Mechanistic study on vasodilatory and antihypertensive effects of hesperetin: ex vivo and in vivo approaches.

Hesperetin is one of the prominent flavonoids found in citrus fruit. Several research studies have reported that hesperetin can promote vasodilation in vascular tissue by increasing the level of nitric oxide and cyclic nucleotides. However, these may not be the only pathway for hesperetin to exert its vasodilatory effect. In addition to vasodilation, hesperetin has been found to carry an antihypertensive effect through intraperitoneal injection, although no study has comprehensively investigated the antihypertensive effect of hesperetin through oral administration. Therefore, this study aimed to determine the possible mechanism pathways involved in hesperetin-induced vasodilation and investigated its antihypertensive effects on hypertensive rats' model via oral administration. The ex vivo experimental findings showed that the NO/sGC/cGMP signalling pathway was involved in hesperetin-mediated vasodilation. Moreover, hesperetin activated the AC/cAMP/PKA pathway through PGI2 and activated the ß2-adrenergic receptor. Hesperetin can act as a voltage-gated potassium channel (KV) and ATP-sensitive potassium channel (KATP) opener. The intracellular calcium in vascular smooth muscle was reduced by hesperetin through blocking the voltage-operated calcium channels (VOCC) and inositol triphosphate receptor (IP3R). In the in vivo assessment, hesperetin shows a significant decrease in Spontaneously Hypertensive rats' blood pressure following 21 days of oral treatment. The sub-chronic toxicity assessment demonstrated that hesperetin exhibited no deleterious effects on the body weights, clinical biochemistry and haematological profile of Sprague-Dawley rats. This study implies that hesperetin holds promise as a potential medication for hypertension treatment, devoid of undesirable side effects.

Discrimination of Dioscorea species (Chinese yam) using FT-IR integrated with chemometric approach.

Dioscorea oppositifolia is an important crop and functional food. D. oppositifolia tuber is often adulterated with D. persimilis, D. alata, and D. fordii tuber in the commercial market. This study proposed an integrated Fourier transform infrared spectroscopy (FT-IR) with chemometric approach to differentiate these four Dioscorea species. A total of 107 Dioscorea spp. tuber samples were collected from different locations in China. Principal Component Analysis (PCA), PCA-Class, and Orthogonal Partial Least Square Discriminant Analysis (OPLS-DA) were utilised to classify the FT-IR spectra. In this PCA is unable to differentiate the Dioscorea spp. tuber effectively. However, PCA-Class and OPLS-DA can distinguish spp. these 4 species Dioscorea tuber with high accuracy, sensitivity, and specificity. Additionally, the RMSEE, RMSEP and RMSECV values for OPLS-DA model were low, showing that it is a good model. The combination of FT-IR with the PCA-Class and OPLS-DA is practical in discriminating Dioscorea spp. tubers.

Evaluation of vasodilatory effect and antihypertensive effect of chrysin through in vitro and sub-chronic in vivo study.

Chrysin, a bioflavonoid belonging to the flavone, occurs naturally in plants such as the passionflower, honey and propolis. Few studies have demonstrated that chrysin can promote vasorelaxant activities in rats' aorta and mesenteric arteries. To date, no research has explored the signalling system routes that chrysin may utilise to produce its vasorelaxant action. Therefore, this study aimed to investigate the underlying mechanisms involved in chrysin-induced vasorelaxant in rats' aortic rings and assess the antihypertensive effect of chrysin in spontaneously hypertensive rats (SHRs). The findings revealed that chrysin utilised both endothelium-dependent and endothelium-independent mechanisms. The presence of L-NAME (endothelial NO synthase inhibitor), ODQ (sGC inhibitor), methylene blue (cGMP lowering agent), 4-AP (voltage-gated potassium channel inhibitor), atropine (muscarinic receptors inhibitor) and propranolol (ß-adrenergic receptors inhibitor) significantly reduced the chrysin's vasorelaxant action. Furthermore, chrysin can reduce intracellular Ca2+ levels by limiting the extracellular intake of Ca2+ through voltage-operated calcium channels and blocking the intracellular release of Ca2+ from the sarcoplasmic reticulum via the IP3 receptor. These indicate that chrysin-induced vasorelaxants involved NO/sGC/cGMP signalling cascade, muscarinic and ß-adrenergic receptors, also the potassium and calcium channels. Although chrysin had vasorelaxant effects in in vitro studies, the in vivo antihypertensive experiment discovered chrysin does not significantly reduce the blood pressure of SHRs following 21 days of oral treatment. This study proved that chrysin utilised multiple signalling pathways to produce its vasorelaxant effect in the thoracic aorta of rats; however, it had no antihypertensive effect on SHRs.

Application of FT-IR spectroscopy and chemometric technique for the identification of three different parts of Camellia nitidissima and discrimination of its authenticated product.

Camellia nitidissima C.W. Chi is a golden camellia recognized in Chinese herbology and widely used as tea and essential oil in Chinese communities. Due to its diverse pharmacological properties, it can be used to treat various diseases. However, unethical sellers adulterated the flower with other parts of Camellia nitidissima in their product. This study used an integrated tri-step infrared spectroscopy method and a chemometric approach to distinguish C. nitidissima's flowers, leaves, and seeds. The three different parts of C. nitidissima were well distinguished using Fourier transform infrared spectroscopy (FT-IR), second-derivative infrared (SD-IR) spectra, and two-dimensional correlation infrared (2D-IR) spectra. The FT-IR and SD-IR spectra of the samples were subjected to principal component analysis (PCA), PCA-class, and orthogonal partial least square discriminant analysis (OPLS-DA) for classification and discrimination studies. The three parts of C. nitidissima were well separated and discriminated by PCA and OPLS-DA. The PCA-class model's sensitivity, accuracy, and specificity were all >94%, indicating that PCA-class is the good model. In addition, the RMSEE, RMSEP, and RMSECV values for the OPLS-DA model were low, and the model's sensitivity, accuracy, and specificity were all 100%, showing that it is the excellent one. In addition, PCA-class and OPLS-DA obtained scores of 27/32 and 26/32, respectively, for detecting adulterated and other TCM reference flower samples from C. nitidissima. Combining an infrared spectroscopic method with a chemometric approach proved that it is possible to differentiate distinct sections of C. nitidissima and discriminate adulterated samples of C.nitidissima flower.

The predominance of endothelium-derived relaxing factors and beta-adrenergic receptor pathways in strong vasorelaxation induced by 4-hydroxybenzaldehyde in the rat aorta.

4-hydroxybenzaldehyde (4HB), known as ρ-hydroxybenzaldehyde, is commonly present in traditional Chinese medicine herb, most frequently used for hypertension treatment. This research aims to determine the potency of 4HB's vasorelaxant action. In the study, the vasodilation effect of 4HB was evaluated using in vitro isolated rat aortic rings assay. The aortic rings were pre-incubated with respective antagonists before being pre-contracted with phenylephrine (PE) and challenged with various concentrations of 4HB for mechanistic action studies. Rmax (maximal vasodilation) and pEC50 (negative logarithm of half-maximal effective concentration) values of each experiment were determined for comparison purposes. 4HB caused vasodilation on endothelium-intact aortic rings which pre-contracted with PE (pEC50 = 3.53 ± 0.05, Rmax = 100.95 ± 4.25%) or potassium chloride (pEC50 = 2.96 ± 0.13, Rmax = 72.13 ± 4.93%). The vasodilation effect of 4HB was significantly decreased in the absence of an endothelium (pEC50 = 2.21 ± 0.25, Rmax = 47.96 ± 4.16%). The atropine, 4-aminopyridine, Nω-nitro-L-arginine methyl ester, glibenclamide, and propranolol significantly reduced the vasorelaxation effect of 4HB. Besides that, 4HB blocked the voltage-operated calcium channel (VOCC) and regulated the intracellular Ca2+ release from the sarcoplasmic reticulum (SR) in the aortic ring. Thus, the results indicated that 4HB exerted its vasodilatory effect via cGMP and ß2 pathways, M3-dependent PLC/IP3 pathways, and potassium and calcium channels.

Vasorelaxant effect of 5,7,4'- Trihydroxyflavanone (Naringenin) via endothelium dependent, potassium and calcium channels in Sprague Dawley rats: Aortic ring model.

Naringenin is a naturally occurring flavanone (flavonoid) known to have bioactive effects on human health. It has been reported to show cardiovascular effects. This study aimed to investigate the possible vasorelaxant effect of naringenin and the mechanism behind it by using a Sprague Dawley rat aortic ring assay model. Naringenin caused significant vasorelaxation of endothelium-intact aortic rings precontracted with phenylephrine (pD2 = 4.27 ± 0.05; Rmax = 121.70 ± 4.04%) or potassium chloride (pD2 = 4.00 ± 0.04; Rmax = 103.40 ± 3.82%). The vasorelaxant effect decreased in the absence of an endothelium (pD2 = 3.34 ± 0.10; Rmax = 62.29 ± 2.73%). The mechanisms of the vasorelaxant effect of naringenin in the presence of antagonists were also investigated. Indomethacin, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, atropine, 4-aminopyridine, Nω-nitro-l-arginine methyl ester, glibenclamide and propranolol significantly reduced the relaxation stimulated by naringenin in the presence of endothelium. Besides that, the effect of naringenin on the voltage-operated calcium channel (VOCC) in the endothelium-intact aortic ring was studied, as was intracellular Ca2+ release from the sarcoplasmic reticulum (SR) in the endothelium-denuded aortic ring. The results showed that naringenin also significantly blocked the entry of Ca2+ via the VOCC, SERCA/SOCC and suppressed the release of Ca2+ from the SR. Thus, the vasorelaxant effect shown by naringenin mostly involve the COX pathway, the endothelium-dependent pathway via NO/sGC/prostaglandin, calcium and potassium channels.

Underlying mechanism of vasorelaxant effect exerted by 3,5,7,2',4'-pentahydroxyflavone in rats aortic ring.

Morin (3,5,7,2',4'-pentahydroxyflavone) is a yellow coloured natural flavonoid found in plants of the Moraceae family. This favonoid is easily sources from readily available fruits, vegetables and eve certain beverages. Among the sources that was identified, it is clear that morin is most abundantly found in almond, old fustic, Indian guava, and Osage orange. Multiple studies have suggested that morin has multiple therapeutic actions and possess potential to be a functional potent drug. Previous studies demonstrated that morin is capable of resolving deoxycorticosterone acetate-salt-induced hypertension and possess strong vasorelaxant properties. However, the exact mechanisms remains unknown. Therefore, this study is designed to investigate the in vitro mechanism of morin-induced vasorelaxant effects. The underlying mechanisms of morin's vasorelaxant activities were evaluated on thoracic aortic rings isolated from Sprague-Dawley rats. Results from the study demonstrated morin causing vasodilatory reaction in phenylephrine and potassium chloride pre-contracted endothelium-intact aortic rings with the effect being significantly affected in endothelium-denuded aortic rings. Pre-incubation of the aortic rings with ODQ (selective cGMP-independent sGC inhibitor), indomethacin (nonselective COX inhibitor), L-NAME (endothelial nitric oxide inhibitor), propranolol (ß2-adrenegic receptors blocker), and atropine (muscarinic receptors blocker) significantly reduced the vasorelaxant effect of morin. It was also found to be able to reduce the intracellular calcium level by blocking VOCC and calcium intake from the extracellular environment and the intracellular release of calcium from the sarcoplasmic reticulum. The present study showed that the vasorelaxant effect of morin potentially involves the NO/sGC, muscarinic receptors, ß2-adrenegic receptors, and calcium channels.

New flavonoid-based compound synthesis strategy for antihypertensive drug development.

Hypertension is one of the leading causes of mortality in relation to the cardiovascular conditions and easily the most overlooked and poorly managed disease in mankind. With well over 200 drugs available in the market globally, there is still an urgency to search for antihypertensive alternatives due to the subpar efficacy and unwarranted side effects of the current choices. Present studies reported over 250 types of plant-derived compounds were being investigated for potential pharmacological effects on the vasculature in the last 3 decades. There were numerous literatures that claimed various compounds exhibiting vasorelaxant properties to a certain extent with low numbers of these compounds being successfully adapted into the current medicinal practice for treatment of hypertension. The issue is the scarcity of reviews that summarizes the discovery of this field and the lack of thorough comparison of these compounds to identify which of these vasodilators should be the next face of hypertension management. Thus, this review is aiming towards identifying the relationship between a major class of plant-derived compounds, flavonoid's activity as a vasodilator with their signalling pathways and their structural characteristics according to their vasorelaxant properties. Interestingly, we found that both nitric oxide and voltage-operated calcium channels pathways, and two of the flavonoid's structural characteristics play crucial roles in eliciting strong vasorelaxant effects. We have faith that the insights of this review will serve as a reference for those researching similar topics in the future and potentially lead to the development of more promising antihypertensive alternative.

Vasorelaxant effect of 3,5,4'-trihydroxy-trans-stilbene (resveratrol) and its underlying mechanism.

Resveratrol is found in numerous plant-based foods and beverages and is known to have an impact on the cardiovascular system. The aim of this study was to investigate the vasorelaxant effect of resveratrol and its underlying mechanisms by employing an aortic ring assay model. Resveratrol caused relaxation of aortic rings that had been precontracted with phenylephrine in the presence of endothelium or with potassium chloride in endothelium-intact aortic rings. The vasorelaxant effect was decreased in the absence of an endothelium. The mechanisms underlying the vasorelaxant effect of resveratrol were determined through the addition of antagonists. In the presence of the endothelium, indomethacin (a nonselective cyclooxygenase inhibitor), methylene blue (cyclic guanosine monophosphate lowering agent), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, selective soluble guanylate cyclase inhibitor), Nω-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor), tetraethylammonium (TEA, nonselective calcium activator potassium channel blocker), 4-aminopyridine (4-AP, voltage-dependent K+ channel blocker), barium chloride (BaCl2, inwardly rectifying K+ channel blocker), glibenclamide (non-specific ATP-sensitive K+ channel blocker) and propranolol (ß-adrenergic receptor blocker) led to a significant reduction in the vasorelaxation effect induced by resveratrol. Resveratrol was also found to reduce Ca2+ release from the sarcoplasmic reticulum and block calcium channels. In conclusion, resveratrol targets multiple signalling pathways for exerting its vasorelaxant effects in the rat aortic ring model in both the presence and absence of endothelium.