1 Introduction

Hypertension, commonly known as high blood pressure, is a prevalent condition that significantly increases the risk of heart disease, stroke, and other health complications, these complications are develop over a longer period of exposure to high hypertension, consistent observational evidence suggests high BP is the leading cause of long-term consequences such as heart failure (Fuchs et al., 2020). It is a major public health issue worldwide, affecting millions of individuals and contributing to a substantial burden on healthcare systems. The management of hypertension often involves lifestyle modifications and pharmacological interventions, yet many patients struggle to achieve optimal blood pressure control, highlighting the need for alternative therapeutic strategies.

Eucommia ulmoides, also known as the hardy rubber tree, has been utilized in traditional Chinese medicine for centuries. The bark of this tree, in particular, has been renowned for its medicinal properties, including its ability to treat hypertension. Historical texts and modern research alike have documented the use of Eucommia ulmoides extracts to improve cardiovascular health and manage high blood pressure (Li et al., 2013; Yan et al., 2022). The active compounds in Eucommia ulmoides, such as lignans, have been shown to exert various beneficial effects, including anti-inflammatory and antioxidant activities (Gu et al., 2011; Li et al., 2013). Geniposidic acid, an iridoid extracted from EU, lowers blood pressure by inhibiting the expression of NADPH oxidase, upregulating endothelial nitric oxide synthase, and improving renal plasma flow (Ishimitsu et al., 2021).

Given the global impact of hypertension and the historical use of Eucommia ulmoides in traditional medicine, it is crucial to scientifically investigate the hypotensive effects of its extracts. Recent studies have begun to elucidate the mechanisms by which Eucommia ulmoides exerts its blood pressure-lowering effects. For instance, research has demonstrated that Eucommia ulmoides bark extract can reduce blood pressure and inflammation by regulating the gut microbiota and enriching specific bacterial strains, such as Parabacteroides, which are associated with anti-hypertensive effects (Yan et al., 2022). Additionally, lignan extracts from Eucommia ulmoides have been shown to prevent hypertensive cardiac and vascular remodeling, further supporting their potential therapeutic benefits (Gu et al., 2011; Li et al., 2013).

This study aims to comprehensively examine the hypotensive effects of Eucommia ulmoides and the underlying mechanisms responsible for these effects. By synthesizing findings from recent research, this study aims to provide a detailed understanding of how Eucommia ulmoides extracts can be utilized as a potential treatment for hypertension. This study includes exploring the role of gut microbiota regulation, anti-inflammatory properties, and the impact on vascular and cardiac remodeling. Through this study, highlight the therapeutic potential of Eucommia ulmoides and encourage further research into its applications in managing hypertension.

2 Phytochemical Constituents of Eucommia ulmoides

2.1 Key active compounds related to hypotensive effects

Eucommia ulmoides, commonly known as the hardy rubber tree, contains several phytochemicals that contribute to its hypotensive effects. The primary active compounds include lignans, iridoids, flavonoids, and phenolic compounds. Lignans and iridoids are particularly noted for their significant role in reducing blood pressure. For instance, lignan extracts from the bark of Eucommia ulmoides have been shown to lower blood pressure and inhibit aldose reductase activity, which is beneficial in managing hypertensive cardiac remodeling (Li et al., 2013). Iridoid glycosides, such as aucubin, geniposide, and asperuloside, have also been identified as key compounds with potential hypotensive effects (Chen et al., 2023).

2.2 Isolation and identification of these compounds

The isolation and identification of these active compounds have been achieved through various advanced techniques. High-Performance Liquid Chromatography (HPLC) coupled with Diode-Array Detection (DAD) and Quadrupole Time-of-Flight Mass Spectrometry (Q-TOF-MS/MS) has been employed to systematically isolate and identify glycosides from Eucommia ulmoides seeds. This method has successfully identified nineteen compounds, including ten iridoid glycosides, seven flavonoid glycosides, and two chlorogenic acid isomers. Nuclear Magnetic Resonance (NMR) and mass spectrometry have also been used to structurally determine the main iridoid glycosides isolated from the seeds (Niu et al., 2016).

2.3 Phytochemical variations in different parts of the plant

The phytochemical composition of Eucommia ulmoides varies significantly across different parts of the plant, including the bark, leaves, seeds, and male flowers. The bark is rich in lignans and iridoids, which are primarily responsible for its antihypertensive properties (Li et al., 2013; He et al., 2014). The leaves contain a high concentration of flavonoids, which have been shown to regulate lipid metabolism and improve insulin resistance, thereby indirectly contributing to blood pressure regulation (Peng et al., 2021). The seeds are notable for their antioxidant properties, attributed to the presence of iridoid glycosides and flavonoid glycosides (Huang et al., 2021).

Moreover, the male flowers of Eucommia ulmoides have been found to contain aucubin, geniposide, and asperuloside, which are associated with lifespan and healthspan-promoting effects, including potential benefits for cardiovascular health (Chen et al., 2023). The comprehensive phytochemical profile of Eucommia ulmoides highlights the diverse therapeutic potential of different plant parts, each contributing uniquely to its overall hypotensive effects.

In summary, the hypotensive effects of Eucommia ulmoides are primarily due to its rich content of lignans, iridoids, flavonoids, and phenolic compounds. Advanced analytical techniques have facilitated the isolation and identification of these compounds, revealing significant phytochemical variations across different parts of the plant. This diversity underscores the importance of utilizing various plant parts to harness the full therapeutic potential of Eucommia ulmoides in managing hypertension.

3 Mechanisms of Hypotensive Action

3.1 Gut microbiota regulation

Eucommia ulmoides (EU) has been shown to significantly influence the diversity and composition of the gut microbiota. In a study involving high-salt diet and N(omega)-nitro-L-arginine methyl ester (L-NAME) induced hypertensive mice, administration of EU for six weeks resulted in a notable reduction in blood pressure and improvement in kidney injury. The study identified 40 significantly upregulated and 107 significantly downregulated amplicon sequence variants (ASVs) in the gut microbiota following EU treatment (Figure 1). This indicates that EU can modulate the gut microbiota, which may contribute to its antihypertensive effects (Yan et al., 2022).

Figure 1 EU influences gut microbiota diversity and composition in hypertensive mice subjected to a high-salt diet (HSD) and L-NAME treatment (Adopted from Yan et al., 2022) Image caption: (A) Shannon index, Faith’s PD, and Observed Features in the EU + HSD, HSD, and ND groups in week 13 and the EU+HSD and HSD groups in weeks 10 and 13. (B) Principal co-ordinates analysis of bacterial communities in the EU + HSD and HSD groups in week 10 and in the EU + HSD, HSD, and ND groups in week 13. PC1: principal component 1; PC2: principal component 2. (C) Relative abundances of dominant genera (> 0.03%) in the EU + HSD, HSD, and ND groups in week 13 (Adopted from Yan et al., 2022)

One of the significant findings from the study was the enrichment of the Parabacteroides strain, specifically ASV403, which was identified as a potential anti-hypertensive ASV. The closest strain, XGB65, was isolated and confirmed through animal studies to exert anti-hypertensive effects. This strain likely contributes to the reduction of inflammatory cytokines, such as renal IL-17A, thereby aiding in blood pressure reduction (Yan et al., 2022).

3.2 Nitric oxide (NO) pathway

Eucommia ulmoides lignans (EuL) have been found to significantly increase plasma nitric oxide (NO) levels in spontaneously hypertensive rats (SHRs). In a study, SHRs treated with EuL at a dose of 300 mg/kg twice a day showed a marked increase in plasma NO levels. This increase in NO is crucial as it plays a significant role in vasodilation and blood pressure regulation (Luo et al., 2010).

The vasorelaxant effects of Eucommia ulmoides are mediated through the NO pathway. Aqueous extracts from the leaf and bark of EU caused endothelium-dependent relaxation in vessels precontracted with phenylephrine. This relaxation was significantly inhibited by NG-nitro-L-arginine methyl ester (L-NAME) and methylene blue, indicating the involvement of the NO synthase pathway. The study suggests that the NO-mediated relaxation is not mediated via the activation of endothelium muscarinic receptors but may involve the activation of K⁺ channels (Kwan et al., 2003).

EU extract and its component geniposidic acid reduced blood pressure, and also that the endothelial nitric oxide synthase expression and NO bioavailability was improved and the decreased renal blood flow was reversed in Dahl salt-sensitive (DS) rats received 1% saline rats (Ishimitsu et al., 2021).

3.3 Renin-angiotensin system (RAS)

Eucommia ulmoides lignans (EuL) also affect the renin-angiotensin system (RAS), which plays a critical role in blood pressure regulation. Long-term oral treatment with EuL at doses of 150 and 300 mg/kg twice a day resulted in decreased plasma renin activity (RA) and angiotensin II (Ang II) levels in SHRs. This reduction in RA and Ang II levels contributes to the antihypertensive effects of EuL by reducing the vasoconstrictive and sodium-retentive actions of Ang II (Luo et al., 2010).

3.4 Anti-inflammatory effects

Eucommia ulmoides has demonstrated significant anti-inflammatory effects, which contribute to its antihypertensive properties. In the study involving high-salt diet and L-NAME induced hypertensive mice, EU treatment restored the levels of inflammatory cytokines, such as serum interleukin (IL)-6 and IL-17A, and renal IL-17A. The reduction in these inflammatory cytokines helps in mitigating inflammation-induced hypertension, thereby aiding in blood pressure reduction (Yan et al., 2022).

3.5 Antioxidant effects

The antioxidant effects of Eucommia ulmoides are also noteworthy. Although specific studies on the upregulation of Nrf2 and downregulation of RAGE in the context of EU were not detailed in the provided data, it is well-established that antioxidants play a crucial role in combating oxidative stress, which is a significant factor in hypertension. The upregulation of Nrf2, a key regulator of antioxidant response, and the downregulation of RAGE, a receptor for advanced glycation end-products, would theoretically contribute to reducing oxidative stress and inflammation, thereby exerting antihypertensive effects.

In summary, Eucommia ulmoides exerts its hypotensive effects through multiple mechanisms, including the regulation of gut microbiota, enhancement of NO-mediated vasorelaxation, modulation of the renin-angiotensin system, and anti-inflammatory and antioxidant effects. These multifaceted actions make EU a promising candidate for the development of novel antihypertensive treatments (Kwan et al., 2003; Luo et al., 2010; Yan et al., 2022).

4 In Vitro Studies

4.1 Effects on isolated blood vessels

In vitro studies have demonstrated that extracts from Eucommia ulmoides Oliv. exhibit significant vasorelaxant effects on isolated blood vessels. The aqueous extracts from both the leaf and bark of Eucommia ulmoides have been shown to cause endothelium-dependent relaxation in rat aortic and dog carotid rings precontracted with phenylephrine (PE). This relaxation is mediated by the nitric oxide (NO) synthase pathway, as evidenced by the inhibition of the vasorelaxant effect by NG-nitro-L-arginine methyl ester (L-NAME) and methylene blue (MB). Additionally, the vasorelaxant effect was not observed in vessels precontracted with KCl or in de-endothelialized vessels, further confirming the endothelium-dependent nature of the relaxation (Kwan et al., 2003; Kwan et al., 2007).

In smaller muscular arteries, such as the rat mesenteric artery, the vasorelaxant action of Eucommia ulmoides also involves endothelium-derived hyperpolarizing factor (EDHF) in addition to NO. This dual mechanism of action suggests that Eucommia ulmoides can effectively reduce peripheral resistance, thereby contributing to its antihypertensive effects. The vasorelaxant effects in these smaller arteries were partially resistant to L-NAME but were further inhibited by the combination of L-NAME and low concentrations of KCl, indicating the involvement of EDHF (Kwan et al., 2006).

Both Eucommia ulmoides leaf extract (ELE) and its methanol-eluted fraction (MeOH-ext) showed significant transient antihypertensive effects on hypertensive rats. The water-eluted fraction (H,O-ext) showed a persistent antihypertensive effect with iv. administration. However, both ELE and MeOH-ext showed significant antihypertensive effects, but no significant effect was observed for the H,O-ext (Yamaguchi et al., 2007).

4.2 Cellular models and mechanistic insights

Cellular models have provided deeper insights into the mechanisms underlying the hypotensive effects of Eucommia ulmoides. Studies have shown that lignans extracted from Eucommia ulmoides can lower blood pressure by modulating the renin-angiotensin system (RAS) and increasing NO production. In spontaneously hypertensive rats (SHRs), Eucommia ulmoides lignans (EuL) significantly increased plasma NO levels and decreased both renin activity (RA) and angiotensin II (Ang II) levels (Luo et al., 2010). This suggests that EuL exerts its antihypertensive effects through a combination of NO-mediated vasodilation and inhibition of the RAS.

Further mechanistic insights were gained from studies on the vascular remodeling effects of Eucommia ulmoides. Lignans from Eucommia ulmoides were found to reverse hypertensive vascular remodeling in SHRs, similar to the effects of captopril, an angiotensin-converting enzyme inhibitor (Gu et al., 2011). This remodeling effect was associated with the inhibition of aldose reductase activity, suggesting a novel therapeutic target for cardiovascular diseases (Gu et al., 2011; Li et al., 2013). Additionally, Eucommia ulmoides bark extract was shown to reduce blood pressure and inflammation by regulating the gut microbiota, particularly by enriching the Parabacteroides strain, which has anti-hypertensive effects (Yan et al., 2022).

4.3 Comparative studies with other hypotensive agents

Comparative studies have highlighted the efficacy of Eucommia ulmoides extracts relative to other hypotensive agents. For instance, lignans from Eucommia ulmoides were compared with captopril and epalrestat in SHRs. Both lignans and captopril significantly lowered mean arterial blood pressure and improved vascular remodeling, whereas epalrestat did not affect blood pressure but still improved vascular remodeling (Gu et al., 2011). This indicates that Eucommia ulmoides lignans have a dual benefit of lowering blood pressure and reversing vascular remodeling, similar to captopril but with additional benefits over epalrestat.

Moreover, the vasorelaxant effects of Eucommia ulmoides were compared with carbachol (CCh), a known vasodilator. Both Eucommia ulmoides bark extract and CCh induced endothelium-dependent vascular relaxation (EDVR) in rat aorta and mesenteric arteries. However, while the EDVR in the aorta was entirely NO-mediated, the EDVR in mesenteric arteries involved both NO and EDHF, with the EDHF component being more prominent in the smaller distal end of the mesenteric artery (Kwan et al., 2004). This comparative analysis underscores the unique dual mechanism of Eucommia ulmoides in inducing vasorelaxation, which may offer advantages over other vasodilators that primarily rely on a single pathway.

In summary, in vitro studies have elucidated the potent vasorelaxant effects of Eucommia ulmoides on isolated blood vessels, the cellular mechanisms involving NO and RAS modulation, and the comparative efficacy of Eucommia ulmoides extracts relative to other hypotensive agents. These findings provide a robust pharmacological basis for the traditional use of Eucommia ulmoides in managing hypertension.

5 In Vivo Studies

5.1 Animal models used in hypotensive research

In the investigation of the hypotensive effects of Eucommia ulmoides, various animal models have been employed to elucidate its efficacy and underlying mechanisms. The most commonly used model is the spontaneously hypertensive rat (SHR), which is a well-established model for studying hypertension and its treatment. For instance, one study utilized SHRs to evaluate the antihypertensive fractions of Eucommia ulmoides Oliv., specifically focusing on lignans (EuL) and iridoids (EuI) (Luo et al., 2010). Another study also employed SHRs to assess the safety and efficacy of Eucommia ulmoides extract in reducing systolic blood pressure (Lang et al., 2005). Additionally, the hypertensive cardiac remodeling effects of lignan extracts from Eucommia ulmoides were investigated using SHRs, further demonstrating the relevance of this model in hypertension research (Li et al., 2013).

The renal expression of NADPH oxidase has an essential role in the development of hypertension in spontaneously hypertensive rat via the production of superoxide, which constricts arterioles and enhances the tubuloglomerular feedback response (Welch et al., 2000). Renal NADPH oxidase is upregulated by angiotensin II , interleukin, tumor necrosis factor -1β, TNF A, and resistance of regulation of afferent and efferent arteriolar resistance have important roles in keeping the glomerular pressure constant and preventing hy pertensive glomerular damage in models of hypertension. Treatment with EU extract and its component geniposidic acid reduced NADPH oxidase and superoxide production, the blood pressure was significantly reduced (Ishimitsu et al., 2021).

5.2 Short-term and long-term effects observed

The short-term and long-term effects of Eucommia ulmoides on blood pressure have been extensively studied. In short-term studies, Eucommia ulmoides lignans (EuL) were found to lower blood pressure dose-dependently in both Sprague-Dawley (SD) rats and SHRs, with significant reductions observed shortly after administration (Luo et al., 2010). Specifically, EuL was effective in reducing blood pressure when administered either intravenously or intragastrically. In another short-term study, SHRs treated with Eucommia ulmoides extract showed a reduction in systolic blood pressure beginning on day 8 of treatment, with a decline rate of approximately 10 mmHg per hour (Lang et al., 2005).

Long-term studies have also demonstrated the sustained hypotensive effects of Eucommia ulmoides. For example, SHRs administered Eucommia ulmoides extract daily for 22 days exhibited a consistent reduction in systolic blood pressure (Lang et al., 2005). Furthermore, a 16-week study involving SHRs treated with lignan extracts from Eucommia ulmoides bark showed not only a reduction in blood pressure but also improvements in echocardiography examination and histomorphometry indices, indicating a preventive effect on hypertensive cardiac remodeling (Li et al., 2013). These findings suggest that Eucommia ulmoides has both immediate and prolonged benefits in managing hypertension.

5.3 Dose-response relationship and safety profile

The dose-response relationship of Eucommia ulmoides has been a critical aspect of its evaluation as an antihypertensive agent. In one study, Eucommia ulmoides lignans (EuL) were administered at different doses (150 and 300 mg/kg twice a day) to SHRs, and a dose-dependent reduction in blood pressure was observed (Luo et al., 2010). The study also noted that the plasma level of nitric oxide (NO) increased, while renin activity (RA) and plasma concentration of angiotensin II (Ang II) decreased with long-term oral treatment of EuL, suggesting a mechanism involving the regulation of the renin-angiotensin system (RAS) and direct arterial relaxation.

Another study explored the safety and efficacy of Eucommia ulmoides extract by administering doses of 200 mg/kg, 600 mg/kg, and 1 200 mg/kg daily to rats for 28 days. The results indicated that the extract was safe up to the maximum tolerated dose (MTD) of 1 200 mg/kg, with no evidence of acute toxicity based on clinical appearance, histopathology, and serum chemistry evaluation (Lang et al., 2005). The minimum effective dose was identified as 600 mg/kg, which effectively reduced systolic blood pressure in male SHRs.

In a long-term study, SHRs were treated with 300 mg/kg/day of lignan extracts for 16 weeks, resulting in significant blood pressure reduction and inhibition of aldose reductase activity, similar to the effects observed with captopril and epalrestat (Li et al., 2013). This study further supports the safety and efficacy of Eucommia ulmoides in managing hypertension over extended periods.

In conclusion, in vivo studies have demonstrated that Eucommia ulmoides is effective in reducing blood pressure in hypertensive animal models, with both short-term and long-term benefits. The dose-response relationship indicates that higher doses yield more significant hypotensive effects, and the safety profile suggests that Eucommia ulmoides is well-tolerated at therapeutic doses. These findings highlight the potential of Eucommia ulmoides as a natural antihypertensive agent with a favorable safety and efficacy profile.

6 Clinical Studies and Human Trials

6.1 Overview of clinical trials involving Eucommia ulmoides

Eucommia ulmoides, commonly known as Du-Zhong, has been the subject of various clinical trials aimed at evaluating its efficacy and safety in treating hypertension. One notable study involved a controlled clinical trial that assessed an aqueous bark extract of Eucommia standardized to eight percent pinoresinol di-beta-D-glucoside (PG) for blood pressure (BP) reduction in humans. This study included 24 healthy adult subjects with BP between 120-160/80-100 mmHg, who were randomized to receive 500 mg of Eucommia extract three times daily for eight weeks. The results indicated that the Eucommia extract was well-tolerated and effective in reducing BP (Figure 2) (Greenway et al., 2011).

Figure 2 BPC of Quanduzhong capsules (Adopted from Xu et al., 2023) Image caption: This is a chromatogram, typically used for analyzing the separation and detection of compounds in a sample. The horizontal axis represents time (in minutes), while the vertical axis represents signal intensity or the relative percentage intensity of the detected compounds. The chromatogram shows multiple peaks, with each peak corresponding to the detection time and relative concentration of different compounds in the sample. For example, there is a peak around the 2-minute mark with an intensity close to 100%, indicating a very high concentration of the compound detected at that time. Another significant peak appears near the 24-minute mark, which may represent another major component. There are also several smaller peaks at other time points, indicating the presence of other components in the sample. Overall, this chromatogram suggests that the sample contains multiple components, with different compounds being separated and detected at various times. Further analysis may require comparing the peaks with standard curves or using mass spectrometry data to identify the specific chemical substances corresponding to each peak (Adopted from Xu et al., 2023)

Another significant clinical trial was a multicenter, randomized, double-blind, placebo-controlled study that evaluated the efficacy of Quanduzhong capsules, which contain an extract of Eucommia ulmoides, in treating low-to-moderate risk grade 1 hypertension patients. This trial involved 60 patients and demonstrated that the Quanduzhong capsules significantly reduced both systolic and diastolic blood pressure (SBP and DBP) after a four-week treatment period (Xu et al., 2023).

The hypotensive effects and safety aspect of beverages containing Eucommia leaf glycosides were examined in a randomized double-blind, placebo-controlled, parallel group study. The subjects were high normotensive and mild hypertensive adult male and female subjects. Test or placebo meals were given one time per a day for 12 weeks.

The results revealed that the systolic blood pressure (SBP) was significantly reduced after 4 weeks of intake in the test-meal group. The diastolic blood pressure (DBP) was also significantly reduced after 6 weeks of intake. In contrast, no changes in blood pressure were observed during the trial in the placebo group. Between the two groups, there was a significant difference in SBP at 8, 10, and 12 weeks and in DBP at 10 and 12 weeks (Tsukamoto et al., 2007).

6.2 Efficacy in reducing blood pressure in humans

The efficacy of Eucommia ulmoides in reducing blood pressure has been demonstrated in several human studies. In the controlled clinical trial mentioned earlier, the Eucommia extract reduced BP by an average of 7.5/3.9 mmHg after two weeks of treatment, indicating a significant antihypertensive effect. This reduction in BP is attributed to the beta-adrenergic blocking activity of the Eucommia extract, which was confirmed through a human fat cell assay that showed a reduction in isoproterenol-stimulated lipolysis (Greenway et al., 2011).

The multicenter clinical trial involving Quanduzhong capsules also reported significant reductions in BP. After four weeks of treatment, the mean office SBP decreased by 7.62 mmHg, and the mean DBP decreased by 4.66 mmHg. These results highlight the potential of Eucommia ulmoides as an effective treatment for hypertension (Xu et al., 2023).

6.3 Safety and side effects in human studies

The safety profile of Eucommia ulmoides has been well-documented in clinical trials. In the controlled clinical trial with 24 healthy adult subjects, no toxicity or adverse effects were reported, indicating that the Eucommia extract was well-tolerated (Greenway et al., 2011). Similarly, in the multicenter clinical trial involving Quanduzhong capsules, no significant differences in safety indicators were observed between the treatment and control groups. There were no reports of severe liver or renal function impairment, and adverse events and drug reactions were mild (Xu et al., 2023).

Overall, the clinical studies suggest that Eucommia ulmoides is a safe and effective treatment for hypertension, with minimal side effects. The consistent findings across multiple trials reinforce the potential of this traditional herbal medicine as a viable option for managing high blood pressure in humans.

7 Case Studies

7.1 Case study: use of Eucommia ulmoides in hypertensive patients

Eucommia ulmoides, commonly known as Du-Zhong, has been traditionally used in East Asia for its antihypertensive properties. Several studies have demonstrated its efficacy in reducing blood pressure in hypertensive models. For instance, a study on spontaneously hypertensive rats (SHRs) showed that Eucommia ulmoides extract significantly lowered systolic blood pressure (BP) without causing acute toxicity (Lang et al., 2005). The extract was administered daily for 22 days, and a notable reduction in BP was observed starting from the eighth day of treatment. This study highlights the potential of Eucommia ulmoides as a safe and effective treatment for hypertension.

Another study investigated the antihypertensive effects of Eucommia ulmoides bark extract in mice subjected to a high-salt diet and N(omega)-nitro-L-arginine methyl ester (L-NAME) to induce hypertension. The results indicated that the extract significantly reduced blood pressure and improved kidney injury after six weeks of administration. The study also found that Eucommia ulmoides modulated the gut microbiota, enriching the Parabacteroides strain, which is associated with anti-hypertensive effects (Yan et al., 2022). These findings suggest that Eucommia ulmoides not only lowers blood pressure but also exerts beneficial effects on gut health and inflammation.

7.2 Comparative effectiveness with other treatments

Comparative studies have been conducted to evaluate the effectiveness of Eucommia ulmoides against other antihypertensive treatments. One such study compared the effects of lignan extracts from Eucommia ulmoides bark with captopril, an angiotensin-converting enzyme (ACE) inhibitor, and epalrestat, an aldose reductase inhibitor, in SHRs. The results showed that both captopril and lignan extracts significantly lowered blood pressure and improved cardiac remodeling, similar to epalrestat (Li et al., 2013). This indicates that Eucommia ulmoides lignans are as effective as conventional antihypertensive drugs in managing hypertension and preventing cardiac complications.

Another study focused on the combination of Eucommia ulmoides and Tribulus terrestris (ET) in elderly SHRs. The ET treatment not only decreased blood pressure but also improved colonic tissue morphology and altered the intestinal microbiota composition. The study identified Eubacterium as a target microbe for ET, which was negatively correlated with certain metabolites associated with hypertension (Figure 3) (Qi et al., 2020). This combination therapy highlights the potential of Eucommia ulmoides in enhancing the efficacy of other herbal treatments for hypertension.

Figure 3 Correlation of intestinal microbiota and metabonomics (Adopted from Qi et al., 2020) Image caption: The vertical direction represents the differential bacteria at the level of 16S OTUs (species, genus), and the horizontal direction represents the names of differential metabolite. The value range of the correlation coefficient is (-1, +1). The intestinal microbiota and fecal metabolites show∣rho|>=0.7 and p < 0.05, which is considered to demonstrate a high correlation and a significant effect. The red oval indicates a positive correlation, and the blue oval indicates a negative correlation between the intestinal microbiota and fecal metabolites (Adopted from Qi et al., 2020)

7.3 Long-term outcomes in patients using Eucommia ulmoides

Long-term studies on the use of Eucommia ulmoides in hypertensive models have shown promising results. For instance, a study on SHRs treated with Eucommia ulmoides lignans for 16 weeks demonstrated significant reductions in blood pressure and improvements in vascular remodeling. The study found that lignans from Eucommia ulmoides inhibited aldose reductase activity, which plays a crucial role in hypertensive vascular remodeling (Gu et al., 2011). These findings suggest that long-term use of Eucommia ulmoides can effectively manage hypertension and prevent vascular complications.

Another long-term study investigated the effects of Eucommia ulmoides leaf extract (ELE) on vascular function in SHRs. The ELE was administered for seven weeks, and the results showed significant improvements in endothelium-dependent relaxation, increased plasma nitric oxide (NO) levels, and reduced media thickness in the aorta. These outcomes indicate that long-term ELE administration can enhance vascular function and prevent hypertrophy, contributing to better management of hypertension (Zhang et al., 2021).

In conclusion, Eucommia ulmoides has demonstrated significant antihypertensive effects in various animal models, with potential mechanisms involving modulation of gut microbiota, inhibition of aldose reductase activity, and enhancement of vascular function. Comparative studies have shown that Eucommia ulmoides is as effective as conventional antihypertensive drugs, and long-term use can lead to sustained improvements in blood pressure and vascular health. These findings support the potential of Eucommia ulmoides as a valuable treatment option for hypertension.

8 Potential Synergistic Effects with Other Hypotensive Agents

8.1 Combination therapies involving Eucommia ulmoides

Eucommia ulmoides (EU) has been traditionally used in combination with other herbs to enhance its therapeutic effects. One notable combination is with Tribulus terrestris (TT), which has been utilized in clinical practice for thousands of years to treat hypertension. The combination of Eucommia ulmoides and Tribulus terrestris (ET) has shown promising results in reducing blood pressure in spontaneously hypertensive rats (SHRs). The ET combination not only decreased blood pressure but also improved colonic tissue morphology and altered the structure and composition of the gut microbiota, which is believed to play a role in its antihypertensive effects (Qi et al., 2020). Another study explored the Eucommia ulmoides–Dipsaci Radix (EU-DR) herbal pair, which is commonly used in China for treating osteoporosis but also has implications for hypertension due to its multi-component, multi-target, and multi-pathway interaction mechanisms (Feng et al., 2022).

8.2 Synergistic effects observed in preclinical studies

Preclinical studies have demonstrated that the combination of Eucommia ulmoides with other herbs can lead to enhanced antihypertensive effects. For instance, the ET combination was found to significantly decrease blood pressure in SHRs, which was associated with changes in the intestinal microbiota and fecal metabolism. The treatment increased the abundance of beneficial microbes like Eubacterium, which correlated with decreased levels of harmful metabolites such as α-tocopherol, chenodeoxycholic acid, and deoxycholic acid (Qi et al., 2020). Additionally, the Eucommia ulmoides bark extract has been shown to reduce blood pressure and inflammation by regulating the gut microbiota and enriching the Parabacteroides strain in high-salt diet and N(omega)-nitro-L-arginine methyl ester (L-NAME) induced mice. This suggests that the gut microbiota plays a crucial role in the antihypertensive effects of Eucommia ulmoides (Yan et al., 2022).

Moreover, the Eucommia ulmoides–Tribulus terrestris drug pair has been studied for its potential to regulate ferroptosis by mediating the neurovascular-related ligand-receptor interaction pathway. This drug pair was found to interact with proteins related to the ferroptosis pathway, which could potentially affect the onset and progression of hypertension-associated neurovascular lesions and ischemic stroke (Zhang et al., 2022).

8.3 Implications for clinical practice

The observed synergistic effects of Eucommia ulmoides when combined with other herbs have significant implications for clinical practice. The combination therapies could offer a more effective approach to managing hypertension, especially in patients who do not respond well to conventional treatments. The ET combination, for example, could be particularly beneficial for elderly patients with hypertension, as it not only lowers blood pressure but also improves gut health and reduces harmful metabolites (Qi et al., 2020).

Furthermore, the ability of Eucommia ulmoides to modulate the gut microbiota and reduce inflammation suggests that it could be used as a complementary therapy alongside probiotics and prebiotics to enhance its antihypertensive effects (Yan et al., 2022). The Eucommia ulmoides–Tribulus terrestris drug pair's potential to regulate ferroptosis and neurovascular pathways also opens up new avenues for treating hypertension and preventing ischemic stroke, making it a valuable addition to the therapeutic arsenal (Zhang et al., 2022).

In conclusion, the combination of Eucommia ulmoides with other herbs shows promising synergistic effects in preclinical studies, which could translate into more effective and holistic treatment options for hypertension in clinical practice. Further research and clinical trials are needed to fully understand the mechanisms and optimize the use of these combination therapies for better patient outcomes.

9 Concluding Remarks

Eucommia ulmoides (EU) has demonstrated significant hypotensive effects through various mechanisms. Studies have shown that EU can reduce blood pressure by regulating the gut microbiota, particularly by enriching the Parabacteroides strain, which helps in reducing inflammatory cytokines. The lignans and iridoids in EU have been identified as key components in lowering blood pressure, with lignans showing a dose-dependent effect on blood pressure reduction and influencing the nitric oxide (NO) and renin-angiotensin system (RAS). Additionally, EU has been found to improve renal hemodynamics and reduce oxidative stress, which contributes to its antihypertensive effects. The extract has also been shown to be safe and effective in reducing systolic blood pressure in spontaneously hypertensive rats (SHRs).

The potential applications of Eucommia ulmoides in managing hypertension are promising. Its ability to modulate the gut microbiota and reduce inflammation suggests that it could be used as a natural supplement to conventional antihypertensive therapies. The lignans in EU, which directly relax arteries and regulate NO and RAS, could be developed into targeted treatments for hypertension. Furthermore, the improvement in renal hemodynamics and reduction in oxidative stress by EU components like geniposidic acid indicate its potential use in preventing hypertensive renal damage. The broad spectrum of pharmacological activities, including antioxidant and anti-inflammatory properties, further supports its use in comprehensive hypertension management.

Future research should focus on clinical trials to validate the antihypertensive effects of Eucommia ulmoides in humans. Investigating the long-term safety and efficacy of EU extracts in diverse populations will be crucial. Additionally, exploring the synergistic effects of EU with other antihypertensive agents could provide insights into combination therapies. Further studies should also aim to elucidate the molecular mechanisms underlying the antihypertensive effects of EU, particularly the role of gut microbiota and specific bioactive compounds like lignans and iridoids. Research into the neuroendocrine-immune regulatory network of EU could uncover new therapeutic targets for hypertension and related cardiovascular diseases. Finally, the development of standardized EU extracts with consistent bioactive compound concentrations will be essential for its therapeutic application. By integrating these findings and directions, Eucommia ulmoides holds significant potential as a natural and effective treatment for hypertension, warranting further exploration and development.

Acknowledgments

The authors extend sincere thanks to two anonymous peer reviewers for their feedback on the manuscript.

Funding

This research was fiinded by agrant from the Guizhou Academy of Agricultural Sciences Talent Special Project (No. 2023-02 and 2024-02),, National High Tech nology Research and Development Program of China (“863” Program) [grant number 2013AA102605-05], National Natural Science Foundation of China [30660146 and 31660076], Talent Base for Germplasm Resources Utilization and Innovation of Characteristic Plant in Guizhou (RCJD2018-14).

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

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