RESUMEN
Hawthorn (Crataegus spp.) has been used for the treatment of several heart diseases and hypertension. The studies carried out on several hawthorn species have led to the development of standardized extracts useful in the cure of mild chronic cardiac diseases. In Mexico, the most common Crataegus species are C. mexicana and C. gracilior. Decoctions prepared from the fruits and leaves of these species have been employed to the treat respiratory diseases, tachycardia and to improve coronary blood flow. Considering that to date there are no reports of the use of Mexican Crataegus species to treat cardiovascular diseases, we propose an analytical method to obtain a quantified extract of Crataegus mexicana leaves for the development of a standardized extract with therapeutic value in cardiovascular diseases as an alternative source to the extracts obtained from Crataegus species of European and Asian origin. Therefore, the aim of this study was to obtain an extract prepared from C. mexicana leaves with the highest vasodilator activity to select the optimal chemical marker to stablish and validate a reversed-phase high-performance liquid chromatography (RPHPLC-DAD) analytical method for obtaining a quantified extract with vasodilator effect. The results obtained from the analytical method validation, which was carried out according to the guidelines stablished in the Eurachem Guide and the ICH guidelines proved that the RPHPLC-DAD method we developed was specific, precise, accurate, and showed good linearity over the concentration range of 3 - 21 µg/ml for (-)-epicatechin and rutin, which were selected as chemical markers.
RESUMEN
Recently, our research group demonstrated that uvaol and ursolic acid increase NO and H2S production in aortic tissue. Molecular docking studies showed that both compounds bind with high affinity to endothelial NO synthase (eNOS) and cystathionine gamma-lyase (CSE). The aim of this study was to identify hits with high binding affinity for the triterpene binding-allosteric sites of eNOS and CSE and to evaluate their vasodilator effect. Additionally, the mechanism of action of the most potent compound was explored. A high-throughput virtual screening (HTVS) of 107,373 compounds, obtained from four ZINC database libraries, was performed employing the crystallographic structures of eNOS and CSE. Among the nine top-scoring ligands, isoxsuprine showed the most potent vasodilator effect. Pharmacological evaluation, employing the rat aorta model, indicated that the vasodilation produced by this compound involved activation of the NO/cGMP and H2S/KATP signaling pathways and blockade of α1-adrenoceptors and L-type voltage-dependent Ca2+ channels. Incubation of aorta homogenates in the presence of isoxsuprine caused 2-fold greater levels of H2S, which supported our preliminary in silico data. This study provides evidence to propose that the vasodilator effect of isoxsuprine involves various mechanisms, which highlights its potential to treat a wide variety of cardiovascular diseases.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Isoxsuprina/química , Isoxsuprina/farmacología , Redes y Vías Metabólicas/efectos de los fármacos , Relación Estructura-Actividad Cuantitativa , Vasodilatadores/química , Vasodilatadores/farmacología , Adenosina Trifosfato/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/química , Bloqueadores de los Canales de Calcio/química , GMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Humanos , Sulfuro de Hidrógeno/metabolismo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Óxido Nítrico/metabolismo , Bibliotecas de Moléculas Pequeñas , Flujo de TrabajoRESUMEN
Arterial hypertension is one of the main risk factors in the development of cardiovascular diseases. Therefore, it is important to look for new drugs to treat hypertension. In this study, we carried out the screening of 19 compounds (triterpenes, diterpenes, sesquiterpenes, lignans, and flavonoids) isolated from 10 plants used in Mexican traditional medicine to determine whether they elicited vascular smooth muscle relaxation and, therefore, could represent novel anti-hypertension drug candidates. The vasorelaxant activity of these compounds was evaluated on the isolated rat aorta assay and the results obtained from this evaluation showed that three compounds induced a significant vasodilatory effect: meso-dihydroguaiaretic acid [half maximal effective concentration (EC50), 49.9 ± 11.2 µM; maximum effect (Emax), 99.8 ± 2.7%]; corosolic acid (EC50, 108.9 ± 6.7 µM; Emax, 96.4 ± 4.2%); and 5,8,4'-trihydroxy-3,7-dimethoxyflavone (EC50, 122.3 ± 7.6 µM; Emax, 99.5 ± 5.4%). Subsequently, involvement of the NO/cyclic guanosine monophosphate (cGMP) and H2S/ATP-sensitive potassium channel (KATP) pathways on the vasodilator activity of these compounds was assessed. The results derived from this analysis showed that the activation of both pathways contributes to the vasorelaxant effect of corosolic acid. On the other hand, the vasodilator effect of meso-dihydroguaiaretic acid and 5,8,4'-trihydroxy-3,7-dimethoxyflavone, partly involves stimulation of the NO/cGMP pathway. However, these compounds also showed an important endothelium-independent vasorelaxant effect, whose mechanism of action remains to be clarified. This study indicates that meso-dihydroguaiaretic acid, corosolic acid, and 5,8,4'-trihydroxy-3,7-dimethoxyflavone could be used as lead compounds for the synthesis of new derivatives with a higher potency to be developed as drugs for the prevention and treatment of cardiovascular diseases.
Asunto(s)
Músculo Liso/irrigación sanguínea , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Plantas/química , Vasodilatadores/aislamiento & purificación , Vasodilatadores/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiología , GMP Cíclico/metabolismo , Flavonoides/química , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Lignanos/química , Lignanos/aislamiento & purificación , Lignanos/farmacología , Medicina Tradicional , México , Estructura Molecular , Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Extractos Vegetales/química , Ratas , Terpenos/química , Terpenos/aislamiento & purificación , Terpenos/farmacología , Vasodilatación , Vasodilatadores/químicaRESUMEN
Heliopsis longipes roots have been widely used in Mexican traditional medicine to relieve pain, mainly, toothaches. Previous studies have shown that affinin, the major alkamide of these roots, induces potent antinociceptive and anti-inflammatory activities. However, the effect of H. longipes root extracts and affinin on the cardiovascular system have not been investigated so far. In the present study, we demonstrated that the dichloromethane and ethanolic extracts of H. longipes roots, and affinin, isolated from these roots, produce a concentration-dependent vasodilation of rat aorta. Affinin-induced vasorelaxation was partly dependent on the presence of endothelium and was significantly blocked in the presence of inhibitors of NO, H2S, and CO synthesis (NG-nitro-l-arginine methyl ester (l-NAME), dl-propargylglycine (PAG), and chromium mesoporphyrin (CrMP), respectively); K⺠channel blockers (glibenclamide (Gli) and tetraethyl ammonium (TEA)), and guanylate cyclase and cyclooxygenase inhibitors (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and indomethacin (INDO), respectively). Our results demonstrate, for the first time, that affinin induces vasodilation by mechanisms that involve gasotransmitters, and prostacyclin signaling pathways. These findings indicate that this natural alkamide has therapeutic potential in the treatment of cardiovascular diseases.
Asunto(s)
Amidas/aislamiento & purificación , Amidas/farmacología , Asteraceae/química , Epoprostenol/metabolismo , Gasotransmisores/metabolismo , Transducción de Señal/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Amidas/química , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , AMP Cíclico/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Indometacina/farmacología , Masculino , Cloruro de Metileno , Modelos Biológicos , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Raíces de Plantas/química , Alcamidas Poliinsaturadas , Canales de Potasio/metabolismo , Ratas WistarRESUMEN
The present research aimed to isolate the non-polar secondary metabolites that produce the vasodilator effects induced by the dichloromethane extract of Prunus serotina (P. serotina) fruits and to determine whether the NO/cGMP and the H2S/KATP channel pathways are involved in their mechanism of action. A bioactivity-directed fractionation of the dichloromethane extract of P. serotina fruits led to the isolation of ursolic acid and uvaol as the main non-polar vasodilator compounds. These compounds showed significant relaxant effect on rat aortic rings in an endothelium- and concentration-dependent manner, which was inhibited by NG-nitro-L-arginine methyl ester (L-NAME), DL-propargylglycine (PAG) and glibenclamide (Gli). Additionally, both triterpenes increased NO and H2S production in aortic tissue. Molecular docking studies showed that ursolic acid and uvaol are able to bind to endothelial NOS and CSE with high affinity for residues that form the oligomeric interface of both enzymes. These results suggest that the vasodilator effect produced by ursolic acid and uvaol contained in P. serotina fruits, involves activation of the NO/cGMP and H2S/KATP channel pathways, possibly through direct activation of NOS and CSE.
Asunto(s)
Sulfuro de Hidrógeno/agonistas , Óxido Nítrico/agonistas , Prunus avium/química , Triterpenos/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Alquinos/antagonistas & inhibidores , Alquinos/farmacología , Animales , Aorta/citología , Aorta/efectos de los fármacos , Aorta/metabolismo , GMP Cíclico/metabolismo , Cistationina gamma-Liasa/química , Cistationina gamma-Liasa/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Frutas/química , Gliburida/antagonistas & inhibidores , Gliburida/farmacología , Glicina/análogos & derivados , Glicina/antagonistas & inhibidores , Glicina/farmacología , Sulfuro de Hidrógeno/metabolismo , Canales KATP/agonistas , Canales KATP/metabolismo , Masculino , Simulación del Acoplamiento Molecular , NG-Nitroarginina Metil Éster/antagonistas & inhibidores , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo III/química , Óxido Nítrico Sintasa de Tipo III/metabolismo , Extractos Vegetales/química , Unión Proteica , Ratas , Triterpenos/aislamiento & purificación , Vasodilatadores/aislamiento & purificación , Ácido UrsólicoRESUMEN
Prunus serotina (black cherry), commonly known in Mexico as capulín, is used in Mexican traditional medicine for the treatment of cardiovascular, respiratory, and gastrointestinal diseases. Particularly, P. serotina seeds, consumed in Mexico as snacks, are used for treating cough. In the present study, nutritional and volatile analyses of black cherry seeds were carried out to determine their nutraceutical potential. Proximate analysis indicated that P. serotina raw and toasted seeds contain mostly fat, followed by protein, fiber, carbohydrates, and ash. The potassium content in black cherry raw and toasted seeds is high, and their protein digestibility-corrected amino acid scores suggest that they might represent a complementary source of proteins. Solid phase microextraction and gas chromatography/flame ionization detection/mass spectrometry analysis allowed identification of 59 and 99 volatile compounds in the raw and toasted seeds, respectively. The major volatile compounds identified in raw and toasted seeds were 2,3-butanediol and benzaldehyde, which contribute to the flavor and odor of the toasted seeds. Moreover, it has been previously demonstrated that benzaldehyde possesses a significant vasodilator effect, therefore, the presence of this compound along with oleic, linoleic, and α-eleostearic fatty acids indicate that black cherry seeds consumption might have beneficial effects on the cardiovascular system.
Asunto(s)
Carbohidratos de la Dieta/análisis , Grasas de la Dieta/análisis , Análisis de los Alimentos , Valor Nutritivo , Proteínas de Vegetales Comestibles/análisis , Prunus domestica/química , Semillas/química , Compuestos Orgánicos Volátiles/análisisRESUMEN
In Mexico black cherry (Prunus serotina Ehrh.) fruits are consumed fresh, dried or prepared in jam. Considering the evidence that has linked intake of fruits and vegetables rich in polyphenols to cardiovascular risk reduction, the aim of this study was to characterize the phenolic profile of black cherry fruits and to determine their antioxidant, vasorelaxant and antihypertensive effects. The proximate composition and mineral contents of these fruits were also assessed. Black cherry fruits possess a high content of phenolic compounds and display a significant antioxidant capacity. High-performance liquid chromatography/mass spectrometric analysis indicated that hyperoside, anthocyanins and chlorogenic acid were the main phenolic compounds found in these fruits. The black cherry aqueous extract elicited a concentration-dependent relaxation of aortic rings and induced a significant reduction on systolic blood pressure in L-NAME induced hypertensive rats after four weeks of treatment. Proximate analysis showed that black cherry fruits have high sugar, protein, and potassium contents. The results derived from this study indicate that black cherry fruits contain phenolic compounds which elicit significant antioxidant and antihypertensive effects. These findings suggest that these fruits might be considered as functional foods useful for the prevention and treatment of cardiovascular diseases.
Asunto(s)
Antihipertensivos/química , Antioxidantes/química , Suplementos Dietéticos/análisis , Frutas/química , Extractos Vegetales/química , Prunus/química , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacología , Antioxidantes/farmacología , Aorta/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Flavonoides/química , Masculino , Espectrometría de Masas , Minerales/análisis , Minerales/química , Estructura Molecular , Fenoles/química , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , RatasRESUMEN
The present paper reviews vasodilator compounds isolated from plants that were reported in the past 22 years (1990 to 2012) and the different mechanisms of action involved in their vasodilator effects. The search for reports was conducted in a comprehensive manner, intending to encompass those metabolites with a vasodilator effect whose mechanism of action involved both vascular endothelium and arterial smooth muscle. The results obtained from our bibliographic search showed that over half of the isolated compounds have a mechanism of action involving the endothelium. Most of these bioactive metabolites cause vasodilation either by activating the nitric oxide/cGMP pathway or by blocking voltage-dependent calcium channels. Moreover, it was found that many compounds induced vasodilation by more than one mechanism. This review confirms that secondary metabolites, which include a significant group of compounds with extensive chemical diversity, are a valuable source of new pharmaceuticals useful for the treatment and prevention of cardiovascular diseases.