International Journal of Clinical Case Reports 2024, Vol.14, No.5, 262-275 http://medscipublisher.com/index.php/ijccr 266 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 fromEucommia 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
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