α acid fraction from Hop extract exerts an endothelium-derived hyperpolarization vasorelaxant effect through TRPV4 employing the feedforward mechanism of PKCα.

Until now, the beneficial vascular properties of Hop reported in the literature have been mainly attributed to specific compound classes, such as tannins and phenolic acids. However, the potential vascular action of a Hop subfraction containing a high amount of α or ß acids remains completely understood. Therefore, this study aims to investigate the vascular effects of the entire Hop extract and to fraction the Hop extract to identify the main bioactive vascular compounds. A pressure myograph was used to perform vascular reactivity studies on mouse resistance arteries. Phytocomplex fractionation was performed on a semi-prep HPLC system and characterized by UHPLC-PDA-MS/MS coupled to mass spectrometry. Western blot analysis was performed to characterize the phosphorylation site enrolled. The entire Hop extract exerts a direct dose-dependent endothelial vascular action. The B1 subfraction, containing a high concentration of α acids, recapitulates the vascular effect of the crude extract. Its vasorelaxant action is mediated by the opening of Transient Receptor Potential Vanilloid type 4 (TRPV4), potentiated by PKCα, and subsequent involvement of endothelial small-conductance calcium-activated potassium channels (SKCa) and intermediate-conductance calcium-activated potassium channels (IKCa) that drives endothelium-dependent hyperpolarization (EDH) through heterocellular myoendothelial gap junctions (MEGJs). This is the first comprehensive investigation of the vascular function of Hop-derived α acids in resistance arteries. Overall, our data suggest that the B1 subfraction from Hop extracts, containing only α acids, has great potential to be translated into the useful armamentarium of natural bioactive compounds with cardiovascular benefits.

Bio-guided isolation of androsta-1,4-dien-3,16-dione as a vasodilator active principle from the inflorescence of Ravenala madagascariensis Sonn. (Strelitziaceae).

Androsta-1,4-dien-3,16-dione was isolated for the first time from the plant kingdom of the ethanolic extract of the Ravenala madagascariensis' inflorescence by the bio-guided method. Its structure was elucidated by NMR and MS spectroscopic data analysis. The vascular effects of ethanol extracts, fractions and androsta-1,4-dien-3,16-dione were assessed on the phenylephrine pre-contracted isolated rat aorta. The isolated compound exerted the most potent vaso-relaxing effect (EC50 = 109.32 ± 15.82 µM) than the ethanol extract and fractions. The pharmacological mechanism of its vaso-relaxing action was analysed on isolated rat aorta using free-endothelial vascular tissue, specific contracting reagents (CaCl2 and KCl), antagonist (propranolol), enzyme inhibitors (L-NAME, methylene blue) and channel blocker (glibenclamide). Its vaso-relaxing activity could be due, at least partly, to the non-specific inhibition of the calcic influx.

Definition of chemical markers for Hancornia speciosa Gomes by chemometric analysis based on the chemical composition of extracts, their vasorelaxant effect and α-glucosidase inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Hancornia speciosa Gomes (Apocynaceae) is a tree found in the Brazilian savannah, traditionally used to treat several diseases, including diabetes and hypertension. The anti-hypertensive activity of H. speciosa leaves (HSL) has been demonstrated in different models and is credited to the vasodilator effect and ACE (angiotensin-converting enzyme) inhibition. The hypoglycemic effect of HSL has been also reported. AIM OF THE STUDY: To establish correlations between the biological activities elicited by H. speciosa extracts and the contents of their major compounds, aiming to define chemical markers related to the potential antihypertensive and antidiabetic effects of the species. Additionally, it aimed to isolate and characterize the chemical structure of a marker related to the α-glucosidase inhibitory effect. MATERIALS AND METHODS: Extracts of a single batch of H. speciosa leaves were prepared by extraction with distinct solvents (ethanol/water in different proportions; methanol/ethyl acetate), employing percolation or static maceration as extraction techniques, at different time intervals. The contents of chlorogenic acid, rutin and FlavHS (a tri-O-glycoside of quercetin) were quantified by a developed and validated HPLC-PDA method. Bornesitol was determined by HPLC-PDA after derivatization with tosyl chloride, whereas total flavonoids were measured spectrophotometrically. Identification of other constituents in the extracts was performed by UPLC-DAD-ESI-MS/MS analysis. The vasorelaxant activity was assayed in rat aortic rings precontracted with phenylephrine, and α-glucosidase inhibition was tested in vitro. Principal component analysis (PCA) was employed to evaluate the contribution of each marker to the biological responses. Isolation of compound 1 was carried out by column chromatography and structure characterization was accomplished by NMR and UPLC-DAD-ESI-MS/MS analyses. RESULTS: The contents of the chemical markers (mean ± s.d. % w/w) varied significantly among the extracts, including total flavonoids (2.68 ± 0.14 to 5.28 ± 0.29), bornesitol (5.11 ± 0.26 to 7.75 ± 0.78), rutin (1.46 ± 0.06 to 1.97 ± 0.02), FlavHS (0.72 ± 0.05 to 0.94 ± 0.14) and chlorogenic acid (0.67 ± 0.09 to 0.91 ± 0.02). All extracts elicited vasorelaxant effect (pIC50 between 4.97 ± 0.22 to 6.48 ± 0.10) and α-glucosidase inhibition (pIC50 between 3.49 ± 0.21 to 4.03 ± 0.10). PCA disclosed positive correlations between the vasorelaxant effect and the contents of chlorogenic acid, rutin, total flavonoids, and FlavHS, whereas a negative correlation was found with bornesitol concentration. No significant correlation between α-glucosidase inhibition and the contents of the above-mentioned compounds was found. On the other hand, PCA carried out with the areas of the ten major peaks from the chromatograms disclosed positive correlations between a peak ascribed to co-eluted triterpenes and α-glucosidase inhibition. A triterpene was isolated and identified as 3-O-ß-(3'-R-hydroxy)-hexadecanoil-lupeol. CONCLUSION: According to PCA results, the vasorelaxant activity of H. speciosa extracts is related to flavonoids and chlorogenic acid, whereas the α-glucosidase inhibition is associated with lipophilic compounds, including esters of lupeol like 3-O-ß-(3'-R-hydroxy)-hexadecanoil-lupeol, described for the first time for the species. These compounds can be selected as chemical markers for the quality control of H. speciosa plant drug and derived extracts.

Aristolone in Nardostachys jatamansi DC. induces mesenteric vasodilation and ameliorates hypertension via activation of the KATP channel and PDK1-Akt-eNOS pathway.

BACKGROUND: Nardostachys jatamansi DC. is a common medicinal herb used to treat cardiovascular diseases, particularly hypertension. Previously, our lab characterized the chemical compounds of N. jatamansi. However, the bioactive compounds of N. jatamansi and their mechanisms of action on blood pressure and blood vessels are unknown. PURPOSE: The vasorelaxant effects of the methanolic extract (MeOH ext.) of the roots and rhizomes of N. jatamansi, its main compounds, and their underlying mode of action, were investigated. METHODS: The main compounds of N. jatamansi were isolated and identified using UHPLC-TOF MS. The antihypertensive effect of N. jatamansi extracts and (-)-aristolone were determined using spontaneously hypertensive rats. The extracts, fractions, and compounds were also evaluated for their vasorelaxant effects on U46619 contractile responses in isolated thoracic aortic and mesenteric arterial rings. The endothelial-dependent relaxation, as well as the regulatory pathways and targets of (-)-aristolone, were studied in-vitro and ex-vivo. Molecular docking and biophysical characterization (Surface plasmon resonance) studies were utilized to investigate the molecular interaction between (-)-aristolone and the target protein. RESULTS: MeOH ext. (200 mg/kg) reduces the systolic and diastolic blood pressure in spontaneously hypertensive rats. MeOH ext. and its ethyl acetate fraction (EtOAc Fr.), but not the H2O fraction, had a significant relaxing effect on the thoracic aorta. (-)-aristolone and kanshone H from EtOAc Fr. induced vasorelaxation of the thoracic aorta and mesenteric artery. In human umbilical vein endothelial cells, (-)-aristolone treatment upregulated phosphorylation of Akt (T308) and eNOS. Molecular docking and surface plasmon resonance experiments revealed an interaction between (-)-aristolone and phosphoinositide-dependent protein kinase 1 (PDK1), an upstream protein kinase that phosphorylates Akt at T308. Treatment with PDK1 inhibitor PHT-427 and eNOS inhibitor L-NAME consistently inhibited (-)-aristolone-induced vasorelaxation. In addition, KATP channel inhibitor glibenclamide dramatically inhibited the vasorelaxant effects of (-)-aristolone and kanshone H in the endothelium-denuded thoracic aorta. Finally, (-)-aristolone lowers hypertensive rats' systolic and diastolic blood pressure. CONCLUSIONS: The extracts of N. jatamansi promote vasorelaxation and alleviate hypertension. The essential chemicals responsible for producing vasorelaxation effects are (-)-aristolone and kanshone H, which activate the PDK1-Akt-eNOS-NO relaxing pathway and stimulate the opening of the KATP channel. These findings point to N. jatamansi and aristolone as possible antihypertensive agents.

Comparative evaluation of relaxant effects of three prangos species on mouse corpus cavernosum: Chemical characterization and the relaxant mechanisms of action of P. pabularia and (+)-oxypeucedanin.

ETHNOPHARMACOLOGICAL RELEVANCE: Erectile dysfunction (ED) is the most common form of sexual dysfunction which has been the topic of great interest through the history by all cultures. It is now among the most treated health problems in men of all ages that develop under the influence of lifestyle factors and some diseases. Plants are extensively used to cure sexual dysfunction for centuries. Roots of Prangos sp. have been used to improve sexual performance in Anatolian traditional medicine and are rich of coumarin, furanocoumarin and their derivatives. Scientific research is necessary to support and validate the ethno-traditional uses of these plants. AIM OF THE STUDY: The aim of this study is to investigate the effects of the root extracts of P. pabularia, P. uechtritzii and P. heyniae on erectile function and to isolate and identify the chemical compounds of the most active extract and reveal possible pharmacological mechanism of the major compound of the extract with the strongest relaxant effect in mouse corpus cavernosum (MCC). MATERIALS AND METHODS: The roots of plants were extracted with chloroform, n-hexane and methanol. The compounds were isolated from the extract by column chromatography and structures were identified by NMR and MS. The relaxant effects of extracts (10-7-10-4 g/mL), (+)-oxypeucedanin (10-7-10-4 M) and Na2S (10-7-3 × 10-3 M) were tested in MCC strips by DMT myograph. To investigate the mechanism, the synthesis inhibitors of aminooxyacetic acid (AOAA, 10-2 M) and nitro-L-arginine methyl ester (L-NAME, 10-4 M) were used, respectively. H2S formation was evaluated basal and L-cysteine (L-cyst)-stimulated conditions by H2S microsensor. RESULTS: All extracts relaxed MCC in a concentration dependent manner. The maximum relaxing effects were achieved with chloroform extracts. Chloroform extract of P. pabularia (Pp-CE) was more potent than the others. Pp-CE-induced relaxations were significantly decreased by AOAA and L-NAME. (+)-Oxypeucedanin, the major compound of Pp-CE, induced relaxant responses and this effect was inhibited by AOAA, but not L-NAME. The relaxation of (+)-oxypeucedanin was found to be similar in view of Emax to positive control H2S donor Na2S. (+)-Oxypeucedanin increased L-cyst-stimulated H2S formation. Augmentation of H2S synthesis with (+)-oxypeucedanin was inhibited by AOAA. CONCLUSIONS: Pp-CE has the strongest effect on relaxation of MCC and this result supports the traditional aphrodisiac use of P. pabularia root extract in Anatolia. The pharmacological mechanisms of Pp-CE to relax MCC involve NO and H2S formation. (+)-Oxypeucedanin could be responsible for the H2S-mediated relaxations of Pp-CE in MCC.

8-, 9-, and 11-Aryloxy Dimeric Aporphines and Their Pharmacological Activities.

Aporphines, a major group of aporphinoid alkaloids, exhibit interesting and diverse pharmacological activities. A set of dimeric aporphines with an aryloxy group at C8, C9, and C11 have been isolated from six genera and shown to elicit various biological activities such as antitumor, antimalarial, antimicrobial, antiplatelet aggregation, antifibrotic, immunosuppressive, and vasorelaxant properties. In this review, the nomenclature, chemical structures, botanical sources, pharmacological activities, and synthetic approaches of this set of dimeric alkaloids are presented.

Standardized root extract of Withania somnifera and Withanolide A exert moderate vasorelaxant effect in the rat aortic rings by enhancing nitric oxide generation.

ETHNO-PHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal, commonly known as Ashwagandha, belongs to the family Solanaceae. In Ayurveda, Ashwagandha has been defined as one of the most important herb and is considered to be the best adaptogen. It is also an excellent rejuvenator, a general health tonic and cure for various disorders such as cerebrovascular, insomnia, asthma, ulcers, etc. Steroidal lactones (Withanolides: Withanolide A, Withaferin A, Withanolide D, Withanone, etc) isolated from this plant, possess promising medicinal properties such as anti-inflammatory, immune-stimulatory etc. Standardized root extract of the plant NMITLI-118R (NM) was prepared at CSIR-CIMAP, and was investigated for various biological activities at CSIR-CDRI. Among the notable medicinal properties, NM exhibited excellent neuroprotective activity in the middle cerebral artery occlusion (MCAO) rat model. AIM OF THE STUDY: Endothelial dysfunction is the primary event in the cerebrovascular or cardiovascular disorders, present study was thus undertaken to evaluate vasoprotective potential of NM and its biomarker compound Withanolide A (WA) using rat aortic rings and EA.hy926 endothelial cells. MATERIAL AND METHODS: Transverse aortic rings of 10 weeks old Wistar rats were used to evaluate effect of NM and WA on the vasoreactivity. While, mechanism of NM and WA mediated vasorelaxant was investigated in Ea.hy926 cell line by measuring NO generation, nitrite content, Serine 1177 phosphorylation of eNOS, reduced/oxidized biopterin levels and expression of endothelial nitric oxide synthase (eNOS) mRNA and protein. RESULTS: Fingerprinting of NM using HPLC identified presence of WA in the extract. NM as well as WA exerted moderate vasorelaxant effect in the endothelium intact rat aortic rings which was lesser than acetylcholine (ACh). NM and WA augmented ACh induced relaxation in the rat aortic rings. NM and WA dependent vasorelaxation was blocked by N-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ), indicating role of NO/cGMP. Further Ea.hy926 cells treated with NM and WA showed accumulation of nitrite content, enhanced NO levels, eNOS expression and eNOS phosphorylation (Serine 1177). CONCLUSION: Altogether NM and WA dependent improvement in the NO availability seems to be mediated by the enhanced eNOS phosphorylation. WA, seems to be one of the active constituent of NM, and presence of other vasoactive substances cannot be ruled out. The data obtained imply that the vasorelaxant property of NM is beneficial for its neuroprotective potential.

Secondary Metabolites of Plants as Modulators of Endothelium Functions.

According to the World Health Organization, cardiovascular diseases are the main cause of death worldwide. They may be caused by various factors or combinations of factors. Frequently, endothelial dysfunction is involved in either development of the disorder or results from it. On the other hand, the endothelium may be disordered for other reasons, e.g., due to infection, such as COVID-19. The understanding of the role and significance of the endothelium in the body has changed significantly over time-from a simple physical barrier to a complex system encompassing local and systemic regulation of numerous processes in the body. Endothelium disorders may arise from impairment of one or more signaling pathways affecting dilator or constrictor activity, including nitric oxide-cyclic guanosine monophosphate activation, prostacyclin-cyclic adenosine monophosphate activation, phosphodiesterase inhibition, and potassium channel activation or intracellular calcium level inhibition. In this review, plants are summarized as sources of biologically active substances affecting the endothelium. This paper compares individual substances and mechanisms that are known to affect the endothelium, and which subsequently may cause the development of cardiovascular disorders.

Mammalian Arginase Inhibitory Activity of Methanolic Extracts and Isolated Compounds from Cyperus Species.

Polyphenolic enriched extracts from two species of Cyperus, Cyperus glomeratus and Cyperus thunbergii, possess mammalian arginase inhibitory capacities, with the percentage inhibition ranging from 80% to 95% at 100 µg/mL and 40% to 64% at 10 µg/mL. Phytochemical investigation of these species led to the isolation and identification of two new natural stilbene oligomers named thunbergin A-B (1-2), together with three other stilbenes, trans-resveratrol (3), trans-scirpusin A (4), trans-cyperusphenol A (6), and two flavonoids, aureusidin (5) and luteolin (7), which were isolated for the first time from C.thunbergii and C. glomeratus. Structures were established on the basis of the spectroscopic data from MS and NMR experiments. The arginase inhibitory activity of compounds 1-7 was evaluated through an in vitro arginase inhibitory assay using purified liver bovine arginase. As a result, five compounds (1, 4-7) showed significant inhibition of arginase, with IC50 values between 17.6 and 60.6 µM, in the range of those of the natural arginase inhibitor piceatannol (12.6 µM). In addition, methanolic extract from Cyperus thunbergii exhibited an endothelium and NO-dependent vasorelaxant effect on thoracic aortic rings from rats and improved endothelial dysfunction in an adjuvant-induced arthritis rat model.

Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator.

Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.

Vasorelaxant property of Plectranthus vettiveroides root essential oil and its possible mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Plectranthus vettiveroides (Jacob) N.P. Singh & B.D. Sharma is a traditional medicinal plant used in Siddha System of Medicine and its aromatic root is used to reduce the elevated blood pressure. AIM: The aim of the present study was to study vasorelaxant property of the root essential oil nanoemulsion (EON) of P. vettiveroides. METHODS: The EON was formulated to enhance the solubility and bioavailability and characterized. The preliminary screening was performed by treating the EON with aortic rings pre-contracted with phenylephrine (1 µM) and potassium chloride (80 mM). The role of K⁺ channels in EON induced vasorelaxation was investigated by pre-incubating the aortic rings with different K⁺ channel inhibitors namely, glibenclamide (a non-specific ATP sensitive K⁺ channel blocker, 10 µM), TEA (a Ca2⁺ activated non-selective K⁺ channel blocker, 10-2 M), 4-AP (a voltage-activated K⁺ channel blocker, 10-3 M) and barium chloride (inward rectifier K⁺ channel blocker, 1 mM). The involvement of extracellular Ca2+ was performed by adding cumulative dose of extracellular calcium in the presence and absence of EON and the concentration-response curve (CRC) obtained is compared. Similarly, the role of nitric oxide synthase, muscarinic and prostacyclin receptors on EON induced vasorelaxation were evaluated by pre-incubating the aortic rings with their inhibitors and the CRC obtained in the presence and absence of inhibitor were compared. RESULTS: The GC-MS and GC-FID analyses of the root essential oil revealed the presence of 62 volatile compounds. The EON exhibited significant vasorelaxant effect through nitric oxide-mediated pathway, G-protein coupled muscarinic (M3) receptor pathway, involvement of K+ channels (KATP, KIR, KCa), and blocking of the calcium influx by receptor-operated calcium channel. CONCLUSION: It is concluded that the root essential oil of P. vettiveroides is possessing marked vasorelaxant property. The multiple mechanisms of action of the essential oil of P. vettiveroides make it a potential source of antihypertensive drug.

Ajuga iva water extract antihypertensive effect on stroke-prone spontaneously hypertensive rats, vasorelaxant effects ex vivo and in vitro activity of fractions.

ETHNOPHARMACOLOGICAL RELEVANCE: Ajuga iva (L.) Schreb. (Labiatae) (AI) is used in folk medicine for a variety of ailments, including diabetes mellitus and hypertension. AIM OF THE STUDY: In this work, we aimed to investigate the antihypertensive and vasorelaxant effects of AI aqueous extract in stroke prone spontaneously hypertensive rats (SHR-SP). MATERIAL AND METHODS: Male SHR-SP rats were orally force-fed AI aqueous extract (500 mg/kg body weight) daily for one week. Systolic blood pressure and urine output were recorded in vivo by non-invasive methods. AI vasoactive effects on noradrenaline contractile response and acetylcholine-evoked relaxation were assessed ex vivo on aorta rings of treated and untreated SHR-SP rats. AI extract was then subjected to bio-guided fractionation using solvents of increasing polarity. For each fraction, in vitro vasorelaxation assay was performed on noradrenaline-precontracted aorta of Wistar rats, in the absence/presence of N-nitro-L-arginine (L-NNA). HPLC analysis of AI total extract, and the most in vitro active AI residual aqueous extract fraction (A1) was performed using naringin, naringenin, apigenin, apigenin 7-O-glucoside as marker compounds. RESULTS: AI aqueous extract (500 mg/kg) significantly (P < 0.05) decreased systolic blood pressure (SBP) in SHR-SP rats, while not affecting the urine output. In ex vivo experiments, the total extract decreased contractile response to noradrenaline of aortic rings isolated from AI-treated SHR-SP rats with or without addition of N-nitro-L-arginine, but endothelium dependent relaxation evoked by acetylcholine in noradrenaline-contracted aortic rings was not affected by the extract treatment. In vitro experiments on AI aqueous extract fractions showed that its polar fraction was the only one affecting in vitro noradrenaline induced contractions, but only in an endothelium dependent manner. This fraction was shown by HPLC-UV to contain flavonoid glycosides among other polar compounds whose activity and mode of action may be modified in vivo by metabolization. CONCLUSION: These results support the use of AI as antihypertensive treatment in folk medicine. The systolic blood pressure decrease may be attributed at least in part to vasorelaxant glycosylated/polar phenolic compounds as flavonoids and/or their metabolites.

Pharmacological Justification for the Medicinal Use of Plumeria rubra Linn. in Cardiovascular Disorders.

Plumeria rubra (L.) is a traditional folkloric medicinal herb used to treat cardiovascular disorders. The present investigation was methodically planned to investigate the pharmacological foundations for the therapeutic effectiveness of P. rubra in cardiovascular illnesses and its underlying mechanisms. Ex vivo vaso-relaxant effects of crude leaf extract of P. rubra were observed in rabbit aorta ring preparations. Hypotensive effects were measured using pressure and force transducers connected to the Power Lab data acquisition system. Furthermore, P. rubra displayed cardioprotective properties in rabbits when they were exposed to adrenaline-induced myocardial infarction. In comparison to the intoxicated group, the myocardial infarction model showed decreased troponin levels, CK-MB, LDH, ALT, ALP, AST, and CRP, as well as necrosis, apoptosis, oedema, and inflammatory cell enrollment. P. rubra has revealed good antioxidant properties and prolonged the noradrenaline intoxicated platelet adhesion. Its anticoagulant, vasorelaxant, and cardioprotective effects in both in vivo and ex vivo investigations are enabled by blocking L-type calcium channels, lowering adrenaline, induced oxidative stress, and tissue tear, justifying its therapeutic utility in cardiovascular disorders.

The inhibition effect of uncarialin A on voltage-dependent L-type calcium channel subunit alpha-1C: Inhibition potential and molecular stimulation.

Cardiovascular diseases, such as hypertension and cardiac failure, have become the most major and global cause for threatening human health in recent years. Uncaria rhynchophylla as a traditional Chinese medicine is widely used to treat hypertension for a long history, whereas its medicinal effective components and potential action mechanism are uncertain. Therefore, twenty-four alkaloids (1-24) isolated from U. rhynchophylla were assayed for their relaxant effects against phenylephrine (Phe)-induced contraction of rat mesenteric arteries. Among them, we surprisingly found that uncarialin A (21) exhibited most potent relaxation effect against Phe-induced contraction (IC50 = 0.18 µM) in the manner of independent on endothelium-derived vasorelaxing factors and endothelium. All the experiments including measurement of Ca2+ in vascular smooth muscle cells (VSMCs) by fluorescence microscopy, whole-cell path clamp, molecular docking, and molecular dynamics, demonstrated that uncarialin A (21) could significantly inhibit L-type calcium channel subunit alpha-1C (Cav1.2) via the hydrogen bond interaction with amino acid residue Met1186, allowing the inhibition of Ca2+ inward current. Our results suggested that uncarialin A (21) could be served as a potential L-type Cav1.2 blocker in the effective treatment of cardiovascular diseases.

Vasorelaxant 4,5-seco-abietane diterpenoids with diverse 6/6/6, 6/6/7, and 6/6/8 architectures from Salvia prattii Hemsl.

Salpratins A-D (1-4), four new 4,5-seco-abietane diterpenoids, along with twelve known analogues, featuring diverse 6/6/6, 6/6/7, and 6/6/8 rings system, were isolated from Salvia prattii Hemsl. Particularly, salpratin A is the first example of 4,5;12,13-bis-seco-abietane diterpenoid features with a 5/6/6/6 ring system. Their structures were determined by analyses of comprehensive NMR and MS spectroscopic data and single-crystal X-ray diffractions. In addition, compounds 1, 3, 4, 6, 7, 8 and 14 showed potent vasorelaxant activity on endothelium-intact thoracic aorta rings precontracted with KCl.

Vasorelaxing effect and possible chemical markers of the flowers of the Mexican Crataegus gracilior.

The vasorelaxing effect of the methanol extract of the flowers of Crataegus gracilior, a Mexican medicinal plant used to treat some cardiovascular diseases, was assessed, and its possible chemical markers identified. The extract produced a potent vasodilator effect on isolated rat aortic rings (EC50 = 1.83 ± 1.39 µg/mL; Emax = 100 ± 3.4%). Vitexin, the most commonly identified flavonoid in the flowers and used to standardise some Crataegus species, was not found at all in this plant sample. Instead, daucosterol, and corosolic and euscapic acids were purified. The two triterpene acids have been reported to possess beneficial effects on cardiovascular diseases. These results indicate that the vasodilator effect might induce the hypotensive effect claimed by users, and that euscapic and corosolic acids may be the main vasodilator compounds, and can then be employed as the chemical markers towards the future standardisation of the extract.

Blood pressure lowering effect and vascular activity of Phyllanthus niruri extract: The role of NO/cGMP signaling pathway and ß-adrenoceptor mediated relaxation of isolated aortic rings.

ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus niruri have a long history of use in the traditional treatment of various ailments including hypertension. Literature reports have indicated that it is a potent antihypertensive herbal medication used traditionally. AIM OF THE STUDY: This study was carried out to investigate the antihypertensive and vasodilatory activity of four solvents extracts of P. niruri namely; petroleum ether (PEPN), chloroform (CLPN), methanol (MEPN) and water (WEPN), with the aim of elucidating the mechanism of action and identifying the phytochemical constituents. MATERIALS AND METHODS: Male Spontaneous Hypertensive Rats (SHRs) were given oral gavage of P. niruri extract daily for two weeks and the blood pressure was recorded in vivo. We also determine the vasodilation effect of the extracts on rings of isolated thoracic aorta pre-contracted with phenylephrine (PE, 1 µM). Endothelium-intact or endothelium-denuded aorta rings were pre-incubated with various antagonists like 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 µM) and Methylene blue (MB 10 µM), sGC inhibitors; Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 µM) a nitric oxide synthase (NOS) inhibitor; atropine (10 µM), a cholinergic receptor blocker; indomethacin (10 µM), a cyclooxygenase inhibitor and various K+ channel blockers such as glibenclamide (10 µM) and tetraethyl ammonium (TEA 10 µM) for mechanism study. RESULTS: SHRs receiving P. niruri extracts showed a significant decrease in their blood pressure (BP) when compared to the baseline value, with PEPN being more potent. The extracts (0.125-4 mg/mL) also induced vasorelaxation on endothelium-intact aorta rings. PEPN elicited the most potent maximum relaxation effect (Rmax). Mechanism assessment of PEPN showed that its relaxation effect is significantly suppressed in endothelium-denuded aorta rings. Pre-incubation of aorta rings with atropine, L-NAME, ODQ, indomethacin, and propranolol also significantly attenuated its relaxation effect. Conversely, incubation with TEA and glibenclamide did not show a significant effect on PEPN-induced relaxation. CONCLUSION: This study indicates that the antihypertensive activity of P. niruri extract is mediated by vasoactive phytoconstituents that dilate the arterial wall via endothelium-dependent pathways and ß-adrenoceptor activity which, in turn, cause vasorelaxation and reduce blood pressure.

Synthesis and vasodilator activity of some pyridazin-3(2H)-one based compounds.

Aim: Hypertension is a major health problem worldwide resulting in high death rates due to its consequences and complications. Therefore, searching for new vasorelaxants is a must to find new vasodilators efficient for the treatment of different cardiovascular diseases. Methodology: Different 6-phenyl-3-pyridazinone based derivatives were synthesized and screened for their vasorelaxant activity according to the reported method using hydralazine as a standard. Results: The tested compounds revealed potent to mild activity with EC50 values 0.339-114.300 µM compared with hydralazine EC50 = 18.210 µM. Conclusion: The most active compounds were the acid 5, its ester analog 4 and 4-methoxyphenylhydrazide derivative 10c (EC50 = 0.339, 1.225 and 1.204 µM, respectively). Therefore, 6-phenylpyridazin-3(2H)-one can be a hit for structural optimization to obtain promising vasorelaxants.

Screening active ingredients of rosemary based on spectrum-effect relationships between UPLC fingerprint and vasorelaxant activity using three chemometrics.

Rosmarinus officinalis L., rosemary, is traditionally used to treat headache and improve cardiovascular disease partly due to its vasorelaxant activity, while the vasorelaxant ingredients remain unclear. In this study, chemical spectrum-pharmacological effect relationship (spectrum-effect relationship) was utilized for efficiently discovering the main vasorelaxant ingredients of rosemary. Ten kinds of rosemary extracts were prepared by different extracting solvents and macroporous resin purification, and their chemical components were analyzed by UPLC. At the same time, the vasorelaxant activities of the 10 kinds of rosemary extracts were estimated on isolated rat thoracic aorta, and three chemometrics named partial least squares regression (PLSR), grey correlation analysis (GRA), and the least absolute shrinkage and selection operator (LASSO) were applied to construct spectrum-effect relationship between the UPLC fingerprints and vasorelaxant activity of rosemary extracts. As a result, most rosemary extracts showed dose-dependent increase in vasorelaxant activity and five kinds of ingredients, including carnosol, carnosic acid, epirosmanol methyl ether, carnosol isomer, and augustic acid were screened as vasorelaxant ingredients. Further, the vasorelaxant activities of carnosic acid and carnosol were verified. Moreover, the increase of nitric oxide (NO) and the decrease of angiotensin-II (Ang-II) were thought to contribute to the vasorelaxant activity of rosemary.

Ser-Tyr and Asn-Ala, vasorelaxing dipeptides found by comprehensive screening, reduce blood pressure via different age-dependent mechanisms.

To understand the changes in physiological responses due to aging, a number of bioactive probes based on different signal transduction pathways are necessary. In this study, we comprehensively and systematically investigated changes in blood vessel function with age using a 336-dipeptide library. In the early stage of hypertension, the most potent vasorelaxant dipeptide was Ser-Tyr (SY) in the mesenteric artery isolated from spontaneously hypertensive rats (SHR). SY-induced vasorelaxation and anti-hypertensive effects were blocked by L-NAME, an inhibitor of nitric oxide synthase (NOS), suggesting that SY activates the NO system. On the other hand, the patterns of dipeptides with vasorelaxation activity in early and advanced stages of hypertension were different. In the advanced stage, the most potent vasorelaxing dipeptide was Asn-Ala (NA). Orally administered NA (1.5 mg/kg) reduced the blood pressure in the advanced stage, at which drugs were sometimes less effective, and the anti-hypertensive effects lasted for 6 hr. The NA-induced vasorelaxation and anti-hypertensive activity was blocked by lorglumide, an antagonist of the cholecystokinin CCK1 receptor, suggesting that NA activated the CCK system. Taken together, in the early and advanced stages of hypertension, SY and NA exhibited vasorelaxing and anti-hypertensive effects via the NO and CCK systems, respectively.