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Tarantula venoms may be a natural source of new vasodilator components useful in pharmacological research. Moreover, biological function data of the venoms are important to enhance the knowledge about the biodiversity and evolution of these species. The present study aims to describe the vasodilatory activity induced by the venom of Poecilotheria ornata on isolated rat aortic rings. This venom induced a vasodilator activity that was significantly reduced after incubation with L-NAME or ODQ. Measurements of nitrite concentrations on rat aorta homogenates showed that the venom significantly increased the basal levels. Moreover, the venom attenuates the contraction induced by calcium. These results suggest that P. ornata venom contains a mixture of vasodilator components that act through the activation of the nitric oxide/cGMP pathway, as well as, through an endothelium-independent mechanism that involves the calcium influx into vascular smooth muscle cells.

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Venoms from tarantulas contain low molecular weight vasodilatory compounds whose biological action is conceived as part of the envenomation strategy due to its propagative effects. However, some properties of venom-induced vasodilation do not match those described by such compounds, suggesting that other toxins may cooperate with these ones to produce the observed biological effect. Owing to the distribution and function of voltage-gated ion channels in blood vessels, disulfide-rich peptides isolated from venoms of tarantulas could be conceived into potential vasodilatory compounds. However, only two peptides isolated from spider venoms have been investigated so far. This study describes for the first time a subfraction containing inhibitor cystine knot peptides, PrFr-I, obtained from the venom of the tarantula Poecilotheria regalis. This subfraction induced sustained vasodilation in rat aortic rings independent of vascular endothelium and endothelial ion channels. Furthermore, PrFr-I decreased calcium-induced contraction of rat aortic segments and reduced extracellular calcium influx to chromaffin cells by the blockade of L-type voltage-gated calcium channels. This mechanism was unrelated to the activation of potassium channels from vascular smooth muscle, since vasodilation was not affected in the presence of TEA, and PrFr-I did not modify the conductance of the voltage-gated potassium channel Kv10.1. This work proposes a new envenomating function of peptides from venoms of tarantulas, and establishes a new mechanism for venom-induced vasodilation.

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Senecio nutans Sch. Bip. and its constituents are reported to have antihypertensive effects. We isolated metabolite−1, a natural compound from S. nutans (4-hydroxy-3-(isopenten-2-yl)-acetophenone), and synthesized novel oxime − 1 (4-hydroxy-3-(isopenten-2-yl)-acetophenoxime) to evaluate their effect on vascular reactivity. Compounds were purified (metabolite−1) or synthetized (oxime−1) and characterized using IR and NMR spectroscopy and Heteronuclear Multiple Quantum Coherence (HMQC). Using pharmacological agents such as phenylephrine (PE) and KCl (enhancing contraction), acetylcholine (ACh), L-NAME (nitric oxide (NO) and endothelial function), Bay K8644-induced CaV1.2 channel (calcium channel modulator), and isolated aortic rings in an organ bath setup, the possible mechanisms of vascular action were determined. Pre-incubation of aortic rings with 10−5 M oxime−1 significantly (p < 0.001) decreased the contractile response to 30 mM KCl. EC50 to KCl significantly (p < 0.01) increased in the presence of oxime−1 (37.72 ± 2.10 mM) compared to that obtained under control conditions (22.37 ± 1.40 mM). Oxime−1 significantly reduced (p < 0.001) the contractile response to different concentrations of PE (10−7 to 10−5 M) by a mechanism that decreases Cav1.2-mediated Ca2+ influx from the extracellular space and reduces Ca2+ release from intracellular stores. At a submaximal concentration (10−5 M), oxime−1 caused a significant relaxation in rat aorta even without vascular endothelium or after pre-incubate the tissue with L-NAME. Oxime−1 decreases the contractile response to PE by blunting the release of Ca2+ from intracellular stores and blocking of Ca2+ influx by channels. Metabolite−1 reduces the contractile response to KCl, apparently by reducing the plasma membrane depolarization and Ca2+ influx from the extracellular space. These acetophenone derivates from S. nutans (metabolite−1 and oxime−1) cause vasorelaxation through pathways involving an increase of the endothelial NO generation or a higher bioavailability, further highlighting that structural modification of naturally occurring metabolites can enhance their intended pharmacological functions.

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We investigated the role of triterpene barbinervic acid from Eugenia punicifolia dichloromethane extract in vasopressor responses. Renal arteries were cannulated and perfused with Krebs-Hepes solution. Changes in aorta isometric tension were recorded and transferred to a data acquisition system. Cumulative curves were constructed based on the maximum effect of agonists. Barbinervic acid reduced the renal tonus induced by NA in a NO-dependent manner (IC50 = 30 µM). Triterpene (70 µM) also induced rapid and transient relaxation in aorta that had been precontracted with K+ (53.2 ± 0.05%) or phenylephrine (36.7 ± 0.05%). In silico data revealed two possible active sites for interactions between barbinervic acid and NO synthase. Barbinervic acid showed a vasodilator effect and could potentially be used as a template for developing new molecules for the treatment of cardiovascular disease.

Assuntos

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Heliotropium taltalense is an endemic species of the northern coast of Chile and is used as folk medicine. The polyphenolic composition of the methanolic and aqueous extract of the endemic Chilean species was investigated using Ultrahigh-Performance Liquid Chromatography, Heated Electrospray Ionization and Mass Spectrometry (UHPLC-Orbitrap-HESI-MS). Fifty-three compounds were detected, mainly derivatives of benzoic acid, flavonoids, and some phenolic acids. Furthermore, five major compounds were isolated by column chromatography from the extract, including four flavonoids and one geranyl benzoic acid derivative, which showed vascular relaxation and were in part responsible for the activity of the extracts. Since aqueous extract of H. taltalense (83% ± 9%, 100 µg/mL) produced vascular relaxation through an endothelium-dependent mechanism in rat aorta, and the compounds rhamnocitrin (89% ± 7%; 10-4 M) and sakuranetin (80% ± 6%; 10-4 M) also caused vascular relaxation similar to the extracts of H. taltalense, these pure compounds are, to some extent, responsible for the vascular relaxation.

Assuntos

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We aimed to characterize the participation of rapid non-genomic and delayed non-genomic/genomic or genomic mechanisms in vasoactive effects to triiodothyronine (T3), emphasizing functional analysis of the involvement of these mechanisms in the genesis of nitric oxide (NO) of endothelial or muscular origin. Influences of in vitro and in vivo T3 treatments on contractile and relaxant responsiveness of isolated rat aortas were studied. in vivo T3-treatment was 500 µg·kg-1·d-1, subcutaneous injection, for 1 (T31d) and 3 (T33d) days. In experiments with endothelium- intact aortic rings contracted with phenylephrine, increasing concentrations of T3 did not alter contractility. Likewise, in vitro T3 did not modify relaxant responses induced by acetylcholine or sodium nitroprusside (SNP) nor contractile responses elicited by phenylephrine or angiotensin II in endothelium-intact aortas. Concentration- response curves (CRCs) to acetylcholine and SNP in endothelium-intact aortic rings from T31d and T33d rats were unmodified. T33d, but not T31d, treatment diminished CRCs to phenylephrine in endothelium-intact aortic rings. CRCs to phenylephrine remained significantly depressed in both endothelium-denuded and endothelium- intact, nitric oxide synthase inhibitor-treated, aortas of T33d rats. In endotheliumdenuded aortas of T33d rats, CRCs to angiotensin II, and high K+ contractures, were decreased. Thus, in vitro T3 neither modified phenylephrine-induced active tonus nor CRCs to relaxant and contractile agonists in endothelium-intact aortas, discarding rapid non-genomic actions of this hormone in smooth muscle and endothelial cells. Otherwise, T33d-treatment inhibited aortic smooth muscle capacity to contract, but not to relax, in an endothelium- and NO-independent manner. This effect may be mediated by delayed non-genomic/genomic or genomic mechanisms.

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Metabolic syndrome is a multifaceted condition associated with a greater risk of various disorders (e.g., diabetes and heart disease). In a rat model of metabolic syndrome, an acute in vitro application of rosuvastatin causes relaxation of aortic rings. Since the outcome of a subchronic rosuvastatin treatment is unknown, the present study explored its effect on acetylcholine-induced vasorelaxation of aortic rings from rats with metabolic syndrome. Animals were submitted to a 16-week treatment, including a standard diet, a cafeteria-style diet (CAF-diet), or a CAF-diet with daily rosuvastatin treatment (10 mg/kg). After confirming the development of metabolic syndrome in rats, aortic segments were extracted from these animals (those treated with rosuvastatin and untreated) and the acetylcholine-induced relaxant effect on the corresponding rings was evaluated. Concentration-response curves were constructed for this effect in the presence/absence of L-NAME, ODQ, KT 5823, 4-aminopyridine (4-AP), tetraethylammonium (TEA), apamin plus charybdotoxin, glibenclamide, indomethacin, clotrimazole, and cycloheximide pretreatment. Compared to rings from control rats, acetylcholine-induced vasorelaxation decreased in rings from animals with metabolic syndrome, and was maintained at a normal level in animals with metabolic syndrome plus rosuvastatin treatment. The effect of rosuvastatin was inhibited by L-NAME, ODQ, KT 5823, TEA, apamin plus charybdotoxin, but unaffected by 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. In conclusion, the subchronic administration of rosuvastatin to rats with metabolic syndrome improved the acetylcholine-induced relaxant response, involving stimulation of the NO/cGMP/PKG/Ca2+-activated K+ channel pathway.

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This review discusses the contribution of the use of the isolated rat aorta (IRA) as a model for the evaluation of extracts and metabolites produced by plants with a vasodilator effect in animals. This model continues to be a valuable approach for the search and development of new phytochemicals consumed as medicinal plants or foods. In most cases, the sources of phytochemicals have been used in folk medicine to treat ailments that include hypertension. In this model, the endothelium is emphasized as a key component that modulates the vessel contractility, and therefore the basal tone and blood pressure. Based on the functional nature of the model, we focused on studies that determined the endothelium-dependent and -independent vasodilatory activity of phytochemicals. We describe the mechanisms that account for aorta contraction and relaxation, and subsequently show the vasoactive effect of a series of phytochemicals acting as vasodilators and its endothelium dependence. We highlight information regarding the cardiovascular benefits of phytochemicals, especially their potential antihypertensive effect. On this basis, we discuss the advantages of the IRA as a predictive model to support the research and development of new drugs that may be of help in the prevention and treatment of cardiovascular diseases, the number one cause of death worldwide.

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A group of nitro compounds contains a benzene ring in a short aliphatic chain with the NO2 group, property that supposedly favors its vasodilator profile. In this study, we evaluated in isolated rat aorta the effects of 1-nitro-2-propylbenzene (NPB), a nitro compound containing the NO2 in the aromatic ring. In aorta precontracted with KCl, NPB (1-3000 µm) induced full endothelium-independent relaxation. In endothelium-intact preparations, phenylephrine-induced contractions were fully relaxed by NPB, effect unaltered by N(ω)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). In the concentration range of 30-300 µm, NPB slightly but significantly potentiated the phenylephrine-induced contraction. Such potentiation was unaltered by the thromboxane-prostanoid receptor antagonist seratrodast, but was abolished by endothelium removal or by preincubation of endothelium-intact preparations with L-NAME, ODQ or by ruthenium red and HC-030031, blockers of subtype 1 of ankyrin transient receptor potential (TRPA1 ) channels. Verapamil exacerbated the potentiating effect of NPB. The potentiating effect was undetectable in preparations precontracted by 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α (U-46619). Relaxation was reduced by ruthenium red while it was enhanced by HC-030031. In conclusion, NPB has vasodilator properties but with a mechanism of action distinct from its analogues. Contrary to other nitro compounds, its relaxing effects did not involve recruitment of the guanylyl cyclase pathway. NPB has also endothelium-dependent potentiating properties on phenylephrine-induced contractions, a phenomenon that putatively required a role of endothelial TRPA1 channels. The present findings reinforce the notion that the functional group NO2 in the aliphatic chain of these nitro compounds determines favorably their vasodilator properties.

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BACKGROUND: Xenophyllum poposum is an endemic species of the Andes Cordillera, popularly known as Popusa. Popusa is widely used by mountain communities as a folk medicine to treat altitude sickness and hypertension. PURPOSE: The aim of this study is to evaluate the hypotensive effects and vascular reactivity of Popusa extracts and its pure isolated compounds. METHODS: Hydroalcoholic extract of Xenophyllum poposum (HAE X. poposum; 40 mg/kg dose) were administered to rats by gavage and mean arterial pressures were recorded. Organ bath studies were conducted in endothelium-intact and denuded rings, and the vascular reactivity of the HAE X. poposum extract and its isolated compounds were compared and analysed. Cytosolic Ca2+ was measured in vascular smooth muscle cell line A7r5 using Fura2-AM. RESULTS: HAE X. poposum significantly reduced the mean arterial blood pressure and heart rate in normotensive rats chronically treated with the extract, as well as mice acutely treated with the extract. A negative chronotropic effect was observed in the isolated rat heart. HAE X. poposum induced endothelial vasodilation mediated by nitric oxide (NO), reduced the contractile response to PE, and decreased PE-induced intracellular Ca2+ influx in vascular smooth muscle cells. Pure compounds isolated from HAE X. poposum such as 4­hydroxy­3-(3-methyl-2-butenyl) acetophenone, 5-acetyl-6­hydroxy­2-isopropenyl-2, and 3-dihydrobenzofurane (dihydroeuparin) also triggered endothelium-dependent vasodilation. CONCLUSION: HAE X. poposum decreases blood pressure, heart rate and vascular response. The vasodilation properties of HAE X. poposum extract and its isolated compounds may act through the endothelial nitric oxide synthase, as well as calcium channel blocker mechanisms. The results of the present study provide the first qualitative analysis that supports the use of X. poposum in traditional folk medicine for the treatment of altitude sickness and hypertension.

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