycerides, low-density and very low-density lipoprotein cholesterol fractions, and increase high-density lipoprotein	^152–154
	Astragalus membranaceus	• Alleviate the extent of atherosclerosis in aorta of apolipoprotein E^−/− mice • Suppress the progression of atherosclerotic lesions and the inflammatory reaction • Reduce plasma levels of total cholesterol and low-density lipoprotein cholesterol, increase high density lipoprotein cholesterol levels, and reduce the aortic fatty streak area	^155–157
Thrombus and platelet aggregation	Ginkgo biloba leaf	• Inhibit platelet aggregation induced by oxidative stress, platelet activation factor, or collagen • Reduce the plasma levels of thromboxane B2 and prostacyclin metabolites • Inhibit the production of cyclooxygenase-1-mediated thromboxaneA2 in platelets and cyclooxygenase-2-mediated prostaglandin I2 in endothelial cells non-selectively	^158,159
	Salvia miltiorrhiza Bunge	• Inhibits thrombosis formation, platelet aggregation • Inhibits platelet adhesion to immobilized collagen by interfering with the collagen receptor α2β1 • Suppress [Ca²⁺]ⁱ mobilization and arachidonic acid liberation	^160–165
	Uncaria rhynchophylla	• Inhibit platelet aggregation and antithrombotic • Reduce the thromboxane B2 generation in platelet rich plasma induced by collagen • Suppress the formation of malondialdehyde in platelet suspension stimulated by thrombin and inhibit the release of platelet factor 4	^166–168
	Anemarrhena asphodeloides	• Inhibit platelet aggregation, blood coagulation, as well as the formation of a thrombus • Delay the activated time of thromboplastin • Antiplatelet and anticoagulation	^169,170
	Panax notoginseng	• Inhibit platelet aggregation and plasma coagulation • Suppress thrombin-induced platelet superficial activation and adhesion in vitro and improve hypercoagulable state in vivo • Over-express peroxisome proliferator-activated receptor γ protein and mRNA and upregulate phosphatidylinositol 3 kinase/protein kinase B through endothelial NOS pathway in platelet	^171–173
Hypertension	Ginkgo biloba leaf	• Protect against hypertension with hypercholesterolemia-induced renal injury • Reduce vasospasm and increase relaxation • Suppress renal oxidative stress, nitrosative stress, and inflammation	^174–176
	Salvia miltiorrhiza Bunge	• Lower arterial blood pressure under basal conditions in spontaneously hypertensive rat models and relax coronary arteries in a cumulative dose-dependent manner • Decreased the average blood flow velocity in liver in ET-1 induced portal hypertension • Improve cardiac function and reduce arterial blood pressure partially via inhibiting nicotinamide adenine dinucleotide phosphate oxidase and activating the nitric oxide signaling pathway	^177–179
	Uncaria rhynchophylla	• Anti-hypertensive, anti-arrhythmic, anti-thrombotic and inhibit platelet aggregation • Lower the blood pressure, improve the structural integrity of vascular endothelium • Decrease the expression of intercellular adhesion molecule 1 and selectin P, block the release of calcium from intracellular stores	^180–184
	Ligusticum wallichii Rhizome	• Elicit an effect on vasorelaxation in isolated rat aortas and anti-hypertension in spontaneously hypertensive rat • Reduce portal pressure in portal hypertensive rats	^185,186
Ischemia-reperfusion injury	Ginkgo biloba leaf	• Protect against myocardium ischemic/reperfusion injury by decreasing oxidative stress, repressing inflammatory cascade in vivo, and inhibiting toll-like receptor 4/nuclear factor kappa B pathway in rat model • Suppress renal epithelial tubular cell apoptosis • Decrease NO production by inhibiting gene and protein expression and enzymatic activity of inducible NOS	^187–190
	Salvia miltiorrhiza Bunge	• Prevent cardiac ischemic/reperfusion injury and improve cardiac function in a rat model of hypertrophy • Protect against neonatal hypoxia-ischemia brain injury in vivo by an increase in the ratio of Bcl-2 to Bax expression • Protect the mitochondrial membrane from the ischemia-reperfusion injury and lipid peroxidation through an electron transfer reaction in mitochondria against forming reactive oxygen radicals	^191–193
	Uncaria rhynchophylla	• Protect against cerebral ischemia/reperfusion damage • Significantly reduce infarct volume and improve neurological function after ischemic brain injury through the inhibition of lipopolysaccharide-stimulated production of pro-inflammatory cytokines • Reduce the lipid peroxidation injury of brain cells through inhibiting the NOS activity and increasing the superoxide dismutase activity	^194,195
	Ligusticum wallichii Rhizome	• Suppress ischemia-induced ventricular arrhythmias and reduce the infarct size resulting from ischemia/reperfusion injury • Enhance myocardial antioxidant status through induction of heme oxygenase-1 and inhibition of neutrophil and improve the immunity profile in ischemic-reperfusion rats • Protect cells against glutamate-induced apoptosis via the inhibition of oxidative stress and a change in the levels of apoptosis-related proteins, Bcl-2 and Bax • Reduce cerebral ischemia/reperfusion-induced inflammatory cell activation and pro-inflammatory mediator production	^196–199
	Anemarrhena asphodeloides	• Decrease total infarct volume and edema in the ipsilateral hemispheres of ischemia-reperfusion rats • Inhibit increased neutrophil infiltration of ischemic brain tissue • Reduce myeloperoxidase positive cells in striatal and cortical areas	²⁰⁰

Bcl-2, B cell leukemia/lymphoma 2; Bax, Bcl-2-associated protein x; ET-1, endothelin-1; NO, nitric oxide; NOS, nitric oxide synthase.

Table 2.

Natural plant products for possible PAH treatment.

Category	Natural products	Origin	Efficacy	Mechanism	Subjects	Reference
Alkaloids	Ligustrazine	Ligusticum wallichii Rhizome; Curcuma aromatica Salisb; Jatropha podagrica Hook	Decrease plasma ET-1 level, reduce mPAP and PVR		Dog	¹⁶
			Enhance the synthesis and release of NO and suppress those of ET-1; decrease mPAP, internal diameter of right ventricle, and outflow of right ventricle		Human	¹⁷
			Attenuate the plate aggregation, reduce thrombus formation and blood viscosity, accelerate blood flow restoration		Rat	¹⁸
			Inhibit the platelet aggregation formation and thrombus		Human	¹⁹
			Inhibit platelet activation	Inhibit the intracellular calcium ion concentration	Rat	²⁰
	Tetrandrine	Stephania tetrandra S.Moore; Cyclea barbata (Wall.) Miers; Menispermum dauricum DC	Inhibit PASMCs proliferation, improve endothelial function; reduce mPAP and RVH index; reverse pulmonary vascular remodeling and attenuate oxidation in lung	Adjust the imbalance of the NO signaling pathway and change the expression of inducible NOS and cyclic guanosine monophosphate-dependent protein kinase-1.	Rat	^27,30
			Inhibit the activity of serum angiotensin enzyme, decrease the amount of angiotensin I converted to angiotensin II, suppress the proliferation of medullar collagen and PASMCs in pulmonary acinar artery, reduce pulmonary vasoconstriction and lower PH			^26,28,29,31
				TET is a calcium antagonist that blocks the influx of calcium from vascular smooth muscle, relaxes vascular smooth muscle; it also decreases the content of prostaglandin F2 in the lung, so as to reduce the contractility of the pulmonary vasculature and thus reduce the PH		³²
Flavonoids	Ginkgo biloba extracts	Ginkgo biloba	Relieve RVH and reduce chronic hypoxic PH	Attenuate the function of PKC signal channel	Rat	⁴⁰
	Ginkgo biloba extracts	Ginkgo biloba	Relieve RVH and reduce chronic hypoxic PH	Antagonize platelet activating factor, angiotensin and reduce blood viscosity	Rat	⁴¹
	Puerarin	Puerarin lobat (Willd) Ohwi	Inhibit pulmonary vascular remodeling, RVH, and PH	Inhibit the deposition of collagen	Rat	⁴⁷
			Reduce mitochondrial membrane potential, cytochrome C release and caspase-9 activation, inhibit cell growth and apoptosis	Downregulated the expression of elongation factor 2	Rat	⁴⁸
				Downregulate Bcl-2 and upregulate Bax.	Human	⁴⁹
Glycosides	Salidroside	Rhodiola rosea L	Rhodiola has been shown to be beneficial in high-altitude PH			⁵⁶
			Reduce mPAP and RVH, attenuate remodeling of pulmonary arterial	Lower VEGF expression	Rat	⁵⁷
			Inhibit transforming growth factor beta expression and attenuate PH		Rat	⁵⁸
			Reverse hypoxia-induced inhibition of Cytochrome C release from mitochondria into cytoplasm, enhance the cleavage of caspase 3, and increase adenosine A2a receptor expression	Enhance adenosine A2a receptor related mitochondria-dependent apoptosis	Mice	⁶⁰
			Exert protective effect against PAH via rebalancing cell proliferation and mitochondria-dependent apoptosis of PASMCs	Decrease the expression of cyclin D1 and increase the accumulation of P27 by blocking the protein kinase B/glycogen synthase kinase 3 beta signaling pathway	Rat PASMCs	⁶¹
			Inhibit DNA synthesis and proliferation of rabbit PASMCs, reduce pulmonary vascular remodeling	Inhibit upregulation of Ca²⁺ concentration induced by hypoxia in PASMCs	Rabbit	⁶²
			Reverse hypoxia-induced PASMC proliferation and apoptosis resistance, attenuate chronic hypoxia-induced RVH and pulmonary artery remodeling	Inhibit PASMC proliferation via AMPKα-p53-p27/p21 pathway and reverse apoptosis resistance via AMPKα1-P53-Bax/Bcl-2-caspase 9-caspase 3 pathway	Rat	^63,64
	Polydatin	Polygonumcuspidatum Sieb. et Zucc; Fallopia multiflora (Thunb.) Harald	Improve fibrinolytic activity, increase cardiac output, and reduce PAP		Pig	⁶⁹
	Polydatin		Regulate NO, angiotensin II, ET contents in the serum and lung samples, reverse remodeling, and attenuate hypoxic PH	Attenuate the phosphorylation of PKCα and δ induced by H₂O₂; meanwhile, increase the phosphorylation of PKCɛ which has antioxidant effects	Rat	⁷⁰
	Icariin	Epimedium	Markedly shorten right ventricle systolic duration and notably prolong diastolic duration and attenuate the abnormal hemodynamics of pulmonary artery and right ventricle		Rat	⁸⁷
			Attenuate mPAP, RVH index and pulmonary artery remodeling	Decrease the contents of serum angiotensin II, ET, prostaglandin F2_, thromboxane A2_, and prostaglandin I2, and inhibit the gene expression of angiotensin I converting enzyme, cytochrome c oxidase subunit II, and thromboxane A synthase		⁸⁸
			Upregulate the expression of endothelial NOS and downregulate the expression of 5-type phosphodiesterase inhibitors, increase the content of NO and cyclic guanosine monophosphate in lung tissue and ameliorate PH	Protect against MCT-induced PAH in rats through increase of NO/cyclic guanosine monophosphate signaling pathway		⁹⁰
Diterpenoids	Tanshinone IIA	Salvia miltiorrhiza Bge; Salvia sclarea L; Salvia przewalskii Maxim	Recover acute hypoxia-induced downregulation of I_kv currents and upregulate the mRNA and protein expression of Kv1.5 and Kv2.1 in PASMCs, reduce right ventricular systolic pressure and RVH, and restrain pulmonary wall remodeling	Reverse the I_kv currents through modulate the expression of Kv channels in pulmonary arterioles	Rat	⁹¹
	Tanshinone IIA		Inhibit cell proliferation	Arrest cells in G1/G0-phase by slowing down the hypoxia-induced degradation of p27 via serine threonine kinase 1/S-phase kinase associated protein 2-associated pathway		⁹²
	Sodium Tanshinone IIA sulfonate		Decrease right ventricular systolic PAP and RVH, attenuate medial wall thickening, PVR and remodeling	Inhibit increase of transient receptor potential superfamily members 1,6 and decrease SOCE through reducing the numbers or activity of SOCC and basal [Ca²⁺]		⁹⁵
				Stimulate Kv2.1 expression through the regulation of intracellular Ca²⁺ homeostasis		⁹⁶
			Reduce pulmonary artery systolic pressure and Borg dyspnea score, improve exercise capacity, and decrease WHO FC of PH from III or IV down to II		Human	⁹⁴
	Triptolide	Tripterygium wilfordii Hook. F.	Promote the regression of pulmonary artery neointimal formation, attenuate the development of RVH, pulmonary remodeling, and PH	Antiproliferation and anti-inflammatory effects or enhancement of apoptosis in PAECs	Rat	⁹⁹
				Inhibit the activity of matrix metalloproteinases		^100,101
				Effect the balance of matrix metalloproteinase 9/tissue inhibitor of metalloproteinase 1		¹⁰²
Pyanocoumarins	Praeruptorin A	Peucedanum Praeruptonrum Dunnon	Inhibit PASMC proliferation and attenuate PH	Inhibit chronically hypoxic enhancement of basal [Ca²⁺]ⁱ and SOCE	Rat	¹¹⁴
Pyanocoumarins	Praeruptorin A	Peucedanum Praeruptonrum Dunnon	Inhibit PASMC proliferation and attenuate PH	Inhibit hypoxia caused Kv1.5 and Kv2.1 mRNA expression down, maintain cell membrane potential balance	Rat	¹¹⁷
Stilbenes	Resveratrol	Polygonum cuspidatum; Arachis hypogaea Linn.; Fructus Mori and Vitis vinifera L.	Prevent hypoxia-induced human PASMC proliferation, attenuate RVH	Induct the serine threonine kinase 1-dependent inhibition of arginase II.	Human	¹²²
			Attenuate oxidative stress and inhibit inflammatory reaction, improve the function of PAECs, reverse the right ventricle and pulmonary artery reconstruction		Rat	¹²³
			Reduce mPAP and PH	Suppress the expression of MCP-1 and p- p38-mitogen-activated protein kinase expression	Rat	¹²⁷
Others	Semen lepidii	Descurainia Sophia (L)	Enhance myocardial contractility, reduce PH		Rabbit	¹²⁹
			Increase partial pressure of O₂ and decrease partial pressure of CO₂, reduce mPAP and PVR		Human	¹³⁰
			Reduce right ventricular systolic and diastolic blood pressure and mPAP		Rat	¹³¹
					Rat	¹³²
	Radix Astragali	Astragalus membranaceus (Fisch) Bge.; Astragalus membranaceus (Fisch) Bge.var. Mongholicus (Bge.) Hsiao	Inhibit proliferation of adventitial cells, hypertrophic of tunica media, muscularization of non-muscular arteries and the structural remodeling of intra-acinar pulmonary arteries and PH	Preserve the endothelial cells, dilate the pulmonary circulation, and improve hemodynamic condition	Rat	¹³⁴
			Preserve intra-acinar pulmonary arteries wall cells proliferation, dilate pulmonary artery, inhibit intra-acinar pulmonary arteries remodeling, and improve PH		Rat	¹³⁵
			Regulate the concentration of ET-1and NO in pulmonary tissue, reverse the reconstruction of pulmonary vessels partially			^136,137
			Decrease the concentration of thromboxane A2 and reverse the remodeling of pulmonary artery partly			¹³⁸
			Regulate the concentration of superoxide dismutase and oxygen free radicals in pulmonary tissue	Protect pulmonary vascular from hypoxia by anti-oxidant effects		¹³⁹
			Eliminate oxygen free radicals and reduce blood viscosity		Human	¹⁴⁰

AMPK, adenosine monophosphate-activated protein kinase; Bcl-2, B cell leukemia/lymphoma 2; Bax, Bcl-2-associated protein x; ET-1, endothelin-1; FC, functional class; Kv, voltage-gated K⁺; MCT, monocrotaline; mPAP, mean pulmonary arterial pressure; NO, nitric oxide; PAEC, pulmonary arterial endothelial cell; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PASMC, pulmonary artery smooth muscle cell; PKC, protein kinase C; PVR, pulmonary vascular resistance; RVH, right ventricular hypertrophy; SOCC, store-operated calcium channel; SOCE, SOCC-mediated store-operated Ca²⁺ entry; TET, Tetrandrine; WHO, World Health Organization.

Alkaloids

Alkaloids are a group of alkaline nitrogenous natural products, which are widely distributed in plants and usually exhibit a broad range of pharmacological activities including anti-tumor, anti-inflammatory, anti-viral, and analgesic.^13–15 Many of them have been used in traditional and modern drug development.

Ligustrazine

Ligustrazine, also known as tetramethylpyazine, is an effective constituent of Scechwan Lovage Rhizome. It also exists in the rhizome of Curcuma aromatica Salisb and Jatropha podagrica Hook. Studies have shown that ligustrazine can significantly reduce mean pulmonary arterial pressure (mPAP), PVR, and the plasma endothelin-1 (ET-1) levels in acute hypoxia-induced pulmonary hypertension (PH) dogs;¹⁶ and meanwhile upregulate NO levels in patients with PAH, through alleviating the damage of pulmonary arterial endothelial cells (PAECs) and restoring the balance between vasoactive factors.¹⁷

There are several possible contributions to the function of ligustrazine. It is revealed that ligustrazine can inhibit platelet aggregation and prevent thrombosis effectively.^18,19 It has also been discovered that ligustrazine can block the release of reactive oxygen species from lung tissue²⁰ and moderate the upregulation of hypoxia-inducible factor 1 and vascular endothelial growth factor (VEGF) expression, which consequently reduces hypoxia-induced lung injury.²¹ Also, ligustrazine is a Ca²⁺channel antagonist which can dilate the blood vessels during hypoxia by blocking Ca²⁺ influx.^22,23 This may be one of the principal mechanisms responsible for the protective effect of ligustrazine in patients with PAH.

Tetrandrine

Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid extracted from the root of Stephania tetrandra S. Moore. It also existed in the stem of Menispermum dauricum DC, the root of Stephania cepharantha Hayata, and Cyclea barbata (Wall.) Miers. Xie et al. and Wei et al. found that TET produces multiple pharmacological effects, for instance, protecting myocardial, cerebral, and renal ischemia.^24,25 Remarkably, it also helps to prevent hypoxic PH.

In 2010, Feng et al. reported that TET selectively ameliorated monocrotaline (MCT)-induced PAH in rats by reducing PVR and right ventricular hypertrophy (RVH) without affecting the systemic pressure, thus significantly reversing the damage of pulmonary vascular and lung tissue,²⁶ which merits TET as a candidate for PAH treatment. Furthermore, in 2014, Feng et al. demonstrated that TET could reverse the elevation of mPAP and the remodeling of small pulmonary arteries, induced by MCT.²⁷

TET acts as an antagonist of some vasoconstriction factors such as platelet-activating factor, angiotensin II, and prostaglandin F, which play a significant role in the occurrence and development of PAH. Studies have demonstrated that TET could directly downregulate the expression of platelet-derived growth factor and basic fibroblast growth factor in rats with PAH, thus inhibiting vascular smooth muscle cell (VSMC) proliferation, relieving pulmonary vascular remodeling, and consequently attenuating the development of PAH.^28,29 Furthermore, TET improves the function of PAECs and remits mPAP by attenuating the expression of inducible nitric oxide synthase (NOS) and upregulating the expression of protein kinase 1 in the lung tissue of PAH rats. TET also increases the activity of superoxide dismutase in lung tissue, accelerates the scavenging of oxygen free radicals, and prevents the impairing of lung function cells.³⁰ It is generally accepted that hypoxic vasoconstriction can be inhibited by Ca²⁺ channel blockers via blood vessels dilatation. TET is thought to be a weaker calcium channel antagonists and studies have suggested that TET can turn down Ca²⁺ influx by blocking Ca²⁺ channels, which partly contributes to the protective effect of TET in PAH.^31,32

Flavonoids

Flavonoids are widely distributed in plants and berries, such as Ginkgo biloba Linn, puerarin lobata, Crataegus pinnatifida, and Vitis vinifera. Modern pharmacological studies have revealed that these compounds possess obvious pharmacological effects in the cardiovascular and endocrine system.^33–35 Many preparations have been utilized as medicines, such as puerarin-based Yufeng Ningxin tablets and ginkgo preparations of Tianbao Ning.³⁶

Ginkgo biloba extracts

Nowadays, Ginkgo biloba extracts (GBEs) are widely used in treating cardiovascular diseases for their outstanding pharmacological effects. The main active components of GBEs are flavonoids and diterpenoids. Ginkgo biloba flavonoids have strong anti-oxidation and free-radical scavenging effects. Diterpenoids, such as Ginkgolide B, can also reduce the generation of free radicals.³⁷

Also, GBEs exert promising effects on improving acute lung injury (ALI) via downregulating the c-Jun N-terminal kinase and protein kinase B-dependent nuclear factor κB activation pathway.³⁸ Moreover, they inhibit platelet activation and aggregation induced by platelet factors and therefore have the potential to improve blood circulation.³⁹

Studies have shown that Ginkgo biloba can reduce chronic hypoxic PH and relieve RVH, which is partly related to the attenuation of the function of the protein kinase C (PKC) signal channel.⁴⁰ It is also reported that Ginkgo Plus significantly reduces the hypoxia-induced increase of mPAP and PVR as well as the ratio of right ventricular weight vs. left ventricular plus septal weights.⁴¹ GBEs alleviate the apoptosis of endothelial cells (ECs) caused by hydrogen peroxide.⁴² In addition, they stabilize inflammatory cells and show anti-inflammatory effect by decreasing the release of inflammatory mediators.⁴³ Furthermore, GBEs may decrease the concentration of NO and increase superoxide dismutase activity in plasma accompanied by the downregulation of inducible NOS expression.⁴⁴ Consequently, GBEs indirectly decrease the injury of pulmonary vascular ECs and improve PAH.

Puerarin

Puerarin is isolated from the dried roots of puerarin lobata (Willd.) Ohwi. It dilates blood vessels, decreases myocardial oxygen consumption, and improves myocardial ischemia.^45,46 Recently, Li et al. observed that puerarin could improve pulmonary vascular remodeling in rats with PH by inhibiting the deposition of collagen.⁴⁷ A study also showed that puerarin exerted protective effects in MCT-induced PAH rats.⁴⁸ Furthermore, puerarin can induce the release of cytochrome C, activate caspase-9, downregulate B cell leukemia/lymphoma 2 (Bcl-2), and upregulate Bcl-2-associated protein x (Bax) expression. It can scavenge oxygen free radicals and inhibit the proliferation of smooth muscle cells (SMCs). Studies have also confirmed that puerarin induces human pulmonary artery smooth muscle cells (PASMCs) apoptosis via a mitochondria-dependent pathway.⁴⁹

Glycosides

Many Chinese herbal medicines contain glycosides such as ginseng, liquorice, Rhodiola, Polygonum cuspidatum, etc., which are effective ingredients with powerful activities.

Salidroside

Medicinal plant Rhodiola rosea L is a kind of perennial herb; it contains salidroside, tyrosol, flavonoid compounds, amino acids, trace elements, and other ingredients. Rhodiola mainly possesses effects of anti-aging, anti-anoxia, anti-fatigue, anti-depressants, and anti-radiation.^50–53 It can also enhance immunity, regulate the nervous system, and protect the cardiovascular system.^54,55 Above all, Rhodiola has great therapeutic potential.

Rhodiola can significantly inhibit VSMC proliferation and contraction, and reduce the concentration of plasma ET-1 in rats with PH. It is also suggested that Rhodiola inhibits ET-1 expression and promotes the synthesis and the release of NO by affecting pulmonary vasculature selectively. Furthermore, Rhodiola can alleviate the imbalance of systolic and diastolic pulmonary arterial pressure. It also lowers mPAP, alleviates RVH, and improves PH which may be associated with the declined expression of VEGF in the pulmonary arteriolar wall.^56,57 In addition, Rhodila has a notable effect on high-altitude environment-induced PH rats, and inhibition of transforming growth factor beta-1 expression is one of the possible mechanisms.⁵⁸

Adenosine A2a receptor, which is one of the G protein coupled receptors, shows the effects of anti-inflammation after being activated by adenosine and analogues under physiological and pathological conditions.⁵⁹ Moreover, studies have shown that the Salidroside, as a main pharmacological ingredient of Rhodiola, can increase the expression of Adenosine A2a receptor in PASMCs, reversing the downregulated ratio of Bax and Bcl-2 induced by hypoxia. Furthermore, it also promotes the release of mitochondrial cytochrome C into the cytoplasm, accelerates the elimination of caspase 9 via mitochondrial pathway, and thus enhances apoptosis. In addition, Salidroside can reverse the remodeling of pulmonary arterial pressure induced by chronic hypoxia and therefore alleviate the mPAP.⁶⁰

Also, Salidroside inhibits platelet-derived growth factor-BB-induced proliferation and DNA synthesis of PASMCs by blocking the process of G0/G1 to S phase. This may be related to decreasing the expression of cyclin D1 and increasing the accumulation of p27 by blocking the protein kinase B/glycogen synthase kinase-3β signaling pathway.⁶¹ In recent years, the relationship between adenosine monophosphate-activated protein kinase (AMPK) and lung disease has increasingly caught the attention of researchers. The current studies suggest that AMPK also plays a vital role in treating lung cancer, bronchial asthma, PAH, and other pulmonary diseases. Besides, Salidroside inhibits the increase of G2/M phase cells induced by hypoxia via AMPKα1-P53-P27/P21 pathway. Accordingly, the proliferation and DNA synthesis of PASMCs are inhibited.⁶² In addition, Salidroside lowers the levels of P21 and P27, upregulates P53, and mediates apoptosis by regulating the expression of Bax and Bcl-2 via AMPKα1-P53-Bax/Bcl-2-caspase 9-caspase 3 pathway. Consequently, the imbalance of PASMCs proliferation and apoptosis are restored, the pulmonary arterial remodeling is inhibited and the chronic hypoxia-induced PH⁶³ is relieved via AMPKα1-P53 pathway.⁶⁴

Polydatin

Polygonum cuspidatum Sieb. et Zucc is a TCM which is mainly used for treating chronic bronchitis, traumatic injury, and damp-heat jaundice clinically.^65,66 Polydatin (PD) is the main active ingredient extracted from Polygonum cuspidatum Sieb. et Zucc and Fallopia multiflora (Thunb.) Harald with the pharmacological effects of suppressing myocardial cell contraction and platelet aggregation, anti-oxidation, and anti-shock.^67,68 It is reported that PD significantly reduces PAP in hypoxic animals and it can increase cardiac output and improve fibrinolytic activity.⁶⁹ Moreover, Miao et al. observed that PD can alleviate hypoxic PH and reverse remodeling, which attributes to a protective role in treating oxidative stress injury via PKC signaling pathway.⁷⁰ On the one hand, PD attenuates the phosphorylation of PKCα and δ induced by H₂O₂; meanwhile, it increases the phosphorylation of PKCε which has antioxidant effects.⁷¹ On the other hand, PD alleviates lung injury⁷² through inducing apoptosis and inhibiting proliferation by depressing the cell cycle, upregulating Bax, and downregulating Bcl-2.⁷³ However, the exact mechanism of PD reducing the mPAP needs to be further researched and confirmed.

Icariin

Icariin (ICA), a typical flavonol glycoside isolated from the Chinese medical herb Epimedium and has been reported to have abundant pharmacological effects, including anti-depressant,^74–76 anti-inflammation,^77,78 anti-oxidative stress,^79–81 heart failure inhibition,⁸² cardiovascular protection,⁸³ and sexual and immune function enhancement.^84–86

In 2016, Li et al. confirmed that ICA could alleviate the abnormal hemodynamics of the pulmonary artery and right ventricle in PAH model rats induced by MCT, with systolic PAP, diastolic PAP, mPAP, right ventricular systolic pressure, right ventricular diastolic pressure, mean right ventricular pressure reduced, right ventricular preload decreased, compensatory enhancement of right ventricular systolic and diastolic function eased, and right ventricular maximum dP/dt and right ventricular minimum dP/dt absolute value dropped. Furthermore, ICA can slow down the heart rate and prolong the cardiac cycle of PAH model rats. Also, the length of the diastolic period in the cardiac cycle increases gradually following the increase in ICA administration dosage; therefore, it is conducive to improve cardiac function.⁸⁷ In addition, ICA treatment is reported to significantly attenuate mPAP, RVH index, and pulmonary artery remodeling, and to decrease the contents of serum angiotensin II, ET, prostaglandine F2α, thromboxane A2, and prostacyclin, and to inhibit the gene expression of angiotensin converting enzyme, cyclooxygenase-2 and thromboxane A2 synthetase.⁸⁸ Moreover, Li et al. found that ICA administration could increase the contents of NO and cyclic guanosine monophosphate by improving expression of endothelial NOS⁸⁹ and inhibition of 5-type phosphodiesterase in lung tissue of the MCT-injected rats. That is to say, ICA may be effective in protecting against MCT-induced PAH in rats through the increase of NO/cyclic guanosine monophosphate signaling pathway.¹⁰⁰

Diterpenoids

Diterpenoid compounds mostly exist in the form of resins, lactones, or glycosides in nature. Tanshinone compounds and triptolide are the main tricyclic diterpenes that affect PAH.

Tanshinone IIA

Tanshinone IIA is a main constitute of Salvia miltiorrhiza Bge, Salvia sclarea L, and Salvia przewalskii Maxim. Luo et al. reported that Tanshinone IIA could inhibit cell proliferation and pulmonary vasoconstriction. Furthermore, it can alleviate the downregulation of voltage-gated K⁺(Kv)1.5 and Kv2.1 in messenger RNA (mRNA) and protein levels induced by chronic hypoxia and upregulate the level of Kv-mediated currents in PASMCs, which leads to reduced mPAP.¹⁰¹ There were also reports that Tanshinone IIA inhibited hypoxia-induced PASMC proliferation through arresting the cells in the G1/G0-phase by slowing down the degradation of p27 via protein kinase B/S-phase kinase associated protein 2-associated pathway.¹⁰² Meanwhile, Tanshinone IIA inhibits the binding of non-canonical nuclear factor-κB and activator protein-1 to DNA, thus suppressing tumor necrosis factor (TNF)-α-mediated migration of SMCs.¹⁰³

Sodium Tanshinone IIA Sulfonate is a water-soluble derivative of Tanshinone IIA. Wang et al. have identified that Sodium Tanshinone IIA Sulfonate exerts promising effects on treating PH,¹⁰⁴ including lowering mean right ventricular systolic pressure, and relieving RVH and pulmonary arterial wall thickness.¹⁰⁵ In addition, it is well-known that intracellular Ca²⁺ plays a crucial role in the complex mechanisms of VSMC contraction and proliferation. Store-operated calcium channel (SOCC) is mainly composed of canonical transient receptor potential superfamily members and the expression of transient receptor potential superfamily member 1,6 are upregulated selectively by chronic hypoxia. Recently, studies indicated that the upregulation of SOCC induced by hypoxia is the main reason for the imbalance of calcium ions in SMCs. Consequently, the results indicate that Sodium Tanshinone IIA Sulfonate reduces SOCC-mediated store-operated Ca²⁺ entry (SOCE) by inhibiting the chronic hypoxia-induced expression upregulation of transient receptor potential superfamily member 1,6 in remote PASMCs of rat.¹⁰⁵ Thus, it lowers the concentration of intracellular calcium, dilates pulmonary vasculature, and decreases mPAP.¹⁰⁶

Triptolide

Triptolide is the active component of TCM Tripterygium wilfordii Hook. F., which exhibits a variety of pharmacological effects, such as anti-inflammatory and immune suppression.^107,108 Research shows that Triptolide can alleviate the development of PH and RVH, and promote regression of pulmonary arterial neointimal formation, possibly through the inhibition of matrix metalloproteinases activity.^109–111 Moreover, it attenuates the development of PH and RVH in rats receiving MCT injection. Effects on the expressions of matrix metalloproteinases-9 and tissue inhibitor of metallopmteinase-1 may play an important role in facilitating the regression of vascular remodeling.¹¹² Furthermore, it also can improve the early inflammatory infiltration of PAH and reduce inflammation reaction. In addition, Triptolide may improve the MCT-induced PAH by inhibiting cell proliferation and inducing apoptosis.¹¹³

Pyranocoumarins

Pyranocoumarin compounds are widely found in the plant kingdom, especially in angiosperms such as Umbelliferae, Rutaceae, Leguminosae, etc., with biological activities of anti-acquired immunodeficiency syndrome, anti-tumor, and cardiovascular disease treatment.^104,105

Praeruptorin A

Peucedanum Praeruptonrum Dunnon, a well-known TCM, is mainly used for the treatment of respiratory diseases in people. In the 1980s and 1990s, Wang et al. found that Peucedanum Praeruptonrum Dunnon and its extracts had therapeutic effects on PAH animals. Not only can they reduce mPAP and ameliorate pulmonary circulation of a PAH animal model, but they can also suppress pulmonary inflammation.^106,107 The following studies demonstrated that Peucedanum Praeruptonrum Dunnon can reduce mPAP without influencing the systemic artery pressure and can decrease the right heart index and thickness of small pulmonary artery media significantly. It was also reported that the composition of tenascin-C decreased significantly in pulmonary vasculature of rats upon treatment with Peucedanum Praeruptonrum Dunnon.¹⁰⁸ Several angular-type pyranocoumarins, such as Praeruptorin A, B, C, D, and E, have been identified as the main components of Peucedanum Praeruptonrum Dunnon.¹⁰⁹ Among them, Praerutorin A is considered to be the bioactive component, which showed relaxant effect on ex vivo pulmonary arteries.¹¹⁰

It is well accepted that chronic hypoxia increases the basic calcium concentration of PASMCs in both hypoxia PH rats and cell models. SOCC-induced SOCE enhancement is the main reason for the imbalance of intracellular Ca²⁺ concentration.^111–113 Previous studies reported that Praerutorin A could significantly decrease the enhancement of basal Ca²⁺ and SOCE in distal PASMCs of rat, which might suppress cell proliferation and improve PAH.¹¹⁴

Also, the expression and function reduction of the potassium channel, especially the voltage-dependent K⁺ channel causes a series of pulmonary vascular pathological changes in the pathogenesis of PAH. Particularly, abnormal expression and function of Kv 1.5 and Kv 2.1 channel are key factors for PASMC proliferation and apoptosis, which ultimately lead to pulmonary vascular remodeling.^115,116 Furthermore, it was confirmed that Praerutorin A obviously suppressed the downregulation of Kv 1.5 and Kv 2.1 mRNA expression caused by hypoxia in rats PASMCs, which may maintain the balance of cell membrane potential, consequently inhibiting cell proliferation and ameliorating PAH.¹¹⁷

Stilbenes

The stilbene compound is a general term for a class of substances which have a polystyrene nucleus or a polymer thereof. Stilbene compounds have a variety of biological activities. In addition to the already known antibacterial effects, in recent years it has been found that some stilbene compounds possess lipid-lowering, expansion of coronary blood vessels and inhibition of platelet aggregation, and anti-hypertensive and anti-tumor effects.¹¹⁸

Resveratrol

Resveratrol (RES) is a kind of polyphenol mainly derived from polygonum cuspidatum, Arachis hypogaea Linn, Fructus Mori, and Vitis vinifera L. It exists free-form or as a corresponding glycoside in two geometric isomers: cis- (Z) and trans– (E), both of which have anti-oxidative activity.¹¹⁹ RES is a new type of compound which can protect ECs and show antioxidant and anti-inflammatory effects on systemic circulatory system.¹²⁰ Furthermore, it can be used for the prevention and treatment of a variety of cardiovascular diseases, including PH.¹²¹

Recently, Chen et al. confirmed that RES, the deglycosylation form of polydatin, could prevent hypoxia-induced human PASMC proliferation and attenuate RVH through the phosphoinositide 3 kinase -protein kinase B signaling pathway.¹²² It was also suggested that resveratrol could improve endothelial function, attenuate oxidative stress, and inhibit inflammatory reaction, while suppressing vascular reconstruction in MCT-induced PAH rats. RES also alleviates mPAP by controlling the proliferation of SMCs and the vascular remodeling. ¹²³ Accordingly, RES achieves the purpose of prevention and treatment of PAH by playing a vasodilation role.

Moreover, anti-inflammatory effects of RES may be associated with lower expression of inflammatory factors such as interleukins and TNF-α.¹²⁴ Studies have shown that monocyte chemoattractant protein-1 (MCP-1) recruits huge amounts of inflammatory cells for the injured part after ALI to form positive feedback.¹²⁵ At the same time, a series of inflammation-related mediators are generated to cause pulmonary vascular EC damage and mPAP increase.¹²⁶ RES significantly decreases the mRNA and protein levels of MCP-1. It suggests that RES can reduce the recruitment of monocytes and alleviate the injury of PAECs caused by inflammatory cells and inflammatory mediators. Previous studies have demonstrated that p38-mitogen-activated protein kinases is the key upstream molecule to generate MCP-1. Experimental results have also revealed that RES suppresses the expression of MCP-1 mainly by limiting the activation of p-p38-mitogen-activated protein kinases. Hence, those effects of RES mitigate PAH eventually.¹²⁷

Other natural products

Semen lepidii

Semen lepidii, the seeds of Descurainia Sophia (L), have been used in TCM to relieve cough, prevent asthma, reduce edema, and promote urination.¹²⁸ Studies have shown that the compound capsule of Semen lepidii evidently decreases rabbit PH induced by 5-hydroxytryptamine in vivo and increases the contraction amplitude of myocardial, that is, enhances myocardial contractility.¹²⁹ So it seems that Semen lepidii have effects of improving cardiac output and lowering mPAP and PVR.¹³⁰ Furthermore, it is observed that Semen lepidii can improve arterial blood gas in PAH rats.¹³¹

Mustard glucoside and G-sitosterol, the active ingredients of Semen lepidii, can relieve cough, relax bronchial smooth muscle, and remit bronchial spasm. Moreover, research has found that the Hlvetivoside of Semen lepidii distinctly decreases MCT-induced right ventricular systolic and diastolic blood pressure, as well as mPAP.¹³²

Radix Astragali

Radix Astragali, the traditional Chinese herb, is the root of Astragalusmembranaceus (Fisch) Bge. or Astragalusmembranaceus (Fisch) Bge.var.Mongholicus (Bge.) Hsiao, which has been used as folk herbal medicine in China for many years. Several experimental and clinical studies have provided evidence of its extensive pharmacological effects, including regulating blood pressure and treating nervous, respiratory, and endocrine diseases.¹³³

Although accumulative data have shown that Radix Astragal was beneficial for the treatment of PAH,¹³⁴ its mechanisms were multifaceted, and mainly included the following: (1) inhibition of the remodeling of intra-acinar pulmonary arteries and the hyperplasia of collagen;¹³⁵ (2) decrease in the content of ET-1 and increase in the content of NO, improving the expression level of NOS, maintaining the balance of NO/ET-1;¹³⁶ (3) intervening with mRNA expression of collagen in right ventricle;¹³⁷ (4) lowering the concentration of thromboxane A2 in pulmonary tissue and reversing the reconstruction of pulmonary vessels;¹³⁸ (5) regulating the concentration of superoxide dismutase and oxygen free radical in pulmonary tissue, preserving pulmonary vasculature from hypoxia stimulation by the action of antioxidant;¹³⁹ and (6) exerting impact on the other of vasoactive substances.¹⁴⁰

Perspectives

With the clinical efficacy of natural plant products being fully confirmed from years of practice, they have received more recognition and attention from the international pharmaceutical industry. Proved by numerous studies, natural plant products such as TET have great potential in the treatment of PAH. There are numerous advantages of natural plant products. They are green and with lower economic costs compared with chemical drugs. Natural product treatment is a multi-target and multi-link system with a unique advantage in the therapy of complex diseases, while chemical drugs are primarily for a single target. Meanwhile, some natural plant products exhibit selective functions on pulmonary circulation with no significant effect on system circulation. Hence, there is a good prospect and potential development value for natural plant products in PAH therapy.

From the literature reported so far, we summarize the achievements of this field in PAH. (1) Pre-clinical studies and traditional clinical practices have revealed that a number of natural plant products, such as tetrandrine, ligustrazine, salidroside, etc., harbor potential in PAH therapy. (2) Some natural plant products, such as ligustrazine, Qingning oral solution, Astragalus, etc., show selective effects in pulmonary circulation and cardiac function. (3) Multiple mechanisms have been involved in the treatment of PAH by natural plant products. For example, Rhodiola inhibits the secretion of ET-1 and promotes the synthesis and release of NO from PAECs, while ligustrazine has an antagonistic effect of Ca²⁺.

However, these studies are preliminary and have limitations. (1) Some natural products can reduce systemic blood pressure and even cause hypotensive reactions. (2) Generally, the effects of nature plant products are weaker than chemical medicines in PAH treatment; they are reasonably compatible and doses should be considered seriously. (3) Experimental and clinical studies with large numbers of subjects are still insufficient to form treatment standards in the utilization of nature plant products. (4) Some plants are reported as showing toxicity in system and pulmonary vasculature, such as MCT, Ergotamine,¹⁴¹ and pyrrolizidine alkaloids¹⁴² contained in the Senecio and Crotalaria plants.¹⁴³ The multifunction of natural plant products should be considered carefully.

In summary, natural products have great potential in the treatment of PAH, but the specific mechanisms need further study. We are looking forward to the next efficient medicine for PAH treatment. We also believe that natural products have broad prospects and great value in the future.

Footnotes

Conflict of interest

The authors declare that there is no conflict of interest.

Funding

This work was supported by National Natural Science Foundation of China (grant no. 81503071 to Y Li, grant no. 81773734 to XH Li) and the 2016 Annual Postgraduate Innovation Program of Central South University (grant no. 2016zzts497 to LL Xiang).

References

McLaughlin

McGoon

. Pulmonary arterial hypertension. Circulation 2006; 114: 1417–1431.

Tuder

Archer

et al.

Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 2013; 62: 4–12.

Lau

Tamura

McGoon

et al.

The 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: a practical chronicle of progress. Eur Respir J 2015; 46: 879–882.

Badesch

Champion

Sanchez

et al.

Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54: 55–66.

Bourji

Hassoun

. Right ventricle dysfunction in pulmonary hypertension: mechanisms and modes of detection. Curr Opin Pulm Med 2015; 21: 446–453.

Calcutteea

Lindqvist

Soderberg

et al.

Global and regional right ventricular dysfunction in pulmonary hypertension. Echocardiography 2014; 31: 164–171.

Voswinckel

Reichenberger

Enke

et al.

Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension. Pulm Pharmacol Ther 2008; 21: 824–832.

Hoeper

Barberà

Channick

et al.

Diagnosis, assessment, and treatment of non–pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol 2009; 54: 85–96.

McLaughlin

Shah

Souza

et al.

Management of pulmonary arterial hypertension. J Am Coll Cardiol 2015; 65: 1976–1997.

10.

Fraidenburg

Yuan

. Current and future therapeutic targets for pulmonary arterial hypertension. High Alt Med Biol 2013; 14: 134–143.

11.

Chan

Loscalzo

. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol 2008; 44: 14–30.

12.

Gomez–Arroyo

Farkas

Alhussaini

et al.

The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 2012; 302: 363–369.

13.

Bai

Zhao

et al.

Study on pharmacological effect and mechanism of alkaloids (in Chinese). Journal of Harbin University of Commerce (Natural Sciences Edition) 2013; 29: 8–11.

14.

Meng

Liang

et al.

Advances in pharmacological studies of alkaloids compounds (in Chinese). Lishizhen Med Mater Med Res 2003; 14: 700–702.

15.

Zhao

Gao

Liu

et al.

Research advance on the pharmacological effects of benzyltetrahydroisoquinolines alkaloids (in Chinese). J Pharm Pract 2015; 33: 313–315.

16.

Cao

Zeng

Zhu

et al.

Effects of tetramethylpyrazine, a Chinese medicine, on plasma endothelin–1 levels during acute pulmonary hypoxia in anesthetized dogs. J Cardiovasc Pharmacol 1998; 31: 456–459.

17.

Feng

Yang

Huang

et al.

Plasma endothelin–1 and nitric oxide correlate with ligustrazine alleviation of pulmonary artery hypertension in patients of chronic cor pulmonale from high altitude plateau during acute exacerbation (in Chinese). Zhongguo Ying Yong Sheng Li Xue Za Zhi 2014; 30: 532–537.

18.

Cai

Chen

Pan

et al.

Inhibition of angiogenesis, fibrosis and thrombosis by tetramethylpyrazine: mechanisms contributing to the SDF–1/CXCR4 axis. PLoS One 2014; 9: 1–9.

19.

Handa

Ikeda

et al.

Specific inhibiting characteristics of tetramethylpyrazine, one of the active ingredients of the Chinese herbal medicine ‘Chuanxiong’, on platelet thrombus formation under high shear rates. Thromb Res 2001; 104: 15–28.

20.

Zhao

Liu

Chen

. Mechanisms and clinical application of tetramethylpyrazine (an interesting natural compound isolated from Ligusticum Wallichii): current status and perspective. Oxid Med Cell Longev 2016; 2016: 1–9.

21.

Zhang

Deng

Zhou

. Tetramethylpyrazine inhibits hypoxia–induced pulmonary vascular leakage in rats via the ROS–HIF–VEGF pathway. Pharmacology 2011; 87: 265–273.

22.

Guo

Liu

Shi

. Cardiovascular actions and therapeutic potential of tetramethylpyrazine (active component isolated from Rhizoma Chuanxiong): roles and mechanisms. Biomed Res Int 2016; 2016: 1–9.

23.

Pang

Shan

Chiu

. Tetramethylpyrazine, a calcium antagonist. Planta Med 1996; 62: 431–435.

24.

Xie

Tang

Chen

et al.

Pharmacological actions of tetrandrine in inflammatory pulmonary diseases. Acta Pharmacol Sin 2002; 23: 1107–1113.

25.

Wei

Wang

. Research progress on pharmacological effect of tetrandrine (in Chinese). J Shanxi Coll Tradit Chin Med 2004; 27: 66–68.

26.

. Experiment study of tetrandrine on pulmonary artery hypertension in rats (in Chinese). Heilongjiang Med J 2010; 34: 737–741.

27.

Liu

SJC

et al.

Comparative study of tetrandrine with nifedipine effects on pulmonary arterial hypertension in rats (in Chinese). J Cardiovascular Pulmonary Dis 2014; 33: 473–441.

28.

Wang

Kilfeather

Martin

et al.

Effects of tetrandrine on growth factor–induced DNA synthesis and proliferative response of rat pulmonary artery smooth muscle cells. Pulm Pharmacol Ther 2000; 13: 53–60.

29.

Meng

Zhang

Song

et al.

Research of expression of platelet–derived growth factor A, B in inhibitory processes of tetrandrine on pulmonary hypertension in rats (in Chinese). J Cardiovascular Pulmonary Dis 2000; 29: 10–12.

30.

Wang

Yang

et al.

Tetrandrine prevents monocrotaline–induced pulmonary arterial hypertension in rats through regulation of the protein expression of inducible nitric oxide synthase and cyclic guanosine monophosphate–dependent protein kinase type 1. J Vasc Surg 2015; 64: 1468–1477.

31.

Wang

Zhang

Chang

. Effects of tetrandrine on smooth muscle contraction induced by mediators in pulmonary hypertension. Acta Pharmacol Sin 2002; 23: 1114–1120.

32.

. The research progress of tetrandrine resistance to pulmonary hypertension (in Chinese). China Pharmacist 2000; 3: 77–79.

33.

Kumar

Pandey

. Chemistry and biological activities of flavonoids: an overview. ScientificWorldJournal 2013; 2013: 162750.

34.

Pietta

. Flavonoids as antioxidants. J Nat Prod 2000; 63: 1035–1042.

35.

Romano

Pagano

Montanaro

et al.

Novel insights into the pharmacology of flavonoids. Phytother Res 2013; 27: 1588–1596.

36.

Xiao

Chen

. Distribution in plant, pharmacological effect and application research of isoflavone compounds (in Chinese). World Phytomed 1998; 13: 157–163.

37.

Yao

Chen

. Research advances in the pharmacological effects of Ginkgo biloba leaves (in Chinese). Zhejiang J Integr Tradit Chin West Med 2005; 15: 192–193.

38.

Lee

Yang

Lee

et al.

Protective effect of Ginkgo biloba leaves extract, EGb761, on endotoxin–induced acute lung injury via a JNK– and protein kinase B–dependent NFκB pathway. J Agr Food Chem 2014; 62: 6337–6344.

39.

Smith

Luo

. Studies on molecular mechanisms of Ginkgo biloba extract. Appl Microbiol Biotechnol 2004; 64: 465–472.

40.

Yang

Zhang

. The effect of Ginkgo biloba on hypoxic pulmonary hypertension and the role of protein kinase C (in Chinese). Zhonghua Jie He He Hu Xi Za Zhi 2000; 23: 602–605.

41.

Cheng

Chen

Yang

et al.

Effects of ginkgo plus on hypoxia pulmonary hypertension in rats (in Chinese). Hua Xi Yi Ke Da Xue Bao 1996; 27: 415–417.

42.

Ren

Zhang

. Protective effect of ginkgo biloba extract on endothelial cell against damage induced by oxidative stress. J Cardiovasc Pharmacol 2002; 40: 809–814.

43.

Tulsulkar

Shah

. Ginkgo biloba prevents transient global ischemia–induced delayed hippocampal neuronal death through antioxidant and anti–inflammatory mechanism. Neurochem Int 2013; 62: 189–197.

44.

Liu

et al.

Ginkgo biloba extract (EGb 761) attenuates lung injury induced by intestinal ischemia/reperfusion in rats: roles of oxidative stress and nitric oxide. World J Gastroenterol 2007; 13: 299–305.

45.

Zhou

Zhang

Peng

. Puerarin: a review of pharmacological effects. Phytother Res 2014; 28: 961–975.

46.

Zhang

Lam

Zuo

. Radix Puerariae: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol 2013; 53: 787–811.

47.

Chen

Guan

et al.

Inhibition of Puerarin on pulmonary hypertension in rats with hypoxia and hypercapnia (in Chinese). Zhongguo Zhong Yao Za Zhi 2008; 33: 544–549.

48.

Jun

Liang

et al.

Change of elongation factor 2 in pulmonary hypertension rats and study of interfered with Puerarin (in Chinese). Chin J Clin Pharmacol 2015; 31: 536–539.

49.

Chen

Wang

et al.

Puerarin induces mitochondria–dependent apoptosis in hypoxic human pulmonary arterial smooth muscle cells. PLoS ONE 2012; 7: e34181.

50.

Darbinyan

Aslanyan

Amroyan

et al.

Clinical trial of Rhodiola rosea L. extract SHR–5 in the treatment of mild to moderate depression. Nord J Psychiatry 2007; 61: 343–348.

51.

Panossian

Nikoyan

Ohanyan

et al.

Comparative study of Rhodiola preparations on behavioral despair of rats. Phytomedicine 2008; 15: 84–91.

52.

van Diermen

Marston

Bravo

et al.

Monoamine oxidase inhibition by Rhodiola rosea L. roots. J Ethnopharmacol 2009; 122: 397–401.

53.

Darbinyan

Kteyan

Panossian

et al.

Rhodiola rosea in stress induced fatigue–a double blind cross–over study of a standardized extract SHR–5 with a repeated low–dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine 2000; 7: 365–371.

54.

Kelly

. Rhodiola rosea: a possible plant adaptogen. Altern Med Rev 2001; 6: 293–302.

55.

Panossian

Wikman

Sarris

. Rosenroot (Rhodiola rosea): Traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine 2010; 17: 481–493.

56.

Kosanovic

Tian

Pak

et al.

Rhodiola: an ordinary plant or a promising future therapy for pulmonary hypertension? A brief review. Pulm Circ 2013; 3: 499–506.

57.

Bai

Guo

Bian

et al.

Integripetal rhodiola herb attenuates high altitude-induced pulmonary arterial remodeling and expression of vascular endothelial growth factor in rats (in Chinese). Sheng Li Xue Bao 2011; 2: 143–148.

58.

Guo

Bai

MKZ

et al.

Effetct of rhodiola on the expression of transforming growth factor-β1 in high-altitude environment-induced pulmonary hypertension rats (in Chinese). J Lanzhou Univ (Med Sci) 2011; 37: 1–9.

59.

Sharma

Linden

Kron

et al.

Protection from pulmonary ischemia–reperfusion injury by adenosine A2A receptor activation. Respir Res 2009; 10: 58–66.

60.

Huang

Zou

et al.

Salidroside attenuates chronic hypoxia–induced pulmonary hypertension via adenosine A2a receptor related mitochondria–dependent apoptosis pathway. J Mol Cell Cardiol 2015; 82: 153–166.

61.

Chen

Tang

Deng

et al.

Salidroside blocks the proliferation of pulmonary artery smooth muscle cells induced by platelet–derived growth factor BB. Mol Med Rep 2014; 10: 917–922.

62.

Lin

Liu

Zhao

et al.

Inhibitory effect of Salidroside on the proliferation of rabbit pulmonary artery smooth muscle cells under hypoxia (in Chinese). Chin J Pathophysiol 2001; 10: 968–970.

63.

Huang

Fan

et al.

The protective effect of salidroside on cor pulmonale rats induced by chronic hypoxia in normal pressure (in Chinese). Chin Arch Trad Chin Med 2011; 29: 1868–1871.

64.

Chen

Cai

et al.

Salidroside exerts protective effects against chronic hypoxia–induced pulmonary arterial hypertension via AMPK alpha1–dependent pathways. Am J Transl Res 2016; 8: 12–27.

65.

Zhang

Kwok

et al.

A review of the pharmacological effects of the dried root of Polygonum cuspidatum (Hu Zhang) and its constituents. Evid Based Complement Alternat Med 2013; 2013: 208349.

66.

Lin

Yang

Chen

et al.

Free radical scavenging activity and antiproliferative potential of Polygonum cuspidatum root extracts. J Nat Med 2010; 64: 146–152.

67.

Peng

Zhang

. Polydatin: a review of pharmacology and pharmacokinetics. Pharm Biol 2013; 51: 1347–1354.

68.

Zhao

Jin

Huang

et al.

The mechanism of Polydatin in shock treatment. Clin Hemorheol Microcirc 2003; 29: 211.

69.

Wang

et al.

Effect of Polydatin on hypoxic pulmonary hypertension (in Chinese). J Binzhou Med Coll 2004; 27: 328–329.

70.

Miao

Shi

et al.

Polydatin attenuates hypoxic pulmonary hypertension and reverses remodeling through protein Kinase C mechanisms. Int J Mol Sci 2012; 13: 7776–7787.

71.

Qiao

Chen

Dong

et al.

Polydatin attenuates H₂O₂–induced oxidative stress via PKC pathway. Oxid Med Cell Longev 2016; 2016: 5139458.

72.

Jiang

Guo

et al.

Protective effects of polydatin on lipopolysaccharide–induced acute lung injury through TLR4–MyD88–NF–κB pathway. Int Immunopharmacol 2015; 29: 370–376.

73.

Zhang

Zhuang

Meng

et al.

Polydatin inhibits growth of lung cancer cells by inducing apoptosis and causing cell cycle arrest. Oncol Lett 2014; 7: 295–301.

74.

Pan

Wang

Qiang

et al.

Icariin attenuates chronic mild stress-induced dysregulation of the LHPA stress circuit in rats. Psychoneuroendocrinology 2010; 35: 272–283.

75.

Pan

Hong

Zhang

et al.

Impaired hypothalamic insulin signaling in CUMS rats: restored by icariin and fluoxetine through inhibiting CRF system. Psychoneuroendocrinology 2013; 38: 122–134.

76.

et al.

Icariin attenuates social defeat-induced down-regulation of glucocorticoid receptor in mice. Pharmacol Biochem Behav 2011; 98: 273–278.

77.

Guo

et al.

Protective effects of icariin on brain dysfunction induced by lipopolysaccharide in rats. Phytomedicine 2010; 17: 950–955.

78.

Duan

et al.

Icariin attenuates glucocorticoid insensitivity mediated by repeated psychosocial stress on an ovalbumin-induced murine model of asthma. Int Immunopharmacol 2014; 19: 381–390.

79.

Zeng

Meng

Zhang

. Study on the antioxidative effect of constituents of herba epimedii (in Chinese). China J Chin Mater Med 1997; 1: 46–48.

80.

Luo

Nie

Gong

et al.

Protective effects of icariin against learning and memory deficits induced by aluminium in rats. Clin Exp Pharmacol Physiol 2007; 34: 792–795.

81.

Xiao

Liu

et al.

Icariin regulates PRMT/ADMA/DDAH pathway to improve endothelial function. Pharmacol Rep 2015; 67: 1147–1154.

82.

Song

Chen

et al.

Ethanol extract from Epimedium brevicornum attenuates left ventricular dysfunction and cardiac remodeling through down-regulating matrix metalloproteinase-2 and -9 activity and myocardial apoptosis in rats with congestive heart failure. Int J Mol Med 2008; 21: 117–124.

83.

Zhang

Morita

Shao

et al.

Screening of anti-hypoxia/reoxygenation agents by an in vitro model. Planta Med 2000; 66: 114–123.

84.

Liang

Wei

Chen

et al.

Variation of medicinal components in a unique geographical accession of horny goat weed Epimedium sagittatum Maxim. (Berberidaceae). Molecules 2012; 17: 13345–13356.

85.

Schluesener

. Plant polyphenols in the treatment of age-associated diseases: Revealing the pleiotropic effects of icariin by network analysis. Mol Nutr Food Res 2014; 58: 49–60.

86.

Sun

et al.

Icariin ameliorates cigarette smoke induced inflammatory responses via suppression of NF-κB and modulation of GR in vivo and in vitro. PLoS One 2014; 9: e102345.

87.

Liu

Luo

et al.

Effects of icariin on hemodynamics of pulmonary arterial hypertension induced by monocrotaline in rats (in Chinese). J Zunyi Med Univ 2016; 39: 229–232.

88.

Luo

Liu

et al.

Effects of Icariin on partial vasoactive substances in monocrotaline-induced pulmonary arterial hypertension rat model (in Chinese). Her Med 2017; 36: 847–852.

89.

Koizumi

Hashimoto

et al.

Involvement of androgen receptor in nitric oxide production induced by icariin inhuman umbilical vein endothelial cells. FEBS Letters 2010; 11: 2440–2444.

90.

Luo

Liu

et al.

Icariin inhibits pulmonary hypertension induced by monocrotaline through enhancement of NO/cGMP signaling pathway in rats. Evid Based Complement Alternat Med 2016; 2016: 7915415.

91.

Zheng

Liu

Wei

et al.

Tanshinone IIA attenuates hypoxic pulmonary hypertension via modulating Kv currents. Respir Physiol Neurobiol 2015; 205: 120–128.

92.

Luo

Dong

et al.

Tanshinone IIA inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via Akt/Skp2/p27-Associated pathway. PLoS One 2013; 8: e56774.

93.

Jin

Suh

Chang

et al.

Tanshinone IIA from Salvia miltiorrhiza BUNGE inhibits human aortic smooth muscle cell migration and MMP–9 activity through AKT signaling pathway. J Cell Biochem 2008; 104: 15–26.

94.

Wang

et al.

Promising therapeutic effects of sodium tanshinone IIA sulfonate towards pulmonary arterial hypertension in patients. J Thorac Dis 2013; 5: 169–172.

95.

Wang

Jiang

Wan

et al.

Sodium tanshinone IIA sulfonate inhibits canonical transient receptor potential expression in pulmonary arterial smooth muscle from pulmonary hypertensive rats. Am J Respir Cell Mol Biol 2013; 48: 125–134.

96.

Huang

Liu

Dong

et al.

Effects of sodium tanshinone IIA sulfonate on hypoxic pulmonary hypertension in rats in vivo and on Kv2.1 expression in pulmonary artery smooth muscle cells in vitro. J Ethnopharmacol 2009; 125: 436–443.

97.

Ziaei

Halaby

. Immunosuppressive, anti–inflammatory and anti–cancer properties of triptolide: A mini review. Avicenna J Phytomed 2016; 6: 149–164.

98.

Wang

Meng

Dong

et al.

The pharmacological effects and mechanism of Tripterygium wilfordii Hook F in central nervous system autoimmunity. J Altern Complement Med 2016; 22: 496–502.

99.

Faul

Nishimura

Berry

et al.

Triptolide attenuates pulmonary arterial hypertension and neointimal formation in rats. Am J Respir Crit Care Med 2000; 162: 2252–2258.

100.

Wei

Liu

et al.

Effect of triptolide on the development of monocrotaline-induced pulmonary hypertension in pneumonectomized rat (in Chinese). Sichuan Da Xue Xue Bao Yi Xue Ban 2007; 5: 806–809.

101.

Wei

Liu

et al.

Effect of triptolide on the expression of matrix metalloproteinases 2 and 9 in lungs of experimental pulmonary hypertension (in Chinese). Zhongguo Dang Dai Er Ke Za Zhi 2007; 5: 479–483.

102.

Wei

Liu

et al.

Effect of triptolide on the expression of MMP9/TIMP-1 in the lung of expression pulmonary hypertension (in Chinese). Sichuan Med J 2007; 28: 828–830.

103.

Wei

Liu

Wang

et al.

Effects of triptolide on antiproliferation and the enhancement of apoptosis in pulmonary hypertension (in Chinese). Chin Circ J) 2006; 21: 473.

104.

Cheng

. Advances in pharmacological effects of pyranocoumarin compounds (in Chinese). Chin Trad Pat Med 2013; 35: 1288–1291.

105.

Zuo

Guo

. Pharmacological research progress of pyranocoumarin compounds (in Chinese). Chin Med Mat 2003; 26: 686–689.

106.

Rong

Wang

Zhang

et al.

Effects of Peuceldanum Dunn on hemorrheology and hemodynamics in pulmonary circulation of pulmonary hypertensive rats (in Chinese). J Chin Med Univ 2001; 30: 325–327.

107.

Rong

Wang

Zhang

. Effects of PPD on hemorrheology, hemodynamics of pulmonary circulation and correlation analysis in pulmonary hypertension in rats (in Chinese). Chin J Mod Appl Pharm 2001; 18: 263–266.

108.

Wang

Zhang

. Effects of Peucedanum Praeruptorum Dunnon on the monocrotaline–induced pulmonary hypertension in rats (in Chinese). Chin Pharm J 2000; 35: 90–93.

109.

Sarkhail

Shafiee

Sarkheil

. Biological activities and pharmacokinetics of Praeruptorins from Peucedanum species: a systematic review. Biomed Res Int 2013; 2013: 343808.

110.

Zhao

Jin

Zhang

et al.

Relaxant effects of Pyranocoumarin compounds isolated from isolated from a Chinese medical plant, Bai–Hua Qian–Hu, on Isolated rabbit tracheas and pulmonary arteries. Biol Pharm Bull 1999; 22: 984–987.

111.

Shimoda

Wang

Sylvester

. Ca²⁺ channels and chronic hypoxia. Microcirculation 2006; 13: 657–670.

112.

Wang

Shimoda

Sylvester

. Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 2004; 286: 848–858.

113.

Wang

Weigand

et al.

Hypoxia inducible factor 1 mediates hypoxia–induced TRPC expression and elevated intracellular Ca²⁺ in pulmonary arterial smooth muscle cells. Circ Res 2006; 98: 1528–1537.

114.

Zhang

. Effect of Pd–Ia on intracellular calcium concentration in rat pulmonary arterial smooth muscle cells (in Chinese). Int J Respir 2015; 35: 1004–1007.

115.

Bonnet

Archer

. Potassium channel diversity in the pulmonary arteries and pulmonary veins: implications for regulation of the pulmonary vasculature in health and during pulmonary hypertension. Pharmacol Ther 2007; 115: 56–69.

116.

Wang

Weigand

Wang

et al.

Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery. Am J Physiol Lung Cell Mol Physiol 2005; 288: 1049–1058.

117.

Xiong

Deng

Xiao

. Effect of Pd–Ia on the hypoxia–induced expression of Kv 1.5 and Kv 2.1 in rat pulmonary arterial smooth muscle cells (in Chinese). Guangdong Med J 2015; 36: 3119–3122.

118.

Chen

. A review of pharmacological research on Stilbene compounds (in Chinese). Guangdong Pharm J 2005; 15: 84–86.

119.

Malhotra

Bath

Elbarbry

. An organ system approach to explore the antioxidative, anti–inflammatory, and cytoprotective actions of Resveratrol. Oxid Med Cell Longev 2015; 2015: 803971.

120.

Labinskyy

Csiszar

Veress

et al.

Vascular dysfunction in aging: potential effects of resveratrol, an anti–inflammatory phytoestrogen. Curr Med Chem 2006; 13: 989–996.

121.

Chicoine

Stewart

Jr Lucchesi

. Is resveratrol the magic bullet for pulmonary hypertension? Hypertension 2009; 54: 473–474.

122.

Chen

Xue

Meng

et al.

Resveratrol prevents hypoxia–induced arginase II expression and proliferation of human pulmonary artery smooth muscle cells via Akt–dependent signaling. Am J Physiol Lung Cell Mol Physiol 2014; 307: 317–325.

123.

Csiszar

Labinskyy

Olson

et al.

Resveratrol prevents monocrotaline–induced pulmonary hypertension in rats. Hypertension 2009; 54: 668–675.

124.

Tung

Rodríguez-Bies

Talero

et al.

Anti-inflammatory effect of resveratrol in old mice liver. Exp Gerontol 2015; 64: 1–7.

125.

Itoh

Nagaya

Ishibashi–Ueda

et al.

Increased plasma monocyte chemoattractant protein–1 level in idiopathic pulmonary arterial hypertension. Respirology 2006; 11: 158–163.

126.

Park

JES

Lyon

Shao

et al.

Pulmonary venous hypertension and mechanical strain stimulate monocyte chemoattractant protein–1 release and structural remodelling of the lung in human and rodent chronic heart failure models. Thorax 2014; 69: 1120–1127.

127.

Chen

Wang

Cai

et al.

Resveratrol downregulates acute pulmonary thromboembolism–induced pulmonary artery hypertension via p38 mitogen–activated protein kinase and monocyte chemoattractant protein–1 signaling in rats. Life Sci 2012; 90: 721–727.

128.

Lee

Kim

et al.

Cytotoxic and anti–inflammatory constituents from the seeds of Descurainia sophia. Arch Pharm Res 2013; 36: 536–541.

129.

Bai

Zheng

et al.

Research on the effect of compound caspsule of Semen Lepidii on pulmonary artery hypertension and myocardial contractility (in Chinese). Hunan J Tradit Chin Med 2000; 16: 59–60.

130.

Wang

. The compound injection of Semen Lepidii in the treatment of senile cor pulmonale with acute heart failure 60 cases (in Chinese). Shanxi J Tradit Chin Med 1997; 18: 531.

131.

Xiong

Wang

Jing

. Effect of compound injection of Semen Lepidii on arterial blood gas in rats with MCT–induced pulmonary artery hypertension (in Chinese). Shanxi J Tradit Chin Med 1996; 17: 563–564.

132.

Fang

Xiong

. Effect of the Hlvetivoside of Semen Lepidii on hemodynamic in rats with MCT–induced PAH (in Chinese). Pract Clin J Integr Tradit Chin West Med 2004; 4: 73–74.

133.

Ren

Zhang

et al.

Pharmacological effects of Astragaloside IV: a literature review. J Tradit Chin Med 2013; 33: 413–416.

134.

Ruan

Liu

et al.

The inhibitory effects of Radix Astragali on hypoxic pulmonary hypertension of rats (in Chinese). Chin Med J (Engl) 1998; 111: 956–958.

135.

Ruan

Liu

et al.

Morphometric investigation on hypoxic structural remodeling of intraacinar pulmonary arteries (in Chinese). Zhonghua Jie He He Hu Xi Za Zhi 1998; 21: 303–305.

136.

Liu

Wang

et al.

Influence of Radix Astragali on nitric oxide and endothelin–1 in pulmonary tissue in hypoxemic pulmonary hypertension in rats (in Chinese). Zhonghua Er Ke Za Zhi 2006; 44: 46–48.

137.

Jing

et al.

Collagen expression of intra–acinar pulmonary arteries and right ventricle and intervention of Radix Astragali in rats with hypoxic pulmonary hypertension (in Chinese). Natl Med J China 1999; 79: 654.

138.

Liu

Piao

et al.

Effects of Radix Astragali on remodeling of intra–acinar pulmonary arteries and TXA2 in hypoxemic pulmonary hypertension in rats (in Chinese). Liaoning J Tradit Chin Med 2007; 34: 1641–1642.

139.

Liu

Yan

et al.

Influence of Radix Astragali on superoxide dismutase and malonyldialdehide in pulmonary tissue of hypoxemic pulmonary hypertension in rats (in Chinese). J Med Sci Yanbian Univ 2002; 25: 97–100.

140.

Tang

Sun

. Curative effect of Astragalus injection for pulmonary artery hypertension of patients with pneumocardical disease (in Chinese). Mod J Integr Tradit Chin West Med 2003; 12: 32.

141.

Egermayer

. Epidemics of vascular toxicity and pulmonary hypertension: what can be learned? J Intern Med 2000; 87: 11–17.

142.

Bach

Thung

Schaffner

. Comfrey herb tea-induced hepatic veno-occlusive disease. Am J Med 1989; 87: 97–99.

143.

McDermott

Ridker

. The Budd-Chiari syndrome and hepatic veno-occlusive disease. Recognition and treatment. Arch Surg 1990; 125: 525–527.

144.

Wei

Wang

Gong

et al.

Ginkgo suppresses atherosclerosis through downregulating the expression of connexin 43 in rabbits. Arch Med Sci 2013; 9: 340–346.

145.

Lim

Yoon

Kang

et al.

EGb761, a Ginkgo biloba extract, is effective against atherosclerosis in vitro, and in a rat model of type 2 diabetes. PLoS One 2011; 6: e20301.

146.

Chen

Huang

Wang

et al.

Nrf-2 mediated heme oxygenase-1 expression, an antioxidant-independent mechanism, contributes to anti-atherogenesis and vascular protective effects of Ginkgo biloba extract. Atherosclerosis 2011; 214: 301–309.

147.

Rodríguez

Ringstad

Schäfer

et al.

Reduction of atherosclerotic nanoplaque formation and size by Ginkgo biloba (EGb 761) in cardiovascular high-risk patients. Atherosclerosis 2007; 192: 438–444.

148.

Fang

Lin

Yuan

et al.

Tanshinone IIA inhibits atherosclerotic plaque formation by down-regulating MMP-2 and MMP-9 expression in rabbits fed a high-fat diet. Life Sci 2007; 81: 1339–1345.

149.

Chen

. Anti-inflammatory and immunomodulatory mechanism of Tanshinone IIA for atherosclerosis. Evid Based Complement Alternat Med 2014; 2014: 267976.

150.

Chen

Tang

Xie

et al.

Amelioration of atherosclerosis by tanshinone IIA in hyperlipidemic rabbits through attenuation of oxidative stress. Eur J Pharmacol 2012; 674: 359–364.

151.

Tang

Wang

et al.

Tanshinone II A attenuates atherosclerotic calcification in rat model by inhibition of oxidative stress. Vascul Pharmacol 2007; 46: 427–438.

152.

Minatti

Wazlawik

Hort

et al.

Green tea extract reverses endothelial dysfunction and reduces atherosclerosis progression in homozygous knockout low-density lipoprotein receptor mice. Nutr Res 2012; 32: 684–693.

153.

Cai

Kurita-Ochiai

Hashizume

et al.

Green tea epigallocatechin-3-gallate attenuates Porphyromonas gingivalis-induced atherosclerosis. Pathog Dis 2013; 67: 76–83.

154.

Yin

Huang

et al.

EGCG attenuates atherosclerosis through the Jagged-1/Notch pathway. Int J Mol Med 2016; 37: 398–406.

155.

You

Duan

Liu

et al.

Anti-atherosclerotic function of Astragali Radix extract: downregulation of adhesion molecules in vitro and in vivo. BMC Complement Altern Med 2012; 12: 54.

156.

Wang

Zhuang

Tian

et al.

Study of the effects of total flavonoids of Astragalus on atherosclerosis formation and potential mechanisms. Oxid Med Cell Longev 2012; 2012: 282383.

157.

Qin

Liu

Lin

. Effects of Astragaloside IV on the SDF-1/CXCR4 expression in atherosclerosis of apoE(-/-) mice induced by hyperlipaemia. Evid Based Complement Alternat Med 2015; 2015: 385154.

158.

Akiba

Kawauchi

Oka

et al.

Inhibitory effect of the leaf extract of Ginkgo Biloba L. on oxidative stress-induced platelet aggregation. Biochem Mol Biol Int 1998; 46: 1243–1248.

159.

Kudolo

Dorsey

Blodgett

. Effect of the ingestion of Ginkgo biloba extract on platelet aggregation and urinary prostanoid excretion in healthy and Type 2 diabetic subjects. Thromb Res 2002; 108: 151–160.

160.

Fei

Wang

Yang

et al.

Salvia miltiorrhiza Bunge (Danshen) extract attenuates permanent cerebral ischemia through inhibiting platelet activation in rats. J Ethnopharmacol 2017; 207: 57–66.

161.

Park

Lee

Yang

et al.

15,16-dihydrotanshinone I, a major component from Salvia miltiorrhiza Bunge (Dansham), inhibits rabbit platelet aggregation by suppressing intracellular calcium mobilization. Arch Pharm Res 2008; 31: 47–53.

162.

Huang

Zeng

Zhu

et al.

Salvianolic acid A inhibits platelet activation and arterial thrombosis via inhibition of phosphoinositide 3-kinase. J Thromb Haemost 2010; 8: 1383–1393.

163.

Yao

Liu

et al.

Interaction of salvianolic acids and notoginsengnosides in inhibition of ADP-induced platelet aggregation. Am J Chin Med 2008; 36: 313–328.

164.

Zhao

Wong

et al.

Inhibition of shear-induced platelet aggregation in rat by tetramethylpyrazine and salvianolic acid B. Clin Hemorheol Microcirc 2004; 31: 97–103.

165.

Zhao

Pan

et al.

Salvianolic acid B inhibits platelet adhesion under conditions of flow by a mechanism involving the collagen receptor alpha2 beta1. Thromb Res 2008; 123: 298–305.

166.

Ndagijimana

Wang

Pan

et al.

A review on indole alkaloids isolated from Uncaria rhynchophylla and their pharmacological studies. Fitoterapia 2013; 86: 35–47.

167.

Jin

Chen

et al.

Effects of rhynchophylline on platelet aggregation and experimental thrombosis (in Chinese). Yao Xue Xue Bao 1991; 26: 246–249.

168.

Shi

Huang

et al.

Effects of rhynchophylline on motor activity of mice and serotonin and dopamine in rat brain. Acta Pharmacol Sin 1993; 14: 114–147.

169.

Zhang

Meng

Zhang

et al.

Effect of six steroidal saponins isolated from anemarrhenae rhizoma on platelet aggregation and hemolysis in human blood. Clin Chim Acta 1999; 289: 79–88.

170.

Qiu

et al.

Antiplatelet and antithrombotic activities of timosaponin B-II, an extract of Anemarrhena asphodeloides. Clin Exp Pharmacol Physiol 2011; 38: 430–434.

171.

Lau

Toh

Chua

et al.

Antiplatelet and anticoagulant effects of Panax notoginseng: comparison of raw and steamed Panax notoginseng with Panax ginseng and Panax quinquefolium. J Ethnopharmacol 2009; 125: 380–386.

172.

Yao

Liu

et al.

Interaction of salvianolic acids and notoginsengnosides in inhibition of ADP-induced platelet aggregation. Am J Chin Med 2008; 36: 313–328.

173.

Shen

Zhang

et al.

Panax notoginseng saponins reduce high-risk factors for thrombosis through peroxisome proliferator-activated receptor-γ pathway. Biomed Pharmacother 2017; 96: 1163–1169.

174.

Chen

Salwinski

Lee

. Extracts of Ginkgo biloba and ginsenosides exert cerebral vasorelaxation via anitric oxide pathway. Clin Exp Pharmacol Physiol 1997; 24: 958–959.

175.

Bayar

Erdem

Ozturk

. The effect of EGb-761 on morphologic vasospasm in canine basilar artery after subarachnoid hemorrhage. J Cardiovasc Pharmacol 2003; 42: 395–402.

176.

Abdel-Zaher

Farghaly

HSM

El-Refaiy

AEM

et al.

Protective effect of the standardized extract of ginkgo biloba (EGb761) against hypertension with hypercholesterolemia-induced renal injury in rats: Insights in the underlying mechanisms. Biomed Pharmacother 2017; 95: 944–955.

177.

Tang

Wang

Chen

et al.

Cardiovascular protection with danshensu in spontaneously hypertensive rats. Biol Pharm Bull 2011; 34: 1596–1601.

178.

Wang

Bao

et al.

Tanshinone IIA prevents cardiac remodeling through attenuating NAD(P)H oxidase-derived reactive oxygen species production in hypertensive rats. Pharmazie 2011; 66: 517–524.

179.

Kim

Sanchez

Duran

et al.

Endothelial nitric oxide synthase is a molecular vascular target for the Chinese herb Danshen in hypertension. Am J Physiol Heart Circ Physiol 2007; 292: 2131–2137.

180.

Xie

Wang

Song

et al.

Advances in the pharmacological effects of Rhynchophylline on cardiovascular system (in Chinese). Science & Technology Vision 2017; 1: 65–66.

181.

Kuramochi

Chu

Suga

. Gou-teng (from Uncaria rhynchophylla Miquel)-induced endothelium-dependent and -independent relaxations in the isolated rat aorta. Life Sci 1994; 54: 2061–2069.

182.

Yang

Zhu

et al.

Protective effects on vascular endothelial cell in N'-nitro-L-arginine (L-NNA)-induced hypertensive rats from the combination of effective components of Uncaria rhynchophylla and Semen Raphani. Biosci Trends 2015; 9: 237–244.

183.

Jiang

Yang

et al.

Enhanced protective effect of the combination of Uncaria and Semen Raphani on vascular endothelium in spontaneously hypertensive rats. Evid Based Complement Alternat Med 2015; 2015: 358352.

184.

Ndagijimana

Wang

Pan

et al.

A review on indole alkaloids isolated from Uncaria rhynchophylla and their pharmacological studies. Fitoterapia 2013; 86: 35–47.

185.

Kim

Rhyu

. Synergistic vasorelaxant and antihypertensive effects of Ligusticum wallichii and Angelica gigas. J Ethnopharmacol 2010; 130: 545–551.

186.

Chang

Chen

Lin

et al.

Effects of tetramethylpyrazine on portal hypertensive rats. J Pharm Pharmacol 1998; 50: 881–884.

187.

Tang

Zhou

Yao

et al.

Protective effect of Ginkgo biloba leaves extract, EGb761, on myocardium injury in ischemia reperfusion rats via regulation of TLR-4/NF-κB signaling pathway. Oncotarget 2017; 8: 86671–86680.

188.

DeFeudis

. Effects of Ginkgo biloba extract (EGb 761) on gene expression: possible relevance to neurological disorders and age-associated cognitive impairment. Drug Dev Res 2002; 57: 214–235.

189.

Akdere

Tastekin

Mericliler

et al.

The protective effects of Ginkgo biloba EGb761 extract against renal ischemia-reperfusion injury in rats. Eur Rev Med Pharmacol Sci 2014; 18: 2936–2941.

190.

Wang

Pei

et al.

Protective effect of a standardized Ginkgo extract (ginaton) on renal ischemia/reperfusion injury via suppressing the activation of JNK signal pathway. Phytomedicine 2008; 15: 923–931.

191.

Zhao

Jiang

Zhao

et al.

Scavenging effects of salvia miltiorrhiza on free radicals and its protection for myocardial mitochondrial membranes from ischemia-reperfusion injury. Biochem Mol Biol Int 1996; 38: 1171–1182.

192.

Xia

Yang

Fok

et al.

Partial neuroprotective effect of pretreatment with tanshinone IIA on neonatal hypoxia-ischemia brain damage. Pediatr Res 2005; 58: 784–790.

193.

Zhou

Jiang

Zhao

et al.

Sodium tanshinone IIA sulfonate mediates electron transfer reaction in rat heart mitochondria. Biochem Pharmacol 2003; 65: 51–57.

194.

Kang

Kim

et al.

Anti-neuroinflammatory effects of Uncaria sinensis in LPS-stimulated BV2 microglia cells and focal cerebral ischemic mice. Am J Chin Med 2015; 43: 1099–1115.

195.

Sun

Sui

. Effects of combined use of total alkaloids of Uncaria rhynchophylla and Coryadlis ambailismigo on cerebral ischemia-reperfusion injury in rats (in Chinese). Zhongguo Zhong Xi Yi Jie He Za Zhi 2007; 27: 1007–1009.

196.

Qiao

Liu

. Effect of Ligusticum wallichii aqueous extract on oxidative injury and immunity activity in myocardial ischemic reperfusion rats. Int J Mol Sci 2011; 12: 1991–2006.

197.

Chen

Hsiao

Hwang

et al.

Tetramethylpyrazine induces heme oxygenase-1 expression and attenuates myocardial ischemia/reperfusion injury in rats. J Biomed Sci 2006; 13: 731–740.

198.

Zhang

Teng

et al.

Ultrasound-enhanced protective effect of tetramethylpyrazine against cerebral ischemia/reperfusion injury. PLoS One 2014; 9: e113673.

199.

Liao

Kao

Chen

et al.

Tetramethylpyrazine reduces ischemic brain injury in rats. Neurosci Lett 2004; 372: 40–45.

200.

Hyun

et al.

Effects of Anemarrhena asphodeloides on focal ischemic brain injury induced by middle cerebral artery occlusion in rats. Biol Pharm Bull 2007; 30: 38–43.