Further Quinolizidine Derivatives as Antiarrhythmic Agents- 3.

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1-(quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds 4, 1, 6, and 5 (in ascending order). The last compound (N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC50 = 0.017 µM) for the increase in the threshold of ac-arrhythmia. The tested compounds shared strong negative inotropic activity; however, this does not compromise the value of their antiarrhythmic action. On the other hand, only moderate or modest negative chronotropic and vasorelaxant activities were commonly observed. Compound 5, which has high antiarrhythmic potency, a favorable cardiovascular profile, and is devoid of antihypertensive activity in spontaneously hypertensive rats, represents a lead worthy of further investigation.

Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels.

Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a CaV1.2 channel blocker and a KCa1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the CaV1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the CaV1.2 channel blockade and KCa1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy.

Synthesis and characterization of new pyrazole-tetrazole derivatives as new vasorelaxant agents.

The synthesis of new functionalized tetrazole-pyrazole compounds is reported. They were fully characterized by spectroscopy and spectrometry methods. The vasorelaxant potency of these molecules was also investigated. All compounds showed a good vasorelaxant activity but the Compound 6 "ethyl 1-((2-(3-bromopropyl)-2H-tetrazol-5-yl)methyl)-5-methyl-1H-pyrazole-3-carboxylate" seems to have the highest effect, which reached 70% at 10-4  M concentration. This effect was partially endothelium-dependent; also, the vasorelaxant pattern of this compound was quite similar to that of the verapamil.

Discovery of Three New Monoterpenoid Indole Alkaloids from the Leaves of Gardneria multiflora and Their Vasorelaxant and AChE Inhibitory Activities.

Three novel monoterpenoid indole alkaloids gardflorine A (1), gardflorine B (2), and gardflorine C (3) were isolated from the leaves of Gardneria multiflora. Their structures, including absolute configurations, were established on the basis of spectroscopic methods (MS, UV, IR, 1D and 2D NMR) and circular dichroism experiments. All the compounds were evaluated for their vasorelaxant and acetylcholinesterase (AChE) inhibitory activities. Compound 1 exhibited potent vasorelaxant activity, with an EC50 value of 8.7 µM, and compounds 2 and 3 showed moderate acetylcholinesterase (AChE) inhibitory activities, with IC50 values of 26.8 and 29.2 µM, respectively.

Seven pairs of new enantiomeric sesquiterpenoids from Curcuma phaeocaulis.

Seven pairs of new enantiomeric sesquiterpenoids, (+)/(-)-phaeocauline A - G [(+)/(-)-1-7], were isolated from the rhizomes of Curcuma phaeocaulis by chiral HPLC separation. Their structures, including absolute configurations, were determined by spectroscopic analyses and ECD data. The isolates were assessed for vasorelaxant, anti-platelet aggregative, and neuroprotective activities. Enantiomers (+)-1 and (-)-1 showed similar activity against abnormal platelet aggregation induced by arachidonic acid, while their C-4 epimers (+)-2 and (-)-2 were inactive, which indicated that those effects were stereoselective, but not enantioselective. Compounds (+)/(-)-3-5 exhibited vasorelaxant effects against KCl-induced contraction of rat aortic rings.

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.

Curcumane C and (±)-curcumane D, an unusual seco-cadinane sesquiterpenoid and a pair of unusual nor-bisabolane enantiomers with significant vasorelaxant activity from Curcuma longa.

A new seco-cadinane sesquiterpenoid (curcumane C, 1) and a pair of new nor-bisabolene enantiomers [(+)- and (-)-curcumane D, 2a and 2b] were isolated from C. longa. Compound 1 possesses an unusual 4,5-seco-cadinane skeleton with a tetrahydrophthalide moiety, while 2a and 2b contain an unusual 15-nor-bisabolene skeleton with a chromone core. All compounds exhibited significant vasorelaxant effects against KCl-induced contraction of rat aortic rings. Compound 1 also exhibited a vasorelaxant effect against phenylephrine-induced contraction of rat aortic rings. Meanwhile, compound 1 showed a stronger vasorelaxant effect in endothelium-intact rat aortic rings compared with endothelium-denuded rat aortic rings, indicating that vasodilation by 1 involved both endothelium-dependent and endothelium-independent pathways. Furthermore, compound 1 increased the NO content in human umbilical vein endothelial cells and its vasorelaxant effect could be attenuated by treatment with L-NAME, an endothelium NO synthase inhibitor. Thus, the underlying vasodilatory mechanisms of 1 may be mediated via abrogation of extracellular Ca2+ influx and regulation of NO release in vascular endothelial cells.

Endothelium-independent vasorelaxant activity of Trachyspermum ammi essential oil on rat aorta.

Several pharmacological activities of the essential oil of Trachyspermum ammi seeds (TAEO) have been previously studied. These include antitussive, antihypertensive, and antispasmodic effects. However, its action on isolated aorta has not yet been studied. This study was aimed to investigate the vasorelaxant activity of TAEO and characterize its mechanism of action. Extraction of TAEO was performed using Clevenger-type apparatus with the final content of 4.5% (v/w). To evaluate some probable mechanisms of action of TAEO, the action isometric tension was then measured in the aortic rings from Wistar rats which were precontracted with phenylephrine (PHE) (1 µM) or KCl (60 mM). The major constituents of TAEO included Thymol (38.1%), gamma-terpinene (33.3%), and p-cymene (23.1%), as was analyzed by GC-MS. The cumulative concentrations of TAEO reduced precontraction caused by PHE and KCl (p < 0.05) significantly, which was dose dependent. The vasorelaxation caused by TAEO was not influenced in the presence of methylene blue and L-NAME in the endothelium-intact and denuded aorta ring. The inhibitory effect of TAEO on the aortic rings precontracted with KCl and PHE was considerably reduced by nifedipine. These findings hypothesized that the vasorelaxation caused by TAEO is completely endothelium independent and the extracellular Ca2+ influx was also inhibited by TAEO.

Protostane-Type Triterpenoids from Alisma orientale.

Twenty-eight protostane triterpenoids, including a new degraded one (1), nine new ones (2 - 10), and two new natural ones (11 and 12), have been isolated from the dried rhizomes of Alisma orientale. Alisol R (1) was the first 20,21,22,23,24,25,26,27-octanorprotostane triterpenoid. The absolute configurations of 25-methoxyalisol F (2) and 16ß-hydroperoxyalisol B 23-acetate (3) were determined by X-ray diffraction analysis. In addition, alismaketone-B 23-acetate (28) showed potent vasorelaxant activity on endothelium-intact thoracic aorta rings precontracted with KCl.

Alkaloids and Phenolic Compounds from Sida rhombifolia L. (Malvaceae) and Vasorelaxant Activity of Two Indoquinoline Alkaloids.

The follow-up of phytochemical and pharmacological studies of Sida rhombifolia L. (Malvaceae) aims to strengthen the chemosystematics and pharmacology of Sida genera and support the ethnopharmacological use of this species as hypotensive herb. The present work reports phytoconstituents isolated and identified from aerial parts of S. rhombifolia by using chromatographic and spectroscopic methods. The study led to the isolation of scopoletin (1), scoporone (2), ethoxy-ferulate (3), kaempferol (4), kaempferol-3-O-ß-d-glycosyl-6''-α-d-rhamnose (5), quindolinone (6), 11-methoxy-quindoline (7), quindoline (8), and the cryptolepine salt (9). The alkaloids quindolinone (6) and cryptolepine salt (9) showed vasorelaxant activity in rodent isolated mesenteric arteries.

Structurally diverse monoterpene indole alkaloids with vasorelaxant activities from the branches of Alstonia scholaris.

Seven undescribed monoterpene indole alkaloids alstoscholarinines A‒G, along with nineteen known alkaloids, were isolated from the branches of Alstonia scholaris (L.) R. Br. The isolated alkaloids were classified into ten framework types. The structures of the undescribed alkaloids were elucidated by extensive spectroscopic analysis, ECD calculation, and single-crystal X-ray diffraction analysis. Alstoscholarinine A is an unreported and unusual monoterpene indole alkaloid incorporating three nitrogen atoms, characterized by a compact 6/5/6/6/6/5 hexacyclic system bearing a piperidine ring and a unique oxazolidine ring. Alstoscholarinine B represents the first naturally C-17 nor-isositsirikine-type alkaloid. Plausible biosynthetic pathways of alstoscholarinines A and B were proposed. All isolates were evaluated for their vasorelaxant activities against phenylephrine-induced contraction of rat mesenteric arteries. Among them, seven alkaloids showed significant vasorelaxant activities with EC50 values less than 10 µM. Importantly, the akuammicine-type alkaloids in this study showed much better vasorelaxant activities than other framework type alkaloids, indicating that this type of alkaloid may be a valuable source for the discovery of vasodilators. A preliminary structure-activity relationship for vasorelaxant activities of the isolated akuammicine-type alkaloids is also discussed.

Study of the Antihypertensive Effect of Laurus nobilis in Rats.

AIMS: The study aimed to study the antihypertensive activity of Laurus nobilis. BACKGROUND: Laurus nobilis L. is used to treat hypertension in Morocco. OBJECTIVE: The study was designed to investigate the effect of the aqueous extract leaves of Laurus nobilis (AELN) on blood pressure. MATERIALS AND METHODS: The antihypertensive and vasorelaxant activities of AELN were pharmacologically investigated in normotensive and L-NAME-induced hypertensive rats. Thereafter, blood pressure was evaluated, and the ex-vivo vasorelaxant activity of this extract was performed. RESULTS: A considerable decrease in blood pressure parameters were observed in L-NAMEinduced hypertensive rats treated with AELN. The extract induced a vasorelaxant effect on the aorta precontracted with epinephrine or KCl by inhibiting extracellular Ca2+ entry. CONCLUSION: The study demonstrates that Laurus nobilis aqueous extract exhibits potent antihypertensive and vasorelaxant activities via inhibiting Ca2+ entry.

Ethnobotanical Survey and Pharmacological Screening of Medicinal Plants Used as Antihypertensive in Sefrou Province (Middle-North of Morocco): Benefits and Challenges.

Herbal medicine was used since the old time in the treatment of different types of diseases in Sefrou province, Morocco. However, few studies have been carried out to identify local medicinal flora and to scientifically document the knowledge of the traditional use of these medicinal plants by the population. This study aims to investigate the medicinal plants in Sefrou province, record their usage in folk medicine by the population and evaluate the hypotensive effect of selected plants using in vitro vascular activity. For that, an ethnobotanical survey was conducted among the Arabs and Amazighs population of Sefrou province from January 2017 to December 2018. The survey was conducted through oral interviews with a structured questionnaire. It covered those who knew and/or used plants for medicinal purposes, retailers, and wholesalers, and also included ecological repartition as well as the mode of administration. Then we selected some plants to evaluate the antihypertensive activity based on the in vitro bioassay. A total of 134 medicinal plants belonging to 52 families were identified; 61% are wild species, 49 (36%) are cultivated and 4 (3%) are cultivated as well as spontaneous. Medicinal plants used in Sefrou folk medicine have been investigated for their antihypertensive activity. They were selected based on their usage as cardiotonic, diuretics, and other uses related to the symptoms of hypertension. Most of the plants tested in this study were found to be more sensitive to relaxing contractions induced by noradrenaline. Out of 32 species examined, 14 (44%) showed more than 50% inhibition in isolated rat aortic rings, the vasorelaxant activity of these plants used for the screening was mostly inhibited by pre-treatment with N-ω-nitro-L-arginine (L-NOArg). The plants inventoried are alleged to be active against 104 therapeutic indications. Nine common symptoms are widely treated in indigenous pharmacopeia: gastrointestinal (19 plants), renal (27 plants), broncho-pulmonary system (7 plants), skin (13 species), diabetes (12 plants), cardiovascular (13 plants), eye, ear, nose, teeth, and throat diseases (5 plants); gynecological disorders (6 plants); rheumatism and gnawing pain (11 plants). 14% (19 species) of the plant inventoried are traded on a large scale and scope and more than 90 percent of the medicinal plants purchased from Sefrou go to big cities for export. The expansion of unregulated trade and commercial use of medicinal and aromatic plants poses a major threat to biodiversity in the region. Overall, people in Sefrou hold rich knowledge of herbal medicine. The vasorelaxant activity proved for the documented plants will provide a basis for other preclinical and clinical investigations.

Carissa edulis Vahl (Apocynaceae) extract, a medicinal plant of Benin pharmacopoeia, induces potent endothelium-dependent relaxation of coronary artery rings involving nitric oxide.

BACKGROUND: Hypertension is a major cardiovascular risk factor that affects most countries including those of Africa. Although Carissa edulis Vahl, Diodia scandens Sw. and Cleome gynandra L. are traditionally used in Benin as antihypertensive treatments with some efficacy mentioned by the local population, their biological activity on the cardiovascular system remains poorly studied. AIM: The study investigated the vasoreactivity of the plants and assessed the underlying mechanisms using isolated arteries. STUDY DESIGN: Aqueous-ethanolic extracts of aerial parts of C. edulis, D. scandens and C. gynandra were prepared by maceration before being subjected to multi-step liquid-liquid fractionation with solvents of increasing polarity. The vasoreactivity of the extracts and fractions were assessed on isolated porcine coronary artery and rat aorta using organ chambers, the role of nitric oxide (NO) using NG-nitro-L-arginine (NO synthase inhibitor), prostanoids using indomethacin (cyclooxygenases inhibitor) and endothelium-dependent hyperpolarization using TRAM-34 plus UCL 1684 (inhibitors of calcium-dependent K+ channels), and the vascular uptake of polyphenols using Neu reagent. RESULTS: The aqueous-ethanolic crude extract of C. edulis (CECE) induced potent relaxations that were exclusively endothelium-dependent and more pronounced than those to D. scandens and C. gynandra. The n-butanolic fraction of C. edulis (CEBF) was more active than the cyclohexane, dichloromethane, and ethyl acetate fractions. The relaxation induced by CECE and CEBF were inhibited by NG-nitro-L-arginine and affected neither by TRAM-34 plus UCL 1684 nor by indomethacin. CEBF induced sustained endothelium-dependent relaxations for at least 60 min, and inhibited, in a concentration-dependent manner, contractions to KCl, CaCl2, U46619 and serotonin in rings with endothelium. Analysis of CEBF by LCHRMS indicated the presence of polyphenols, terpenes, and alkaloids. Exposure of coronary artery and aorta rings to CEBF caused the accumulation of polyphenols predominantly in the endothelium. CONCLUSION: C. edulis leaf extract induced pronounced endothelium-dependent relaxations and inhibited contractile responses by stimulating the endothelial formation of NO. LCHRMS analysis of the most active fraction, the butanolic fraction, revealed the presence of numerous compounds including polyphenols, terpenes, and alkaloids. The polyphenols of CEBF accumulated preferentially in the endothelium of the arterial wall. Thus, these observations support the folkloric use of C. edulis in hypertension.

Curcumanes E and F, two rare sesquiterpenoids with a dicyclo[3.3.1]nonane moiety, from Curcuma longa and their vasorelaxant activities.

Two new sesquiterpenoids, curcumanes E (1) and F (2), were isolated from the rhizome of Curcuma longa, and their structures and absolute configurations were examined using extensive spectroscopic analyses and ECD calculations. Interestingly, compounds 1 and 2 are diastereoisomers possessing a rare sesquiterpenoid skeleton that has been reported only once before. Both curcumanes E and F exhibit significant vasorelaxant effects against KCl-induced contraction of rat aortic rings, with EC50 values of 5.10 ± 0.79 and 5.58 ± 1.77 µM, respectively. These findings enrich the data concerning this rare type of sesquiterpenoids and further indicate that these rare sesquiterpenoids can effectively reduce blood pressure.

Chromatographic Techniques and Pharmacological Analysis as a Quality Control Strategy for Serjania triquetra a Traditional Medicinal Plant.

Serjania triquetra is a medicinal plant widely used in traditional medicine for the treatment of urinary tract diseases, renal affections, and its complications. The population can buy this plant in folk markets as a raw material mixed with several herbal remedies or as a health supplement. On the market, two commercial presentations were found for the vegetal material; one had a bulk appearance and the other was marketed wrapped in cellophane bags (HESt-2, HESt-3). Nevertheless, the plant has not been exhaustively investigated and quality control techniques have not been developed. This research aimed to realize a phytochemical study using an authentic, freshly collected sample as a reference for S. triquetra (HESt-1), using the compounds identified. A method for the determination of preliminary chromatographic fingerprinting was developed. Additionally, the vasorelaxant effect from three samples was evaluated with ex vivo rat models. Thus, three hydroalcoholic extracts (HESt-1, HESt-2, and HESt-3) were prepared by maceration. A total of nine compounds were fully identified from HESt-1 after the extract was subjected to open-column chromatography. Seven metabolites were detected by gas chromatography, while ursolic acid (UA) and allantoin were isolated and identified using UPLC-MS and NMR, respectively. Three extracts were analyzed for their chromatographic fingerprint by UPLC-MS. Biological activity was explored by ex vivo rat aorta ring model to evaluate vasorelaxant activity. All extracts showed a vasorelaxant effect in a concentration-dependent and endothelium-dependent manner. S. triquetra vascular activity may be attributed to UA and allantoin compounds previously described in the literature for this activity.

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.

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.

Pharmacological characterization of the cardiovascular effect of Nibethione: ex vivo, in vivo and in silico studies.

OBJECTIVE: This work describes the vasorelaxant and antihypertensive effects and the mechanism of action on vascular smooth muscle cells of Nibethione, a synthetic thiazolidinedione derivative. Additionally, evidence of its cytotoxicity is assessed. METHODS: Nibethione (NB) was synthesized, and its vasorelaxant effect and mechanism of action were assessed through ex vivo experiments. Molecular docking studies were used to predict the mode of interaction with L-type Ca2+ channel, and in vivo antihypertensive activity was assayed on spontaneously hypertensive rats (SHR). The cytotoxicity potential was evaluated in porcine aortic endothelial cells (PAECs) from primary explants. KEY FINDINGS: Nibethione vasorelaxant effect was efficient on KCl (80 mm) and NE-contraction. This effect was deleteriously modified in the presence of potassium channel block drugs, while the maximal contraction induced with NE was significantly decreased by NB; the CaCl2 -induced contraction was abolished entirely. In vivo experiments showed that NB decreased diastolic blood pressure in 20.3 % after its administration on SHR. The molecular docking showed that NB blocks L-type Ca2+ channel, and in vitro tests showed that NB did not produce cytotoxic activity on PAECs (IC50 >1000 µm). CONCLUSIONS: Nibethione showed in vivo antihypertensive and ex vivo vasorelaxant effects with implication of voltage-dependent L-type Ca2+ channel blocking, and this may contribute to the research of novel antihypertensive drugs.

Four new corynanthe-type alkaloids from the roots of Alstonia scholaris.

Four new corynanthe-type alkaloids, meloslines C-F (1-4), together with four known ones (5-8) were isolated from the roots of Alstonia scholaris. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis and electronic circular dichroism (ECD) calculation. Compounds 1 and 2 exhibited potent vasorelaxant activity on endothelium-intact renal arteries precontracted with KCl.