RESUMO

High IL-10 levels are pivotal to parasite survival in visceral leishmaniasis (VL). Antigenic stimuli induce IL-10 expression and release of adenosine by CD39/CD73. Due their intrinsic ability to express IL-10 and produce adenosine from extracellular ATP, we evaluated the IL-10, CD39, and CD73 expression by Regulatory T cells (Treg) correlated with VL pathology. Using flow cytometry, Treg cells was analyzed in peripheral blood samples from VL patients (in the presence and absence of Leishmania infantum soluble antigen (SLA)) and healthy individuals (negative endemic control-NEC group), without any treatment. Additionally, IL-10 levels in leukocytes culture supernatant were measured in all groups by ELISA assay. VL patients presented more Treg frequency than NEC group, independently of stimulation. ELISA results demonstrated that SLA induced higher IL-10 expression in the VL group. However, the NEC group had a higher Treg IL-10+ compared to the VL group without stimulation and SLA restored the IL-10 in Treg. Additionally, an increase in Treg CD73+ in the VL group independently of stimuli compared to that in the NEC group was observed. We suggest that Treg are not the main source of IL-10, while the CD73 pathway may be an attempt to modulate the exacerbation of immune response in VL disease.

RESUMO

This work aimed to explore the cardiovascular effects induced by freeze-dried juice from Syzygium jambolanum (Lam.) DC fruits (JSJ). JSJ presented high polyphenol content and steroids. HPLC analysis revealed that 2,5-dihydroxybenzoic and caffeic acid were present in higher amounts in the JSJ extract. In rat, JSJ induces hypotension and vasodilatation in mesenteric arteries, with or without vascular endothelium. JSJ-mediated vasodilation response against contractions induced with KCl (60 mM) depolarizing solution was significantly lower than the responses induced by JSJ when evaluated against phenylephrine-induced contractions. To investigate the involvement of potassium channels we used Tyrode's solution with KCl (20 mM) or tetraethylammonium (1.0, 3.0, or 5.0 mM). In these conditions JSJ-induced effects were significantly attenuated. To investigate the potassium channel subtypes involved in the response, we used 4-aminopyridine, glibenclamide, BaCl2, and iberiotoxin. In the presence (simultaneous) of different potassium channel blockers we observed a significant attenuation of JSJ-induced effect. Inhibition was also observed when using BaCl2, glibenclamide, or 4-aminopyridine, separately. However, incubation with iberiotoxin did not promote changes in either maximum effect, or potency. We also evidenced a discrete participation of CaV channels in the JSJ-induced vasorelaxant effect. In addition, patch-clamp studies demonstrated that JSJ could activate potassium channels. In conclusion, JSJ promotes hypotension and vasorelaxation in rats, involving, at least, the activation of potassium channels.

Assuntos

Sucos de Frutas e Vegetais , Hipotensão , Artérias Mesentéricas , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/metabolismo , Syzygium/química , Vasodilatação/efeitos dos fármacos , Animais , Liofilização , Hipotensão/induzido quimicamente , Hipotensão/metabolismo , Hipotensão/fisiopatologia , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Bloqueadores dos Canais de Potássio/química , Ratos , Ratos Wistar

RESUMO

BACKGROUND: In northeastern Brazil, grape pomace has become a potential alternative byproduct because of the recover phenolic compounds from the vinification process. Comparative analyses were performed between lyophilized extract of grape skins from pomace, described as fermented (FGS), and fresh, unfermented (UGS) grape skins to show the relevant brand's composition upon the first maceration in winemaking. METHODS: The use of in vitro testing such as Folin-Ciocalteu's, DPPH free radical scavenger and HPLC methods were performed to evidence antioxidant effect and phenolic compounds. Additionally, vascular reactivity studies were performed in third-order branches of rat superior mesenteric arteries, which were obtained and placed in organ baths containing Krebs-Henseleit solution, maintained at 37 °C, gassed with a mixture of 95% O2 and 5% CO2, and maintained at pH 7.4. The in situ formation of reactive oxygen species (ROS) was evaluated in small mesenteric rings using oxidative fluorescent dihydroethidium dye. RESULTS: We found higher phenolic content and antioxidant activity in FGS when compared to UGS. HPLC analyses identified a significant number of phenolic compounds with antioxidant potential in both samples. The vasorelaxant effect induced by FGS was more potent than that induced by UGS, and the activity was attenuated after removal of vascular endothelium or by blockade of endothelium-derived relaxing factors, such as NO and EDHF. CONCLUSIONS: The FGS extract may be a great source of natural polyphenol products with potent antioxidant effects and endothelium-dependent vasodilatory actions involving NO and EDHF pathways.

Assuntos

Antioxidantes/farmacologia , Frutas/química , Fenóis/farmacologia , Epiderme Vegetal/química , Extratos Vegetais/farmacologia , Vasodilatadores/farmacologia , Vitis/química , Animais , Antioxidantes/análise , Artérias/efeitos dos fármacos , Artérias/fisiologia , Compostos de Bifenilo/metabolismo , Brasil , Cromatografia Líquida de Alta Pressão , Fermentação , Fenóis/análise , Picratos/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Vasodilatadores/análise

RESUMO

It has been established that oximes cause endothelium-independent relaxation in blood vessels. In the present study, the cardiovascular effects of the new oxime 3-hydroxy-4-(hydroxyimino)-2-(3-methylbut-2-enylnaphtalen-1(4H)-one (Oxime S1) derived from lapachol were evaluated. In normotensive rats, administration of Oxime S1 (10, 15, 20 and 30 mg/Kg, i.v.) produced dose-dependent reduction in blood pressure. In isolated aorta and superior mesenteric artery rings, Oxime S1 induced endothelium-independent and concentration-dependent relaxations (10(-8) M to 10(-4) M). In addition, Oxime S1-induced vasorelaxations were attenuated by hydroxocobalamin or methylene blue in aorta and by PTIO or ODQ in mesenteric artery rings, suggesting a role for the nitric oxide (NO) pathway. Additionally, Oxime S1 (30 and 100 µM) significantly increased NO concentrations (13.9 ± 1.6 nM and 17.9 ± 4.1 nM, respectively) measured by nitric oxide microsensors. Furthermore, pre-contraction with KCl (80 mM) prevented Oxime S1-derived vasorelaxation in endothelium-denuded aortic rings. Of note, combined treatment with potassium channel inhibitors also reduced Oxime S1-mediated vasorelaxation suggesting a role for potassium channels, more precisely Kir, Kv and KATP channels. We observed the involvement of BKCa channels in Oxime S1-induced relaxation in mesenteric artery rings. In conclusion, these data suggest that the Oxime S1 induces hypotension and vasorelaxation via NO pathway by activating soluble guanylate cyclase (sGC) and K+ channels.

Assuntos

GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Naftoquinonas/farmacologia , Óxido Nítrico/metabolismo , Oximas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Naftoquinonas/química , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Oximas/química , Canais de Potássio/metabolismo , Ratos , Guanilil Ciclase Solúvel , Vasodilatadores/química

RESUMO

The cardiovascular effects induced by a new organic nitrate were investigated in rats. The (Z)-ethyl 12-nitrooxy-octadec-9-enoate (NCOE) was synthesized from ricinoleic acid, the major compound of the castor oil. NCOE induced significant and dose-dependent hypotension and bradycardia in normotensive rats. In rats pretreated with NCOE (60 mg/kg, i.v., once a day) for 4 consecutive days, hypotension induced by the nitrate was similar to that observed in rats that were not pretreated with the compound. The vasorelaxation induced by the compound was concentration-dependent (10(-10)-10(-3) M) in rat mesenteric artery rings, pre-contracted with phenylephrine (1 µM), with or without endothelium. Pre-incubation with PTIO (300 µM), a free radical form of NO (NO) scavenger, attenuated the NCOE vasorelaxation potency. However, in the presence of L-cysteine (3 mM), a reduced form of NO (NO-) scavenger, NCOE response was potentiated. NCOE effect was not changed in the presence of an inhibitor of cytochrome P450, proadifen (10 µM). On the other hand, the vasodilation was reduced in the presence of mitochondrial aldehyde dehydrogenase inhibitor (mtALDH), cyanamide (1 mM); soluble guanylyl cyclase inhibitor (sGC), ODQ (10 µM); and non-selective K+ channels blocker, TEA (3 mM). In addition the NCOE-induced vasorelaxation was reduced by BKCa (iberiotoxin, 100 nM) and KATP selective (glibenclamide, 10 µM) blockers, however the effect was not modified by a KV blocker (4-aminopyridine, 1 mM). Furthermore, NCOE increased NO levels in rat aortic smooth muscle cultured cells, detected by NO-sensitive probe DAF-2DA, by flow cytometry. These results together suggest that NCOE induces short-lasting hypotension and bradycardia, and promotes vasorelaxation due to NO release through the compound metabolism via mtALDH and consequent sGC, KATP and BKCa activation. Furthermore, the compound was not able to induce tolerance.

Assuntos

Artérias Mesentéricas/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nitratos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Ácidos Ricinoleicos/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta/citologia , Bradicardia/induzido quimicamente , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Hipotensão/induzido quimicamente , Técnicas In Vitro , Masculino , Artérias Mesentéricas/fisiologia , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Fenilefrina/farmacologia , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia

RESUMO

Linalool is a monoterpene alcohol and constituent of several Brazilian aromatic medicinal plants, popularly used against hypertension. Cardiovascular effects induced by linalool were evaluated. In normotensive rats, (+/-)-linalool [1, 5, 10, and 20 mg/kg body weight (BW); intravenous (i.v.)]-induced hypotension was associated with tachycardia, which was attenuated by atropine (2 mg/kg BW) and N(G)-nitro-L-arginine methyl ester (20 mg/kg BW), but was not modified after indomethacin (5 mg/kg BW) administration. In hypertensive rats, linalool [200 mg/kg BW; oral (v.o.)] reduced blood pressure without changing the heart rate. In intact rings of rat mesenteric artery precontracted with 10 microM phenylephrine, linalool (from 6.4 x 10(-6) to 6.4 x 10(-3) M) induced relaxations in a concentration-dependent manner [E(max) = (115 +/- 13)%] that were not changed after atropine administration [E(max) = (105 +/- 2)%], and were not different from those obtained in endothelium-denuded rings precontracted with phenylephrine [E(max) = (108 +/- 7)%] or 80 mM KCl [E(max) = (113 +/- 7)%] or tetraethylammonium incubation [E(max) = (105 +/- 12)%]. Linalool (1.9 x 10(-3) M) antagonized the contractions induced by CaCl2 (3 x 10(-6)-10(-2) M) (maximal inhibition, 81%). Furthermore, linalool inhibited the contractions induced by 10 microM phenylephrine or 20 mM caffeine. In conclusion, these results demonstrate that linalool reduces blood pressure probably due to a direct effect on the vascular smooth muscle leading to vasodilation.

Assuntos

Sistema Cardiovascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Monoterpenos/farmacologia , Monoterpenos Acíclicos , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Monoterpenos/uso terapêutico , Ratos , Ratos Wistar

RESUMO

For many years, nitric oxide (NO) has been studied as an important mediator in the control of vascular tone. Endothelial deficiencies that diminish NO production can result in the development of several future cardiovascular diseases, such as hypertension and arteriosclerosis. In this context, new drugs with potential ability to donate NO have been studied. In this study, 3 aromatic oximes [benzophenone oxime, 4-Cl-benzophenone oxime, and E-cinnamaldehyde oxime (E-CAOx)] induced vasorelaxation in endothelium-denuded and intact superior mesenteric rings precontracted with phenylephrine. E-CAOx demonstrated the most potent effect, and its mechanism of action was evaluated. Vascular reactivity experiments demonstrated that the effect of E-CAOx was reduced by the presence of 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one, and (Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate, suggesting the participation of NO/sGC/PKG pathway. NO donation seems to be mediated through nicatinamide adenine dinucleotide phosphate-dependent reductases because 7-ethoxyresorufin decreased the effect of E-CAOx on vascular reactivity and reduced NO formation as detected by flow cytometry using the NO indicator diaminofluorescein 4,5-diacetate. Further downstream of NO donation, K+ subtype channels were also shown to be involved in the E-CAOx vasorelaxant effect. The present study showed that E-CAOx acts like an NO donor, activating NO/sGC/PKG pathway and thus K+ channels.

Assuntos

Acroleína/análogos & derivados , Artéria Mesentérica Superior/efeitos dos fármacos , Óxido Nítrico/fisiologia , Transdução de Sinais/efeitos dos fármacos , Acroleína/farmacologia , Animais , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Luminescência , Masculino , Relaxamento Muscular/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Oximas/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologia , Ratos , Ratos Wistar

RESUMO

The present study used functional and electrophysiological approaches to investigate the mechanisms by which warifteine, a bisbenzylisoquinoline alkaloid isolated from Cissampelos sympodialis Eichl., causes vasorelaxation of the rat thoracic aorta. Warifteine (1 pmol/L-10 µmol/L) induced concentration-dependent relaxation (pD(2) = 9.40 ± 0.06; n = 5) of endothelium-intact aortic rings precontracted with noradrenaline (10-100 µmol/L). The relaxation effects were not attenuated by removal of the endothelium. Warifteine also induced the relaxation of prostaglandin F(2α) (1-10 mmol/L)-precontracted rings (pD(2) = 9.2 ± 0.2; n = 8). In contrast, the relaxant activity of warifteine was nearly abolished in high K(+) (80 mmol/L)-precontracted aortic rings. In preparations incubated with 20 mmol/L KCl or with the K(+) channel blockers tetraethylammonium (1, 3 and 5 mmol/L), iberiotoxin (20 nmol/L), 4-aminopyridine (1 mmol/L) or glibenclamide (10 µmol/L), the vasorelaxant activity of warifteine was markedly reduced. However, BaCl(2) (1 mmol/L) had no effect on the relaxant effects of warifteine. In vascular myocytes, warifteine (100 nmol/L) significantly increased whole-cell K(+) currents (at 70 mV). Under nominally Ca(2+) -free conditions, warifteine did not reduce extracellular Ca(2+) -induced contractions in rings precontracted with high K(+) or noradrenaline (100 µmol/L). Together, the results of the present study indicate that warifteine induces potent concentration-dependent relaxation in the rat aorta via an endothelium-independent mechanism that involves the activation of K(+) channels.

Assuntos

Alcaloides/farmacologia , Células Musculares/efeitos dos fármacos , Canais de Potássio/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Cálcio/metabolismo , Dinoprosta/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Masculino , Células Musculares/metabolismo , Norepinefrina/farmacologia , Potássio/farmacologia , Ratos , Ratos Wistar , Vasodilatadores/farmacologia

RESUMO

The reduced availability of nitric oxide (NO) is associated with cardiovascular diseases. Therefore, NO donors such as organic nitrates are useful for the treatment of these disorders. The 2-nitrate-1,3-dibuthoxypropan (NDBP) is an organic nitrate synthesized from glycerin, which the pharmacological effects have not been investigated. In this study we evaluated the vasorelaxant effect induced by NDBP in superior mesenteric artery from rats. In phenylephrine pre-contracted artery rings, NDBP (10(-8)-10(-4)M) elicited concentration-dependent and endothelium-independent relaxation, which were attenuated by hydroxocobalamin-HDX (30 µM), a NO extracellular scavenger, and 1-H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one-ODQ (10 µM), an inhibitor of soluble guanylyl cyclase (sGC). In addition, the NDBP-induced relaxation was reduced by non-selective K(+) channels blocker KCl (20 mM) or selective K(+) channels blockers such as tetraethylammonium-TEA (B(KCa), 1 mM), charybdotoxin-ChTX (B(KCa), 100 nM), glibenclamide (K(ATP), 1µM) and 4-aminopyridine-4-AP (K(V), 1mM). In preparations with ODQ (10 µM) plus TEA (1 mM), the response was virtually abolished. In rat smooth muscle cells culture, NDBP (10(-6)-10(-4)M) caused concentration-dependent increases in NO levels. These findings suggest that NDBP causes vasorelaxation through NO generation and activation of the sCG/cGMP/PKG pathway.

Assuntos

Artérias Mesentéricas/efeitos dos fármacos , Nitratos/metabolismo , Nitratos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , Propano/análogos & derivados , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Sequestradores de Radicais Livres/farmacologia , Glicerol/química , Guanilato Ciclase/antagonistas & inibidores , Técnicas In Vitro , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Artérias Mesentéricas/citologia , Artérias Mesentéricas/fisiologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Nitratos/síntese química , Nitratos/química , Óxido Nítrico/biossíntese , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/metabolismo , Oxidiazóis/farmacologia , Fenilefrina/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/metabolismo , Propano/síntese química , Propano/química , Propano/metabolismo , Propano/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Guanilil Ciclase Solúvel , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/química , Vasodilatadores/metabolismo

RESUMO

This work presents the observed changes in Wistar rats under long treatment (thirteen weeks) with different oral doses of the ethanolic extract (EE) from Jatropha gossypiifolia L., Euphorbiaceae. The most significant toxic signs indicated a reduction of the activity in the central nervous system and digestive disturbances. The histopathological analysis shows hepatotoxity and pulmonary damages. The lethality was 46.6% among males under the higher experimental dose (405 mg/kg) and 13.3% both in females under the higher dose and among the animals treated with 135 mg/kg of the product. These data show the significant oral chronic toxicity of EE of J. gossypiifolia in rats.

RESUMO

The cardiovascular effects elicited by the ethanolic extract obtained from the roots of Erythroxylum pungens O.E. Schulz, Erythroxylaceae (EEEP) and the vasorelaxant effect induced by its main tropane alkaloid (pungencine) were investigated. In normotensive rats, administration of EEEP (1, 10, 30 and 60 mg/kg i.v., randomly) produced dose-dependent hypotension (-2±1, -7±0.5 -17.6±1, -24±1 Δ mmHg, n=5) followed by tachycardia (3±0.5, 7±2, 7.1±1, 10±5 Δ bpm, n=5). In intact phenylephrine (Phe, 10 µM)-pre-contracted rings, EEEP (0.01-500 µg/mL) induced concentration-dependent vasorelaxation (EC50 13.7±5.5 µg/mL, Maximal Response= 92±2.6%), and this effect was unchanged after the removal of the vascular endothelium (EC50 27.2±4.7 µg/ml, Maximal Response= 88.3±3.3 %). In KCl (80 mM)-pre-contracted-endothelium-denuded rings, EEEP elicited concentration-dependent relaxation (EC50= 128.2±11.2 µg/mL, Maximal Response 76.8±3.4%). Vasorelaxation has also been achieved with tonic contractions evoked by the L-type Ca2+ channel agonist Bay K 8644 (EC50 80.2±9.1 µg/mL, Maximal Response 86.3±8.3%). In addition, in a depolarizing medium, EEEP inhibited CaCl2 (30-500 µg/mL) induced contractions and caused a concentration-dependent rightward shift of the relaxation curves. Lastly, the tropane alkaloid pungencine caused vasorelaxation in mesenteric arteries resembling to the EEEP responses. These results suggests that EEEP induces hypotension and vasorelaxation, at least in part, due to the reduction in [Ca2+]i in vascular smooth muscle cells.

RESUMO

This study aimed to investigate the cardiovascular effects elicited by Dictyota pulchella, a brown alga, using in vivo and in vitro approaches. In normotensive conscious rats, CH(2)Cl(2)/MeOH Extract (CME, 5, 10, 20 and 40 mg/kg) from Dictyota pulchella produced dose-dependent hypotension (-4 ± 1; -8 ± 2; -53 ± 8 and -63 ± 3 mmHg) and bradycardia (-8 ± 6; -17 ± 11; -257 ± 36 and -285 ± 27 b.p.m.). In addition, CME and Hexane/EtOAc Phase (HEP) (0.01-300 µg/mL) from Dictyota pulchella induced a concentration-dependent relaxation in phenylephrine (Phe, 1 µM)-pre-contracted mesenteric artery rings. The vasorelaxant effect was not modified by the removal of the vascular endothelium or pre-incubation with KCl (20 mM), tetraethylammonium (TEA, 3 mM) or tromboxane A(2) agonist U-46619 (100 nM). Furthermore, CME and HEP reversed CaCl(2)-induced vascular contractions. These results suggest that both CME and HEP act on the voltage-operated calcium channel in order to produce vasorelaxation. In addition, CME induced vasodilatation after the vessels have been pre-contracted with L-type Ca(2+) channel agonist (Bay K 8644, 200 nM). Taken together, our data show that CME induces hypotension and bradycardia in vivo and that both CME and HEP induce endothelium-independent vasodilatation in vitro that seems to involve the inhibition of the Ca(2+) influx through blockade of voltage-operated calcium channels.

Assuntos

Bloqueadores dos Canais de Cálcio/farmacologia , Phaeophyceae/química , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Animais , Produtos Biológicos/farmacologia , Canais de Cálcio/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Tetraetilamônio/farmacologia

RESUMO

The aim of this study was to investigate the mechanisms underlying the vasorelaxant effect induced by the polyphenolic compounds found in red wine from Vale do São Francisco. In phenylephrine (10 µM) precontracted mesenteric artery rings, the red wine caused a concentration-dependent relaxation (maximum response to phenylephrine 10 µM = 87.5% ± 6.5%, n = 10). After endothelium removal, the vasorelaxant effect elicited by red wine was attenuated (28.4% ± 4.9%, n = 10). In addition, the vasorelaxant effect induced by red wine in rings pretreated with 100 µM of N(w)-nitro-l-arginine methyl ester and 10 µM of 1H-[1,2,4] oxadiazolo-[4,3-a]-quinoxalin-1-one was attenuated (23.4% ± 5.1%, n = 7 and 11.8% ± 2.7%, n = 6, respectively). Pretreatment with atropine did not affect the vasorelaxant effect induced by red wine (81% ± 3.9%, n = 6). Furthermore, in rabbit aortic endothelial cell line, red wine 100 and 300 µg/mL caused concentration-dependent increases in nitric oxide levels (58 ± 1; 82 ± 7.9; Δ% of fluorescence, n = 5, respectively). In conclusion, we suggest that the alcohol free-lyophilized red wine induces an endothelium-dependent vasorelaxant effect due, at least in part, to a secondary increase in the concentration of nitric oxide and that this effect might be associated with phenolic compounds found in the red wine.

Assuntos

Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Flavonoides/farmacologia , Artéria Mesentérica Superior/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fenóis/farmacologia , Vasodilatadores/farmacologia , Vinho/análise , Animais , Aorta/metabolismo , Brasil , Linhagem Celular , Endotélio Vascular/metabolismo , Inibidores Enzimáticos/farmacologia , Flavonoides/análise , Liofilização , Guanilato Ciclase/antagonistas & inibidores , Técnicas In Vitro , Masculino , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Fenóis/análise , Polifenóis , Coelhos , Ratos , Ratos Wistar

RESUMO

The mechanisms underlying the cardiovascular responses evoked by milonine (i.v.), an alkaloid, were investigated in rats. In normotensive rats, milonine injections produced hypotension and tachycardia, which were attenuated after N(w) -nitro-L-arginine methyl esther (L-NAME; 20 mg/kg, i.v.). In phenylephrine (10 µM), pre-contracted mesenteric artery rings, milonine (10⁻¹° M to 3 × 10⁻4 M) caused a concentration-dependent relaxation (EC50 = 1.1 × 10⁻6 M, E(max) = 100 ± 0.0%) and this effect was rightward shifted after either removal of the vascular endothelium (EC50 = 1.6 × 10⁻5, p < 0.001), or after L-NAME 100 µM (EC50 = 6.2 × 10⁻5, p < 0.001), hydroxocobalamin 30 µM (EC50 = 1.1 × 10⁻4, p < 0.001) or ODQ 10 µM (EC50 = 1.9 × 10⁻4 p < 0.001). In addition, in rabbit aortic endothelial cells, milonine increased NO3⁻ levels. The relaxant effect induced by milonine was attenuated in the presence of KCl (20 mM), a modulator efflux K(+) (EC50 = 1.2 × 10⁻5, p < 0.001), or different potassium channel blockers such as glibenclamide (10 µM) (EC50 = 6.3 × 10⁻5, p < 0.001), TEA (1 mM) (EC50 = 2.3 × 10⁻5 M, n = 6) or Charybdotoxin (0.2 µM) plus apamin (0.2 µM) (EC50 = 3.9 × 10⁻4 M, n = 7). In addition, pre-contraction with high extracellular potassium concentration prevented milonine-induced vasorelaxation (EC50 = 1.0 × 10⁻4, p < 0.001). Milonine also reduced CaCl2 -induced contraction in Ca²(+) -free solution containing KCl (60 mM). In conclusion, using combined functional and biochemical approaches, we demonstrated that the hypotensive and vasorelaxant effects produced by milonine are, at least in part, mediated by the endothelium, likely via nitric oxide release, activation of nitric oxide-cGMP pathway and opening of K(+) channels.

Assuntos

Alcaloides/farmacologia , Endotélio Vascular/efeitos dos fármacos , Hipotensão/induzido quimicamente , Artéria Mesentérica Superior/efeitos dos fármacos , Morfinanos/farmacologia , Taquicardia/induzido quimicamente , Vasodilatadores/farmacologia , Animais , Aorta/citologia , Apamina/farmacologia , Células Cultivadas , Charibdotoxina/farmacologia , Glibureto/farmacologia , Modelos Lineares , Masculino , Músculo Liso Vascular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Bloqueadores dos Canais de Potássio/metabolismo , Cloreto de Potássio/metabolismo , Coelhos , Ratos , Ratos Wistar , Vasodilatação

RESUMO

In some pathological conditions such as hypertension, there is an impairment in the autonomic control of blood pressure resulting in changes in baroreflex sensitivity. In the present study we tested the hypothesis that acute superoxide scavenging would restore the reduced baroreflex sensitivity in renovascular hypertension. Male Wistar rats underwent 2-Kidney-1-Clip (2K1C) or sham surgery and were maintained untouched for six weeks to develop hypertension. After six weeks, animals from the 2K1C group were hypertensive when compared to the sham group (165±9 vs. 108±7mm Hg, P<0.05). As a proof of principle for the hypertension model adopted, animals from the 2K1C group presented increased non-clipped kidney and cardiac mass index and reduced clipped kidney mass index. Regarding baroreflex, 2K1C rats presented diminished baroreflex sensitivity when compared to the sham group (2K1C+saline: -1.61±0.15 vs. sham+saline: -2.79±0.24bpm mm Hg(-1), p<0.05). Moreover, acute administration of Vitamin C (150mg/Kg, i.v.) restored baroreflex sensitivity in 2K1C rats (2K1C+Vit C: -3.08±0.37 vs. 2K1C+saline: -1.61±0.15bpm mm Hg(-1), p<0.05). Furthermore, administration of apocynin (30µg/Kg, i.v.), a NADPH oxidase inhibitor, also improved baroreflex sensitivity in the 2K1C group (2K1C+apocynin: -2.81±0.24 vs. 2K1C+saline: -1.61±0.15bpm mm Hg(-1), p<0.05). In addition, autonomic blockade with either methylatropine or propranolol reduced the changes in heart rate to the same extent in all groups suggesting that improved baroreflex sensitivity by antioxidants were mediated by improvement in autonomic function. Taken together, these data suggest that NADPH oxidase-derived reactive oxygen species are involved in the blunted baroreflex sensitivity in renovascular hypertension and that acute scavenging of superoxide restores baroreflex sensitivity.

Assuntos

Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/fisiologia , Sequestradores de Radicais Livres/farmacologia , Nefropatias/fisiopatologia , Superóxidos/antagonistas & inibidores , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/metabolismo , Barorreflexo/efeitos dos fármacos , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Nefropatias/complicações , Nefropatias/metabolismo , Masculino , Ratos , Ratos Wistar , Superóxidos/metabolismo , Superóxidos/farmacologia

RESUMO

Pradosia huberi (Ducke) Ducke (Sapotaceae), an Amazonian species, is popularly known as "casca-doce" and used in the folk medicine for the treatment of gastritis. The ethanol extract of the bark contains mainly polyphenolic compounds, which are known to show a large number of activities, including cardioprotective and vasorelaxant effects. The aim of this study was to evaluate the pharmacological properties induced by P. huberi ethanol extract (PHEE) and fractions and 2-3-dihydromyricetin-3-O-α-L-rhamnoside derived from this extract, in isolated rat mesenteric arteries. PHEE was separated and the following fractions were obtained: CHCl3, CHCl3:AcOEt (1:1), AcOEt, AcOEt:MeOH (1:1) and MeOH. We isolated 2-3-dihydromyricetin-3-O-α-L-rhamnoside from the MeOH fraction, which was identified by¹H and 13C NMR spectra and compared with data in the literature. PHEE (1-100 µg/mL) induced concentration-dependent relaxations of 10 µM phenylephrine-induced tone (EC50=17,1±2,9 µg/mL; Emax=87.4±2.9 percent, n=8). The MeOH fraction also relaxed mesenteric rings (EC50=31±2.0 µg/mL; Emax=54±12.5 percent, n=6) but less effectively when compared to PHEE. Both effects were completely abolished after removal of the vascular endothelium. The AcOEt:MeOH (1:1) fraction and the isolated flavonoid were ineffective in eliciting vasorelaxation. The study demonstrates that PHEE and MeOH fraction of Pradosia huberi possess a vasorelaxant effect, which may be completely dependent upon endothelium. The isolated flavonoid is not responsible for this vasorelaxant effect.

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Pradosia huberi (Ducke) Ducke (Sapotaceae), espécie Amazônica popularmente conhecida como "casca-doce" é utilizada na medicina tradicional no tratamento de gastrite. O extrato etanólico de suas cascas é rico em polifenóis que podem apresentar um grande número de atividades, incluindo efeito vasorelaxante e cardioprotetor. O objetivo deste estudo foi avaliar as propriedades farmacológicas do extrato etanólico (EPH), de frações e da 2,3-diidromiricetina-3-O-α-L-raminosídeo isolados de P. huberi, em artéria mesentérica isolada de rato. O EPH foi fracionado resultando nas seguintes frações: CHCl3, CHCl3:AcOEt (1:1), AcOEt, AcOEt:MeOH (1:1) e MeOH. Da fração MeOH foi isolada a 2,3-diidromiricetina-3-O-α-L-raminosídeo e identificada através de espectro de RMN de ¹H e 13C, além de comparações com os dados de literatura. EPH (1-100 µg/mL) promoveu relaxamento dependente de concentração no tônus vascular induzido por 10 µM de fenilefrina (CE50=17,1±2,9 µg/mL; Emax=87,4±2,9 por cento, n=8). A fração MeOH também relaxou os anéis mesentéricos (CE50=31±2,0µg/mL; Emax=54±12,5 por cento, n=6), porém com menor eficácia quando comparado ao efeito de EPH. Tanto o efeito de EPH com de MeOH foram completamente abolidos após a remoção do endotélio vascular. A fração AcOEt:MeOH (1:1) e o flavonoide isolado induziram vasorelaxamento. O estudo demonstrou que o EPH e a fração MeOH de Pradosia huberi apresentam propriedade vasorelaxante que pode ser completamente dependente da presença do endotélio. O flavonoide isolado não é o responsável por este efeito vasorelaxante.

RESUMO

The vasorelaxant response of N-p-nitrophenylmaleimide (4-NO2-NPM) was evaluated. The mesenteric rings (1-2 mm i.d.) were suspended by cotton thread for isometric tension recordings in a Tyrode's solution at 37 degrees C and gassed with a mixture of 95% O2 and 5% CO2, under a resting tension of 0.75 g. 4-NO2-NPM induced relaxation in mesenteric rings pre-contracted with phenylephrine (Phe; 10 microM, pD2 = 6.7 +/- 0.3) or KCl (80 mM, pD2 = 3.9 +/- 0.2). This effect was significantly attenuated after removal of the vascular endothelium, N(G)-nitro L-arginine methyl ester (L-NAME; 100 microM), atropine (1 microM), indomethacin (10 microM), L-NAME + indomethacin or 1H-[1,2,3]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM). L-Arginine (1 mM) reversed the inhibitory effect of L-NAME. In endothelium-intact preparations pre-incubated with 20 mM KCl, tetraethylammonium bromide (TEA; 1 mM) or glibenclamide (Glib; 10 microM), the vasorelaxant effect was significantly attenuated when compared to controls (endothelium intact). In denuded rings, separate incubation with 20 mM KCl, TEA or Glib did not change the relaxation when compared with that obtained in denuded rings. 4-NO2-NPM inhibited in a concentration-dependent and non-competitive manner the concentration-response curves induced by CaCl2. In calcium-free medium, the transient contractions induced by Phe (10 microM) or caffeine (20 mM) were inhibited. The relaxant effect induced by 4-NO2-NPM appeared to be due to endothelial muscarinic receptors activation, NO and prostacyclin release and K(ATP) and BK(Ca) (Ca(2+)-activated K+ channels) endothelium-dependent activation. Inhibition of the Ca2+ influx and inhibition of the Ca2+ release from intracellular IP3- and caffeine-sensitive stores are also involved in the vasorelaxation.

Assuntos

Maleimidas/farmacologia , Artérias Mesentéricas/fisiologia , Vasodilatadores/farmacologia , Animais , Atropina/farmacologia , Cafeína/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Imidas/farmacologia , Técnicas In Vitro , Indometacina/farmacologia , Maleimidas/síntese química , Artérias Mesentéricas/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Tetraetilamônio/farmacologia , Vasodilatação/efeitos dos fármacos

RESUMO

1. Alpha-terpineol is a monoterpene found in the essential oils of several aromatic plant species. In the present study, we investigated the mechanisms underlying the cardiovascular changes induced by alpha-terpineol in rats. 2. In normotensive rats, administration of alpha-terpineol (1, 5, 10, 20 and 30 mg/kg, i.v.) produced a dose-dependent hypotension (-10 +/- 3, -20 +/- 8, -39 +/- 16, -52 +/- 21 and -57 +/- 23 mmHg, respectively; n = 5) followed by tachycardia. The hypotensive responses to 1, 5, 10, 20 and 30 mg/kg, i.v., alpha-terpineol were significantly attenuated following the administration of N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg, i.v.; -2 +/- 1, -5 +/- 2, -7 +/- 3, -22 +/- 9 and -22 +/- 10 mmHg, respectively; P < 0.05; n = 5). 3. In 10 micromol/L phenylephrine (PE)-precontracted mesenteric artery rings, alpha-terpineol (10(-12) to 10(-5) mol/L) caused a concentration-dependent relaxation (maximum relaxation 61 +/- 6%; n = 7). After removal of the endothelium, the vasorelaxation elicited by alpha-terpineol was attenuated (maximum relaxation 20 +/- 1%; P < 0.05; n = 7). In addition, vasorelaxation induced by alpha-terpineol in rings pretreated with 100 or 300 micromol/L l-NAME, 30 micromol/L hydroxocobalamin or 10 micromol/L 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one was attenuated (maximum relaxation 18 +/- 3, 23 +/- 3, 24 +/- 7 and 21 +/- 1%, respectively; n = 6; P < 0.05). 4. Furthermore, in a rabbit aortic endothelial cell line, 10(-6), 10(-5) and 10(-4) mol/L alpha-terpineol induced concentration-dependent increases in nitric oxide (NO) levels (12 +/- 6, 18 +/- 9 and 34 +/- 12%Delta fluorescence, respectively; n = 3). 5. In conclusion, using combined functional and biochemical approaches in the present study, we were able to demonstrate that alpha-terpineol-induced hypotension and vasorelaxation are mediated, at least in part, by the endothelium, most likely via NO release and activation of the NO-cGMP pathway.

Assuntos

Fármacos Cardiovasculares/farmacologia , GMP Cíclico/fisiologia , Cicloexenos/farmacologia , Monoterpenos/farmacologia , Óxido Nítrico/fisiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Monoterpenos Cicloexânicos , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Ratos , Ratos Wistar

RESUMO

Citronellol is an essential oil constituent from the medicinal plants Cymbopogon citratus, Cymbopogon winterianus and Lippia alba which are thought to possess antihypertensive properties. Citronellol-induced cardiovascular effects were evaluated in this study. In rats, citronellol (1-20 mg/kg, i.v.) induced hypotension, which was not affected by pre-treatment with atropine, hexamethonium, N(omega)-nitro-L-arginine methyl ester hydrochloride or indomethacin, and tachycardia, which was only attenuated by pre-treatment with atropine and hexamethonium. These responses were less than those obtained for nifedipine, a reference drug. In intact rings of rat mesenteric artery pre-contracted with 10 microM phenylephrine, citronellol induced relaxations (pD(2) = 0.71 +/- 0.11; E(max) = 102 +/- 5%; n = 6) that were not affected by endothelium removal, after tetraethylamonium in rings without endothelium pre-contracted with KCl 80 mM. Citronellol strongly antagonized (maximal inhibition = 97 +/- 4%; n = 6) the contractions induced by CaCl(2) (10(-6) to 3 x 10(-3 )M) and did not induce additional effects on the maximal response of nifedipine (10 microM). Finally, citronellol inhibited the contractions induced by 10 microM phenylephrine or 20 mM caffeine. The present results suggest that citronellol lowers blood pressure by a direct effect on the vascular smooth muscle leading to vasodilation.

Assuntos

Pressão Sanguínea/efeitos dos fármacos , Monoterpenos/farmacologia , Óleos de Plantas/farmacologia , Vasodilatação/efeitos dos fármacos , Monoterpenos Acíclicos , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Relação Dose-Resposta a Droga , Hipotensão/induzido quimicamente , Masculino , Monoterpenos/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Nifedipino/farmacologia , Óleos Voláteis/administração & dosagem , Óleos Voláteis/farmacologia , Óleos de Plantas/administração & dosagem , Ratos , Ratos Wistar , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia

RESUMO

This study aimed to evaluate the molluscicidal and larvicidal activity of some essential oils and phytochemicals from medicinal plants. Molluscicide and larvicidal activity were determined by, respectively, the lethality bioassays using Artemia salina Leach. Artemiidae and Aedes aegypti L. Culicidae larvae. Essential oils from Eugenia uniflora L. Myrtaceae, Laurus nobilis L. Lauraceae, Origanum vulgare L. Lamiaceae and the phytochemicals α-pinene and eugenol presented citotoxicity toward Artemia salina with CL50 values between 9.59 and 253.43 μL/mL. Essential oils from E. uniflora, M. piperita, O. vulgare and R. officinalis showed embryotoxicity on Aedes aegypti larvae with a viability inhibition between 40 and 100 percent. These results show the bioactivity of the assayed essential oils and phytochemicals and, partially, justify their insertion in further evaluation in order to establish a safe exploitation of their biological potentiality.

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Este estudo teve como objetivo avaliar a atividade moluscicida e larvicida de alguns óleos essenciais e fitoconstituintes de plantas medicinais. A atividade moluscicida e larvicida foi determinada empregando-se, respectivamente, o teste de letalidade contra náupilos de Artemia salina Leach. Artemiidae e contra larvas de Aedes aegypti L. Culicidae. Os óleos essenciais de Eugenia uniflora L. Myrtaceae, Laurus nobilis L. Lauraceae, Origanum vulgare L. Lamiaceae e os fitoconstituintes α-pineno e eugenol mostraram bioatividade citotóxica frente A. salina com valores de CL50 entre 9,59 e 253,43 μL/mL. Os óleos essenciais de E. uniflora, M. piperita, O. vulgare e R. officinalis apresentaram atividade de embriotoxicidade sobre as larvas de A. aegypti mostrando uma variação de inibição de viabilidade entre 40 e 100 por cento. Estes resultados demonstram o potencial de bioatividade desses óleos essenciais e fitoconstituintes e justificam, parcialmente, o desenvolvimento de estudos com esses produtos para uso popular.