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1.
Cardiovasc Hematol Agents Med Chem ; 17(2): 135-143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31589128

RESUMO

BACKGROUND: Matricaria pubescens is a medicinal plant from North Africa. This plant is widely used in alternative medicine as a remedy against rheumatism, inflammation, diabetes and hypertension. AIM: The aim of the study was to evaluate the possible antihypertensive and vasodilator activity of the aqueous extract of Matricaria pubescens (M. pubescens). MATERIAL AND METHODS: In the current study, the aqueous extract of the aerial parts of M. pubescens (AEMP) was prepared and its antihypertensive activity was examined in N(ω)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. RESULTS: The results indicated that AEMP reduced the systolic, diastolic, mean arterial blood pressure in hypertensive rats but not in normotensive rats. The data revealed that AEMP exhibits its antihypertensive effect through vasorelaxant activity. More interestingly, this study approved that the vasorelaxant capacity of AEMP seems to be mediated through vascular cyclooxygenase pathway, the opening of K+ channels and sGC-cGMP induction pathway. CONCLUSION: The study illustrates the beneficial action of M. pubescens as an antihypertensive agent.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Matricaria/química , Extratos Vegetais/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Anti-Hipertensivos/química , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/efeitos adversos , Extratos Vegetais/química , Ratos Wistar , Vasodilatadores/química
2.
Fitoterapia ; 139: 104365, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31647954

RESUMO

As a folk medicine, Phlomis likiangensis is traditionally used in China to activate collaterals and protect cardiovascular system. We hypothesized that the beneficial effects of Phlomis likiangensis may be related to vasodilatation. In the present study, twelve known iridoid glucosides (1-12) were isolated from Phlomis likiangensis. The vasodilatory effects and the underlying mechanisms of the main components (iridoid glucosides) of Phlomis likiangensis on rat aortic rings were investigated. The result showed that iridoid glucosides significantly increased the vasodilatation in rat aortic rings, which was abolished by removing the endothelium of the vessels or by eliminating the generation of nitric oxide. Finally, the structure-activity relationship of compounds 1-12 was also speculated. Our findings provide the first evidence that the iridoid glucosides of Phlomis likiangensis may be the pharmacodynamic basis for its traditional efficacy.


Assuntos
Glucosídeos Iridoides/farmacologia , Phlomis/química , Vasodilatadores/farmacologia , Animais , Aorta/efeitos dos fármacos , Células Cultivadas , China , Células Endoteliais/efeitos dos fármacos , Técnicas In Vitro , Glucosídeos Iridoides/química , Masculino , Estrutura Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Plantas Medicinais/química , Ratos , Ratos Sprague-Dawley , Rizoma/química , Relação Estrutura-Atividade , Vasodilatação , Vasodilatadores/química
3.
Nihon Yakurigaku Zasshi ; 154(3): 115-120, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31527360

RESUMO

More than twenty years have passed since the demonstration of hydrogen sulfide (H2S) as a signaling molecule. Various roles of this molecule have been reported including neuromodulation, vascular relaxation, cytoprotection, anti-inflammation, and oxygen sensing. During the study of its effect on neuromodulation, we found TRP channels as a target of H2S, and later identified polysulfides (H2Sn) as chemical entity of the ligand. We found that H2S relaxes vasculatures in synergy with NO, and recently identified H2Sn as products produced by the chemical interaction between H2S and NO to exert the effect, suggesting that it may be a mechanism for the synergy between the two molecules. It has attracted attention that sulfite, a further metabolite of H2S and H2Sn, protects neurons from oxidative stress by a mechanism different from that by H2S and H2Sn.


Assuntos
Sulfeto de Hidrogênio/química , Transdução de Sinais , Sulfetos/química , Sulfitos/química , Humanos , Óxido Nítrico/química , Vasodilatadores/química
4.
Molecules ; 24(15)2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31362388

RESUMO

Alkaloids derived from plants have shown great medicinal benefits, and are often reported for their use in cardiovascular disease management. Aristotelia chilensis (Molina) Stuntz (Maqui) has shown important medicinal properties in traditional useage. In this study, we evaluated the effect of the indole-alkaloid aristoteline (ARI), isolated from leaves of Maqui, on vascular reactivity of isolated aortic rings from normotensive rats. ARI induced relaxation (100%) in a concentration-dependent manner in intact or denuded-endothelium aortic rings pre-contracted with phenylephrine (PE; 1 µM). However, a specific soluble guanylyl cyclase inhibitor (ODQ; 1 µM) significantly reduced the relaxation to ARI in aortic rings pre-contracted with PE. In the presence of ARI, the contraction induced by KCl or PE was significantly (p < 0.05) decreased. Interestingly, the potassium channel blockade with 10 µM BaCl2 (Kir), 10 µM glibenclamide (KATP), 1 mM tetraethylammonium (TEA; KCa1.1), or 1 mM 4-aminopyridine (4-AP; Kv) significantly (p < 0.05) reduced the ARI-induced relaxation. ARI significantly (p < 0.05) reduced the contractile response to agonist of CaV1.2 channels (Bay K8644; 10 nM), likely reducing the influx of extracellular calcium through plasma membrane. The mechanisms associated with this process suggest an activation of the potassium channels, a calcium-induced antagonism and endothelium independent vasodilation that possibly involves the nitric oxide-independent soluble guanylate cyclase pathway.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/química , Canais de Potássio/química , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Cloratos/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Estrutura Molecular , Óxido Nítrico/metabolismo , Fenilefrina/farmacologia , Canais de Potássio/agonistas , Prostaglandinas/farmacologia , Ratos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/química , Vasodilatadores/farmacologia
5.
Molecules ; 24(15)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349544

RESUMO

Hydroalcoholic extracts of Patagonian Calafate berry (Berberis microphylla) contain mono or disaccharide conjugated anthocyanins and flavonols. The Liquid Chromatography-Mass Spectrometry (LC-MS) chemical extract profile identified glycosylated anthocyanidins such as delphinidin-, petunidin- and malvidin-3-glucoside as the major constituents. The predominant flavonols were 3-O substituents quercetin-rutinoside or -rhamnoside. Anthocyanins doubled flavonols in mass (13.1 vs. 6 mg/g extract). Polyphenols vascular actions were examined in the rat arterial mesenteric bed bioassay; extract perfusion elicited concentration-dependent vasodilatation mimicked by conjugated anthocyanins standards. Vascular responses of main glycosylated anthocyanins were endothelium-dependent (p < 0.001) and mediated by NO production (p < 0.05). The anthocyanins antioxidant activity determined in isolated endothelial cells (CAA) showed a reduced redox potential as compared to the extract or quercetin. While in the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assay, the anthocyanins showed an equivalent quercetin potency, the extract was 15-fold less active, proposing that the anthocyanin-induced vasodilation is not due to an antioxidant mechanism. The extract shows promising commercial nutraceutical potential.


Assuntos
Antioxidantes/farmacologia , Berberis/química , Suplementos Nutricionais/análise , Frutas/química , Extratos Vegetais/farmacologia , Vasodilatadores/farmacologia , Animais , Antioxidantes/química , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Estrutura Molecular , Compostos Fitoquímicos , Extratos Vegetais/química , Ratos , Espectrometria de Massas em Tandem , Vasodilatadores/química
6.
Chem Pharm Bull (Tokyo) ; 67(7): 675-689, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257323

RESUMO

An Orobanchaceae plant Cistanche tubulosa (SCHENK) WIGHT (Kanka-nikujuyou in Japanese), which is one of the authorized plant resources as Cistanches Herba in both Japanese and Chinese Pharmacopoeias, is a perennial parasitic plant growing on roots of sand-fixing plants. The stems of C. tubulosa have traditionally been used for treatment of impotence, sterility, lumbago, and body weakness as well as a promoting agent of blood circulation. In recent years, Cistanches Herba has also been widely used as a health food supplement in Japan, China, and Southeast Asian countries. Here we review our recent studies on chemical constituents from the stems of C. tubulosa as well as their bioactivities such as vasorelaxtant, hepatoprotective, and glucose tolerance improving effects.


Assuntos
Produtos Biológicos/química , Cistanche/química , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Cistanche/metabolismo , Glicosídeos/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monoterpenos/química , Monoterpenos/isolamento & purificação , Monoterpenos/farmacologia , Caules de Planta/química , Caules de Planta/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/farmacologia , Vasodilatadores/química , Vasodilatadores/isolamento & purificação , Vasodilatadores/farmacologia
7.
Molecules ; 24(12)2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208086

RESUMO

B. monnieri extract (BME) is an abundant source of bioactive compounds, including saponins and flavonoids known to produce vasodilation. However, it is unclear which components are the more effective vasodilators. The aim of this research was to investigate the vasorelaxant effects and mechanisms of action of saponins and flavonoids on rat isolated mesenteric arteries using the organ bath technique. The vasorelaxant mechanisms, including endothelial nitric oxide synthase (eNOS) pathway and calcium flux were examined. Saponins (bacoside A and bacopaside I), and flavonoids (luteolin and apigenin) at 0.1-100 µM caused vasorelaxation in a concentration-dependent manner. Luteolin and apigenin produced vasorelaxation in endothelial intact vessels with more efficacy (Emax 99.4 ± 0.7 and 95.3 ± 2.6%) and potency (EC50 4.35 ± 1.31 and 8.93 ± 3.33 µM) than bacoside A and bacopaside I (Emax 83.6 ± 2.9 and 79.9 ± 8.2%; EC50 10.8 ± 5.9 and 14.6 ± 5.4 µM). Pretreatment of endothelial intact rings, with L-NAME (100 µM); an eNOS inhibitor, or removal of the endothelium reduced the relaxant effects of all compounds. In K+-depolarised vessels suspended in Ca2+-free solution, these active compounds inhibited CaCl2-induced contraction in endothelial denuded arterial rings. Moreover, the active compounds attenuated transient contractions induced by 10 µM phenylephrine in Ca2+-free medium containing EGTA (1 mM). Thus, relaxant effects occurred in both endothelial intact and denuded vessels which signify actions through both endothelium and vascular smooth muscle cells. In conclusion, the flavonoids have about twice the potency of saponins as vasodilators. However, in the BME, there is ~20 × the amount of vaso-reactive saponins and thus are more effective.


Assuntos
Bacopa/química , Artérias Mesentéricas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Extratos Vegetais/química , Ratos , Vasodilatadores/química
8.
Pharm Dev Technol ; 24(9): 1083-1094, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31215307

RESUMO

This study aims at improving the bioavailability of a poorly soluble phosphodiesterase-5 inhibitor; tadalafil (TD) via developing intranasal (IN) nanoemulsions (NEs). Optimum NE ingredients were selected based on solubility studies, emulsification tests, and phase diagram construction. Both o/w and w/o NEs were selected based on their drug loading capacity. Optimum formulations were subjected to physicochemical characterization and were assessed for nasal toxicity through biochemical analysis of tumor necrosis factor-α (TNF-α) and caspase-3 in rat nasal tissues. Pharmacodynamic study was performed via biochemical analysis of cyclic guanosine monophosphate (cGMP) in rat penis 2-h post-treatment and compared with oral suspension of Cialis® tablets. Optimum o/w and w/o NEs were successfully prepared using different ratios of Capmul-MCM-EP, Labrasol:Transcutol-HP (1:1) and water. Optimized formulations exhibited more than 4000-fold increase in TD solubility compared with its aqueous solubility. Both formulations were optically isotropic with the majority of globules in the nanometric-size range. Nasal toxicity study revealed no significant difference in values of TNF-α and caspase-3 between the NE-treated groups and the control group. Both TD-NEs succeeded to achieve a significant enhancement in cGMP levels. Our findings suggested that IN administration of the developed TD-NEs could provide a safe and effective alternative to TD oral delivery.


Assuntos
Inibidores da Fosfodiesterase 5/administração & dosagem , Tadalafila/administração & dosagem , Vasodilatadores/administração & dosagem , Administração Intranasal , Animais , GMP Cíclico/metabolismo , Emulsões/química , Masculino , Transição de Fase , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacocinética , Inibidores da Fosfodiesterase 5/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Tadalafila/química , Tadalafila/farmacocinética , Tadalafila/farmacologia , Vasodilatadores/química , Vasodilatadores/farmacocinética , Vasodilatadores/farmacologia
9.
J Headache Pain ; 20(1): 47, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053059

RESUMO

BACKGROUND: Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action. METHODS: Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model. RESULTS: The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 µM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses. CONCLUSION: The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.


Assuntos
Vasos Coronários/efeitos dos fármacos , Artérias Meníngeas/efeitos dos fármacos , Metilaminas/farmacologia , Transtornos de Enxaqueca , Veia Safena/efeitos dos fármacos , Adulto , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Vasos Coronários/fisiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Artérias Meníngeas/fisiologia , Metilaminas/química , Metilaminas/uso terapêutico , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Veia Safena/fisiologia , Estereoisomerismo , Vasoconstritores/química , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/química , Vasodilatadores/farmacologia
10.
Eur J Med Chem ; 168: 146-153, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30818175

RESUMO

CGRP, known as the most potent vasodilator substance, plays an important role in hypertension initiation and development. TRPV1 and TRPA1 are critical in promoting the synthesis and release of CGRP, thereby regulating the cardiovascular tone. Rutaecarpine exhibits potent vasodilator and hypertensive effects by stimulating CGRP synthesis and release via activation of TRPV1. And NO has been shown to react with H2S in vivo to form HNO, thereby activating HNO-TRPA1-CGRP pathway. Inspired by combination therapy, 11 rutaecarpine-furoxan hybrids were designed, synthesized and evaluated. The results demonstrated that most hybrids exerted comparable or improved vasodilator activities. Among which, 13a is the most potent both ex vivo (EC50 = 13.1 nM) and in vivo. Mechanistic studies revealed that the vasodilator and anti-hypertensive effects of the hybrids might involve the promotion of CGRP release via dual activation of TRPV1 and TRPA1. This work suggests that dual-targeted hybrids might be an effective and promising approach to discover and develop novel anti-hypertensive drugs.


Assuntos
Anti-Hipertensivos/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Hipertensão/tratamento farmacológico , Alcaloides Indólicos/farmacologia , Oxidiazóis/farmacologia , Quinazolinas/farmacologia , Vasodilatadores/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Pressão Sanguínea/efeitos dos fármacos , Determinação da Pressão Arterial , Relação Dose-Resposta a Droga , Desenho de Drogas , Alcaloides Indólicos/química , Masculino , Estrutura Molecular , Oxidiazóis/química , Quinazolinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Vasodilatadores/síntese química , Vasodilatadores/química
11.
Molecules ; 24(5)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862086

RESUMO

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.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Isoxsuprina/química , Isoxsuprina/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Vasodilatadores/química , Vasodilatadores/farmacologia , Trifosfato de Adenosina/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/química , Bloqueadores dos Canais de Cálcio/química , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Sulfeto de Hidrogênio/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Óxido Nítrico/metabolismo , Bibliotecas de Moléculas Pequenas , Fluxo de Trabalho
12.
Biomed Pharmacother ; 112: 108571, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798130

RESUMO

Sildenafil Citrate (SC) is a US FDA approved drug, have been used to treat wounds due to their nitric oxide (NO) stimulating activity in the tissue. But, there are only a few studies about the topical effect of this drug on the healing of traumatic wounds. The purpose of the study is to develop topical SC hydrogel (SCH) and to investigate its dermal toxicity and wound healing efficacy in Sprague dawley rats. In the present study, hydrogel containing SC showed no change and stable with respect to pH, homogeneity, spreadability and effiecient encapsulation. SEM analysis represents the uniform texture of the SCH. Acute dermal toxicity of the SCH exhibited that the formulations are devoid of any toxic effects and safe to be used. Percentage of wound contraction, re-epithelization, tensile strength and biochemical parameters such as hydroxyproline, collagen, total protein and NO content at dermal level prove the wound healing efficacy of prepared SCH. In addition, histopathology confirmed that the SCH promoted re-epithelization, collagen synthesis, deposition and regeneration of skin appendages. Results demonstrated that SCH has no dermal toxicity and promoted wound healing. Thus, prepared SCH shows promising skin wound healing property against traumatic wounds.


Assuntos
Hidrogéis/administração & dosagem , Citrato de Sildenafila/administração & dosagem , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Composição de Medicamentos , Feminino , Hidrogéis/química , Hidrogéis/toxicidade , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila/química , Citrato de Sildenafila/toxicidade , Pele/metabolismo , Pele/patologia , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vasodilatadores/química , Vasodilatadores/toxicidade , Cicatrização/fisiologia
13.
J Med Food ; 22(3): 248-256, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30735081

RESUMO

Diosgenin is a phytoestrogen and a constituent of Dioscorea. It has several biological effects, and some of them are anti-inflammatory, antidiabetic, antitumor, and vasodilatory. The present study investigated both the vasorelaxing and antioxidant mechanisms of diosgenin in isolated rat aortic rings. Female rats weighing 200-220 g were subjected to sham or OVX operations at 8 weeks of age. Ovariectomy was performed for menopause induction after anesthesia. Diosgenin (10-9 M-3 × 10-4 M) produced a concentration-dependent relaxation in aortic rings precontracted with phenylephrine (1 µM), exhibiting Emax value of 55.34% ± 7.7% (in endothelium-intact rings) and Emax value of 30.30% ± 5.7% (in endothelium-denuded rings). In the endothelium-intact rings, the vasorelaxing effect of diosgenin was reduced by NG-nitro-l-arginine methyl ester (L-NAME) (100 µM), atropine (1 µM), indomethacin (10 µM), 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) (10 µM), 4-aminopyridine (1 mM), tetraethylammonium (3 mM), glibenclamide (10 µM), apamin (10 µM), and Tiron (1 µM). Diosgenin (10-5 M) inhibited the contractions induced by cumulative addition of phenylephrine (10-9-10-5 M). The 28-days treatment with diosgenin (50 mg/kg, v.o.) did not imply changes in the myeloperoxidase parameter, but increased significantly, levels of glutathione, superoxide dismutase, and nitric oxide, as well as reduced the concentration of malondialdehyde related to lipid peroxidation. Our results suggest that diosgenin induced relaxation in aortic rings via an endothelium-dependent pathway, which involves the EDRF, the opening of potassium channels and antioxidant action.


Assuntos
Diosgenina/administração & dosagem , Menopausa/efeitos dos fármacos , Fitoestrógenos/administração & dosagem , Extratos Vegetais/administração & dosagem , Vasodilatadores/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Dioscorea/química , Diosgenina/química , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Glutationa/metabolismo , Humanos , Técnicas In Vitro , Masculino , Menopausa/metabolismo , Nitritos/metabolismo , Ovariectomia , Estresse Oxidativo/efeitos dos fármacos , Fitoestrógenos/química , Extratos Vegetais/química , Canais de Potássio/metabolismo , Ratos , Ratos Wistar , Vasodilatadores/química
14.
Molecules ; 24(3)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736379

RESUMO

A group of nitrate derivatives of naturally occurring sauropunol A and B were designed and synthesized. Nitric oxide (NO) releasing capacity and vasodilatory capacity studies were performed to explore the structure-activity relationship of resulted nitrates. Biological evaluation of these compounds revealed that most of the synthesized mononitrate derivatives demonstrated superior releasing capacity than isosorbide mononitrate (ISMN), and 2MNS-6 even demonstrated stronger NO releasing capacity than isosorbide dinitrate (ISDN). Two dinitrates, DNS-1 and DNS-2, showed higher NO releasing capacity than ISDN. Evaluation of inhibitory activities to the contractions in mesenteric artery rings revealed that 2MNS-8 and DNS-2 showed stronger vasorelaxation activities than ISDN. High level of NO and soluble guanylyl cyclase (sGC) may be essential for the potent vasodilatory effect of DNS-2. The vasodilatory effects of DNS-2 may result from cellular signal transduction of NO-sGC-cGMP. DNS-2 was found to be the most potent sauropunol-derived nitrate vasodilatory agent for further pharmaceutical investigation against cardiovascular diseases.


Assuntos
Desenho de Drogas , Nitratos/química , Nitratos/farmacologia , Vasodilatadores/química , Vasodilatadores/farmacologia , Animais , Técnicas de Química Sintética , Técnicas In Vitro , Artérias Mesentéricas/efeitos dos fármacos , Estrutura Molecular , Nitratos/síntese química , Óxido Nítrico/química , Ratos , Relação Estrutura-Atividade , Vasodilatadores/síntese química
15.
Org Lett ; 21(4): 1197-1201, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30702896

RESUMO

Two novel sesquiterpenoids, curcumanes A (1) and B (2), possessing unprecedented skeletons with a dicyclo[3.2.1]octane and a dicyclo[3.3.1]nonane moiety, respectively, were isolated from Curcuma longa. Both of them had remarkable vasorelaxant activity on rat aorta via blocking extracellular Ca2+ influx through VDCCs and ROCCs. The activity of 1 was endothelium-independent, while that of 2 was endothelium-dependent. Compound 2 also prolonged APTT and TT to inhibit blood coagulation.


Assuntos
Aorta Torácica/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Curcuma/química , Receptores de Detecção de Cálcio/antagonistas & inibidores , Vasodilatadores/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Ratos , Receptores de Detecção de Cálcio/metabolismo , Vasodilatadores/química , Vasodilatadores/isolamento & purificação
16.
Pharmacol Res ; 141: 541-550, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30616017

RESUMO

Rutaecarpine is a bioactive alkaloid isolated from Evodia rutaecarpa (Wu Zhu Yu, Family: Rutaceae), a versatile medicinal herb which is clinically used to treat headache, abdominal pain, postpartum hemorrhage, dysentery, and amenorrhea in China. As one of the most representative indolopyridoquinazoline alkaloids of Evodia rutaecarpa, rutaecarpine has broad pharmacological actions in treating various cardiovascular, cerebrovascular, and metabolic diseases. The cardiovascular actions of rutaecarpine have aroused intense research interest due to its purported inotropic and chronotropic, vasodilatory, anti-platelet activation, anti-oxidant, anti-inflammatory, and lipid-lowering effects. Biochemical and pharmacological studies have illustrated the molecular targets of rutaecarpine, such as TRPV1, CGRP, AMPK, ABCA1, and ß1-AR. Furthermore, several rutaecarpine derivatives (such as bromorutaecarpine and fluororutaecarpine) have been shown to possess cardioprotective and vasculoprotective effects with improved safety profile. Hereby, we provide a systematic overview of pharmacological actions, toxicological effects, and molecular targets of rutaecarpine in cardiovascular disease prevention/treatment, aiming to exploit the therapeutic potential of rutaecarpine and its derivatives in treating cardiovascular diseases.


Assuntos
Cardiotônicos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Evodia/química , Alcaloides Indólicos/farmacologia , Quinazolinas/farmacologia , Alcaloides/química , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cardiotônicos/química , Cardiotônicos/uso terapêutico , Humanos , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Alcaloides Indólicos/química , Alcaloides Indólicos/uso terapêutico , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Quinazolinas/química , Quinazolinas/uso terapêutico , Vasodilatadores/química , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico
17.
Int J Pharm ; 558: 284-290, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30641181

RESUMO

Commercially available cilostazol (CIL) tablet releases drug immediately and is given twice a day as an antiplatelet and vasodilatory agent. However, clinical usefulness of immediate release (IR) preparation is limited due to its extremely poor water solubility and the difficulty in sustaining the blood concentration, resulting in unwanted side effects such as headaches, pyknocardia and heavy-headed symptoms. To achieve once a day dosage form with enhanced solubility and controlled release, double controlled release CIL matrix tablets (DCRT) were designed by modulating a sol-gel process of binary polymeric blends of a pH-independent hydroxylpropylmethylcellulose (HPMC) and a pH-dependent polymer (carbomer) assisted with anionic surfactant (sodium lauryl sulfate, SLS). The release profiles of the DCRT were varied according to the ratio of the two polymers. This DCRT enhanced dissolution rate of CIL in a controlled manner due to the sol-gel and erosion process of HPMC, and SLS-driven modulation of charged carbomer via neutralization and micellar interaction. The near-infrared (NIR) chemical imaging and gravimetric behaviors of DCRT clearly showed dynamic modulation of CIL during the swelling and hydration process. Furthermore, the plasma concentration of CIL in DCRT was highly improved and sustained in beagle dogs in a controlled manner.


Assuntos
Cilostazol/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Vasodilatadores/administração & dosagem , Animais , Disponibilidade Biológica , Cilostazol/química , Cilostazol/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Cães , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacocinética , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacocinética , Dodecilsulfato de Sódio/administração & dosagem , Dodecilsulfato de Sódio/química , Dodecilsulfato de Sódio/farmacocinética , Solubilidade , Tensoativos/administração & dosagem , Tensoativos/química , Tensoativos/farmacocinética , Vasodilatadores/química , Vasodilatadores/farmacocinética
18.
Phytomedicine ; 53: 163-170, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668395

RESUMO

BACKGROUND: Zanthoxylum armatum DC (Z. armatum), belonging to Rutaceae family, has been traditionally used for the treatment of various diseases such as hypertension, abdominal pain, headache, fever, high altitude sickness, diarrhea, dysentery, and as a tonic, condiment, and an anthelmintic treatment. HYPOTHESIS: The present study aims to evaluate the vasorelaxant effect of a methanolic extract of the fruits of Z. armatum, isolate the active components and characterize the underlying mechanism. STUDY DESIGN: A methanolic extract of fruits of Z. armatum was prepared and its vasorelaxant effect was studied using porcine coronary artery rings. Thereafter, the methanolic extract was analyzed, and a major compound was isolated and its structure elucidated (tambulin). Different pharmacological tools were used to characterize the vasorelaxant effect of tambulin. RESULTS: The methanolic extract and the isolated tambulin caused similar endothelium-independent relaxations of porcine coronary artery rings with and without endothelium indicating a direct relaxing effect at the vascular smooth muscle. Tambulin did not affect the relaxation curves to the endothelium-dependent vasodilators, bradykinin and the calcium ionophore A23187 in rings with endothelium. Tambulin (1 µM) slightly but significantly shifted leftwards the concentration-relaxation curve to the endothelium-independent vasodilators, sodium nitroprusside (SNP), forskolin (FC) and isoproterenol but not those to soluble guanylyl cyclase activators (YC-1 and BAY 41-2272) and K+ channel openers (levcromakalim and 1-EBIO). Pretreatment with tambulin inhibited, in a concentration-dependent manner, contractions to KCl, serotonin (5-HT), CaCl2 and U46619 in coronary artery rings without endothelium. Both the protein kinase A (H-89, 10 µM) and the protein kinase G (Rp-8-br-cyclic GMPS, 30 µM) inhibitors significantly reduced relaxations to tambulin in coronary artery rings without endothelium. CONCLUSION: The present findings indicate that tambulin isolated from Z. armatum (fruits) is a major active principle inducing vasorelaxation through a direct effect at the vascular smooth muscle and involving both the cyclic AMP and/or cyclic GMP relaxing pathways.


Assuntos
Benzopiranos/farmacologia , Vasos Coronários/efeitos dos fármacos , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Vasodilatadores/farmacologia , Zanthoxylum/química , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Animais , Benzopiranos/química , Bradicinina/farmacologia , Vasos Coronários/metabolismo , Vasos Coronários/fisiologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Frutas/química , Metanol/química , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Nitroprussiato/farmacologia , Técnicas de Cultura de Órgãos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Suínos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Vasodilatadores/química , Vasodilatadores/isolamento & purificação
19.
Molecules ; 24(2)2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30646523

RESUMO

Pulmonary arterial hypertension (PAH) is a rare and progressive disease arising from various etiologies and pathogenesis. PAH decreases life expectancy due to pulmonary vascular remodeling, elevation of mean pulmonary arterial pressure, and ultimately progresses to heart failure. While clinical treatments are available to reduce the associated symptoms, a complete cure has yet to be found. Phosphodiesterase-5 (PDE-5) inhibition has been identified as a possible intervention point in PAH treatment. The functional vasodilation response to N²,N4-diamino quinazoline analogues with differing PDE-5 inhibitory activities and varying physicochemical properties were assessed in both endothelium-intact and denuded rat pulmonary arteries to gain greater insight into their mode of action. All analogues produced vasorelaxant effects with EC50s ranging from 0.58 ± 0.22 µM to ˃30 µM. It was observed that vasodilation response in intact vessels was highly correlated with that of denuded vessels. The ~10% drop in activity is consistent with a loss of the nitric oxide mediated cyclic guanosine monophosphate (NO/cGMP) pathway in the latter case. A moderate correlation between the vasodilation response and PDE-5 inhibitory activity in the intact vessels was observed. Experimental protocol using the alpha-adrenergic (α1) receptor agonist, phenylephrine (PE), was undertaken to assess whether quinazoline derivatives showed competitive behavior similar to the α1 receptor blocker, prazosin, itself a quinazoline derivative, or to the PDE-5 inhibitor, sildenafil. Competitive experiments with the α1-adrenergic receptor agonist point to quinazoline derivatives under investigation here act via PDE-5 inhibition and not the former. The pre-incubation of pulmonary arterial rings with quinazoline test compounds (10 µM) reduced the contractile response to PE around 40⁻60%. The most promising compound (9) possessed ~32 folds higher selectivity in terms of vasodilation to its mammalian A549 cell cytotoxicity. This study provides experi0 0mental basis for PDE-5 inhibition as the mode of action for vasodilation by N²,N4-diamino quinazoline analogues along with their safety studies that may be beneficial in the treatment of various cardiovascular pathologies.


Assuntos
Diaminas/química , Diaminas/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Quinazolinas/química , Vasodilatação/efeitos dos fármacos , Vasodilatadores/química , Vasodilatadores/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Solubilidade , Relação Estrutura-Atividade
20.
J Ethnopharmacol ; 232: 135-144, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30543913

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Citrus reticulatae Pericarpium (Chen pi) was widely used as an important ingredient in the prescription of TCM to treat phlegm fluid retention type hypertension. Since Chen pi is involved in treatment as antihypertensive TCM formula, we have reasonable expectation in believing that it might possess vasorelaxant activity. AIM OF THE STUDY: This study is designed to investigate the vasorelaxant effect of Chen pi and to study its pharmacology effects. MATERIALS AND METHODS: The vasorelaxant effect of water extract of Chen pi (CRW) were evaluated on thoracic aortic rings isolated from Sprague Dawley rats. The fingerprint of Chen pi and the extracts were developed with quantification of hesperidin content by HPTLC. RESULTS: CRW exhibited the strongest vasorelaxant activity. CRW caused the relaxation of the phenylephrine pre-contracted aortic rings in the presence and absence of endothelium as well as in potassium chloride pre-contracted endothelium-intact aortic ring. The incubation of propranolol (ß-adrenergic receptor blocker), atropine (muscarinic receptor blocker), Nω-nitro-L-arginine methyl ester (NO synthase inhibitor), ODQ (sGC inhibitor), indomethacin (COX inhibitor), 4-aminopyridine (KV blocker), barium chloride (Kir blocker), and glibenclamide (KATP blocker) significantly reduced the vasorelaxant effects of CRW. CRW was also found to be active in reducing Ca2+ releases from the sarcoplasmic reticulum and suppressing the voltage-operated calcium channels. CONCLUSION: The vasorelaxant effect of CRW on rat aorta involves NO/sGC, calcium and potassium channels, muscarinic and ß-adrenergic receptors.


Assuntos
Aorta Torácica/efeitos dos fármacos , Citrus , Extratos Vegetais/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/fisiologia , Canais de Cálcio/fisiologia , Citrus/química , Técnicas In Vitro , Masculino , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Canais de Potássio/fisiologia , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/fisiologia , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/fisiologia , Vasodilatadores/química
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