RESUMO
Although the semi-invariant natural killer T cells (iNKT) are a small subpopulation of cells in the peripheral blood, they are presumed to play a role in early stages of infection against various pathogens, including protozoa. This work investigates the activation status and cytokine profile of iNKT cells during human Leishmania infantum and Leishmania braziliensis infection. We studied iNKT cells in patients with symptomatic active visceral leishmaniasis (AVL) (n = 8), patients with symptomatic active cutaneous leishmaniasis (ACL) (n = 13), negative endemic controls (NEC) (n = 6) and non-endemic controls (NonEC) (n = 6), with and without total Leishmania antigen stimulus (TLA). The number of iNKT cells in the peripheral blood of patients with ACL and AVL unaltered in relation to control groups. Moreover, the iNKT cells from ACL showed a hyperactivation profile compared to patients with AVL. Additionally, TLA induced IFN-gamma production in iNKT cells from patients with ACL, while in iNKT of patients with AVL, TLA induced a decrease in this cytokine. Higher IL-17 and IL-10 production by iNKT cells from patients with ACL were also observed compared to all other groups. There were no changes in iNKT IL-10-producing cells in AVL after TLA stimulation. However, TLA induced increase in IL-10 in iNKT cells in patients with ACL. These findings suggest that, although iNKT cells showed distinct profiles in patients with ACL and AVL, they play a dual role in immune modulation in both Leishmania infections.
Assuntos
Plasticidade Celular/imunologia , Leishmania braziliensis/imunologia , Leishmania infantum/imunologia , Leishmaniose Cutânea/imunologia , Leishmaniose Visceral/imunologia , Células T Matadoras Naturais/imunologia , Adulto , Antígenos de Protozoários/imunologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/parasitologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Adulto JovemRESUMO
Animal toxins are natural resources for pharmacological studies. The venom of Crotalus durissus cascavella (C.d. cascavella) may be a source in the bio-prospecting of new anti-hypertensive agents. The aim of this study was to investigate vascular effects of the venom of C.d. cascavella in normotensive rats. Studies were performed using isolated mesenteric artery segments and aortic endothelial cells. The cumulative administration of the venom of C.d. cascavella (0.001-30 µg/mL) on phenylephrine (Phe; 10 µM) pre-contracted rings induced a concentration-dependent vasorelaxation in the presence of vascular endothelium (Emax = 47.9 ± 5.0% n = 8), and its effect was almost abolished in the absence of endothelium (Emax = 5.8± 2.4% n = 5 (∗∗∗p < 0.001)). Tissue viability was maintained as there was no difference in the contractile capacity of rings before and after the administration of venom. The vasorelaxant effect of the venom was also abolished when arteries were pre-contracted with potassium chloride (KCl; 80 mM) (Emax = 6.4± 0.9% n = 5, ∗∗∗p < 0.001). When assessing the participation of endothelium-derived relaxing factors, it was noted that non-selective COX inhibition with indomethacin (10 µM) caused a significant reduction in the vasorelaxant effect of C.d. cascavella (*p < 0.05). When investigating the participation of NO released by endothelium, there was a significant reduction of the vasorelaxant effect of venom in rings treated with L-NAME (100 µM; Emax = 17.5± 2.2% n = 6; **p < 0.01). Similar results were noted in the presence of ODQ (10 µM), an inhibitor of soluble guanylyl cyclase (Emax = 11.2± 3.5%, n = 6) and PTIO (100 µM), a stable radical scavenger for nitric oxide (Emax = 10.77± 3.6%, n = 6). Moreover, the venom induced the release of NO by isolated aortic endothelial cells through amperometric studies. When assessing the participation of K+ channels on the vasodilatory response of the venom, tyrode solution with 20 mM of KCl caused a significant reduction in the relaxation response (p < 0.001) (Emax = 21.3 ± 8%, n = 7), as did inhibitor of delayed rectifier K+ channels (4-amynopiridine 1 mM; Emax = 9.5 ± 1.3, %, n = 5, ***p < 0.001), and vasorelaxation was almost abolished in the presence of Iberiotoxin (IbTx 100 nM). Therefore, these results suggest that the venom of C.d. cascavella induces vasorelaxation in superior mesenteric artery rings of normotensive rats in an endothelium-dependent manner. Specifically, the venom stimulates the generation of endothelium-derived relaxing factors, especially NO, and activates vascular smooth muscle hyperpolarization through K+ channels. These data illustrate that C.d. cascavella is a source of bioactive molecules and therefore has therapeutic potential in the treatment of cardiovascular diseases such as hypertension.
Assuntos
Venenos de Crotalídeos/farmacologia , Crotalus , Artérias Mesentéricas/efeitos dos fármacos , Óxido Nítrico/metabolismo , Canais de Potássio/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Masculino , Artérias Mesentéricas/fisiologia , Músculo Liso Vascular , Fenilefrina/administração & dosagem , Fenilefrina/farmacologia , Canais de Potássio/fisiologia , Ratos WistarRESUMO
Neurogenic hypertension has been the subject of extensive research worldwide. This review is based on the premise that some forms of neurogenic hypertension are caused in part by the formation of angiotensin-II (Ang-II)-induced reactive oxygen species along the subfornical organ-paraventricular nucleus of the hypothalamus-rostral ventrolateral medulla pathway (SFO-PVN-RVLM pathway). We will discuss the recent contribution of our laboratory and others regarding the mechanisms by which neurons in the SFO (an important circumventricular organ) are activated by Ang-II, how the SFO communicates with two other important areas involved in sympathetic activity regulation (PVN and RVLM) and how Ang-II-induced reactive oxygen species participate along the SFO-PVN-RVLM pathway in the pathogenesis of neurogenic hypertension.
Assuntos
Humanos , Angiotensina II/fisiologia , Hipertensão/etiologia , Bulbo/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Órgão Subfornical/metabolismo , Angiotensina II/biossíntese , Neurônios/metabolismoRESUMO
Neurogenic hypertension has been the subject of extensive research worldwide. This review is based on the premise that some forms of neurogenic hypertension are caused in part by the formation of angiotensin-II (Ang-II)-induced reactive oxygen species along the subfornical organ-paraventricular nucleus of the hypothalamus-rostral ventrolateral medulla pathway (SFO-PVN-RVLM pathway). We will discuss the recent contribution of our laboratory and others regarding the mechanisms by which neurons in the SFO (an important circumventricular organ) are activated by Ang-II, how the SFO communicates with two other important areas involved in sympathetic activity regulation (PVN and RVLM) and how Ang-II-induced reactive oxygen species participate along the SFO-PVN-RVLM pathway in the pathogenesis of neurogenic hypertension.
Assuntos
Angiotensina II/fisiologia , Hipertensão/etiologia , Bulbo/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Órgão Subfornical/metabolismo , Angiotensina II/biossíntese , Humanos , Neurônios/metabolismoRESUMO
A espécie Jatropha gossypiifolia L. (Euphorbiaceae), popularmente conhecida como pião-roxo, entre tantos outros nomes, é um bom exemplo do tênue limiar que separa o efeito terapêutico do tóxico. Apesar de ser classicamente conhecida como planta tóxica possui usos na medicina popular. Alguns desses efeitos têm sido comprovados em estudos experimentais, como os de antimicrobiano, antineoplásico, cicatrizante e hipotensor, sendo possivelmente explicados pela presença de substâncias como alcalóides, terpenóides, flavonóides, lignanas e taninos. Esta revisão aborda aspectos importantes, com ênfase na toxicidade crônica dessa espécie, de modo a servir de fonte de informação aos interessados em avaliar a relação risco/benefício do uso terapêutico de Jatropha gossypiifolia L.
The species Jatropha gossypiifolia L. (Euphorbiaceae), popularly known as bellyache bush, among several other names, is an important example of the tenuous threshold that separates the therapeutic from the toxic effect. Although traditionally known as a toxic plant, it has been used in folk medicine. Some of its effects have been proved by experimental studies as antimicrobial, antineoplastic, healing and hypotensive, likely explained by the presence of substances such as alkaloids, terpenoids, flavonoids, lignans and tannins. This review deals with important aspects, focusing on the chronic toxicity of this species, in order to serve as an information source for those interested in evaluating the risk-benefit ratio of the therapeutic use of Jatropha gossypiifolia L.
Assuntos
Jatropha , Jatropha/química , Jatropha/toxicidade , Euphorbiaceae , Euphorbiaceae/química , Euphorbiaceae/toxicidade , FarmacologiaRESUMO
The aim of this study was to investigate the pharmacological effects of discretamine, an isoquinoline alkaloid isolated from Duguetia magnolioidea Maas, on the cardiovascular system, using a combined in vivo and in vitro approach. Blood pressure and heart rate measurements, as well as changes in isometric tension in rat superior mesenteric arterial rings, elicited by discretamine were recorded. In normotensive non-anaesthetized rats (n = 6), discretamine (0.01; 0.05; 0.1; 0.5; 1, 5 and 10 mg/kg i.v., randomly) injections produced hypotension (-5.2 +/- 1.7; -5.1 +/- 2.1; -7.7 +/- 2; -8.9 +/- 1.7; -9.6 +/- 2.2; -16.8 +/- 2.8 and -13.4 +/- 1.3 mmHg, respectively) accompanied by tachycardia (24.2 +/- 6.1; 36.8 +/- 11.3; 44.2 +/- 7.7; 45.9 +/- 6.4; 48.2 +/- 9.1; 72.1 +/- 14.5 and 64 +/- 17 bpm, respectively). Hypotensive and tachycardic responses were significantly attenuated after L-NAME (20 mg/kg, i.v.) administration. In isolated rat mesenteric artery rings, with endothelium intact, discretamine (10(-12) - 10(-5) M) induced concentration-dependent relaxation of the contractions induced by phenylephrine (10 microM) [pD2 = 6.8 +/- 0.1]. The effect of the discretamine on phenylephrine induced contractions was significantly attenuated after removal of the vascular endothelium [pD2 = 5.8 +/- 0.04]. Similar results were obtained after pre-treatment with L-NAME 100 microM [pD2 = 5.8 +/- 0.04], L-NAME 300 microM [pD2 = 5.9 +/- 0.06], Hydroxocobalamin 30 microM [pD2 = 5.8 +/- 0.06] or ODQ 10 microM [pD2 = 5.8 +/- 0.04]. In addition, in rabbit aorta endothelial cell line, discretamine significantly increased NO3- levels. These results suggest that the hypotensive effect induced by discretamine is probably due to a peripheral vasodilatation, at least, in part, due to the release of NO from vascular endothelium and consequent activation of soluble guanylyl cyclase (GC) in the vascular smooth muscle cells.
Assuntos
Anti-Hipertensivos/farmacologia , Alcaloides de Berberina/farmacologia , Endotélio Vascular/fisiologia , Fatores Relaxantes Dependentes do Endotélio/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Coelhos , Ratos , Ratos WistarRESUMO
In non-anesthetized normotensive rats, Hyptis fruticosa essential oil (HFEO, 5, 10, 20 and 40 mg/kg; i.v.) induced hypotension associated with tachycardia. In intact and isolated rings of rat superior mesenteric artery (control), HFEO (1-1000 microg/ml, n=6, cumulatively) induced concentration-dependent relaxations of tonus induced by 10 microM phenylephrine (Phe) (pD(2)=2.6+/-0.27; E(max)=64+/-8.3%). In denuded endothelium pre-contracted rings with Phe or K(+)-depolarizing solution (80 mM), the concentration-response curves to HFEO were not shifted (pD(2)=2.3+/-0.25 and 2.3+/-0.28, respectively), but their maximal responses were significantly (P<0.05 vs control) increased (E(max)=122.3+/-18.2% and 92+/-3.6%, respectively). HFEO was also capable of antagonizing the concentration-response curves to CaCl(2) (3 microM-30 mM) in a dose-dependent manner.
Assuntos
Anti-Hipertensivos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hyptis , Fitoterapia , Óleos de Plantas/farmacologia , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipertensão/tratamento farmacológico , Injeções Intravenosas , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Óleos de Plantas/administração & dosagem , Óleos de Plantas/uso terapêutico , Ratos , Ratos WistarRESUMO
The vasorelaxantion of the aqueous fraction of the hydroalcoholic extract of the Sida cordifolia leaves (AFSC) was evaluated in this work. In rat superior mesenteric artery, AFSC (3-1000 microg/mL) induced relaxation of phenylephrine-induced contractions. This effect was significantly attenuated after removal of the endothelium, after atropine (1 microM), L-NAME (100 microM), indomethacin (10 microM), high K+ (20 mM), tetraethylammonium (1 microM), a K(Ca) blocker, apamin (1 microM), a SK(Ca) blocker and ChTX (0.1 microM), a BK(Ca) blocker, however, it was not affected after glibenclamide (10 microM), an KATP blocker, and 4-aminopyridine (1 microM), a Kv blocker. ChTX (0.1 microM) was able to induce an additional inhibition of the vasorelaxation induced by AFSC in the presence of L-NAME plus indomethacin. The vasorelaxation induced by AFSC in the presence of L-NAME plus indomethacin plus ChTX was not different from that induced by AFSC in rings without endothelium. In conclusion, the results show that endothelium-derived factors (mainly NO, PGI2) and K+ channels (BK(Ca) and SK(Ca)) play a crucial role in the vasorelaxation induced by AFSC in the rat superior mesenteric artery.
Assuntos
Endotélio Vascular/fisiologia , Malvaceae/química , Artéria Mesentérica Superior/fisiologia , Músculo Liso Vascular/fisiologia , Canais de Potássio/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Charibdotoxina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Indometacina/farmacologia , Artéria Mesentérica Superior/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Relaxamento Muscular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Extratos Vegetais/farmacologia , Folhas de Planta/química , Canais de Potássio/efeitos dos fármacos , Cloreto de Potássio/farmacologia , RatosRESUMO
The cardiovascular activity of the aqueous fraction of the hydroalcoholic extract of Sida cordifolia leaves (AFSC) was evaluated. In normotensive non-anaesthetized rats was observed that AFSC (5, 10, 20, 30 and 40 mg/kg, i.v.) induced hypotension (6 +/- 2%; 8 +/- 2%; 11 +/- 2%; 19 +/- 3% and 33 +/- 3%, respectively) and bradycardia (0.3 +/- 3%; 13 +/- 4%; 38 +/- 6%; 64 +/- 7% and 80 +/- 5%, respectively). Hypotensive response was completely abolished after atropine (2 mg/kg; i.v.) but potentialized after hexamethonium (20 mg/kg; i.v.) (12 +/- 2%; 21 +/- 5%; 28 +/- 3%; 32 +/- 2% and 32 +/- 3%, respectively), while bradycardic response was completely abolished after atropine (2 mg/kg; i.v.) and attenuated with hexamethonium (20 mg/kg; i.v.) (1 +/- 0.3%; 5 +/- 1%; 7 +/- 1%; 7 +/- 1% and 10 +/- 1%, respectively). In hexamethonium treated rats, L-NAME significantly attenuated the hypotensive response (9 +/- 2%; 14 +/- 1%; 16 +/- 1%; 16 +/- 2% and 22 +/- 3%, respectively). In normotensive anaesthetized and vagotomized rats, hypotensive and bradycardic responses were significantly attenuated (0.5 +/- 0.2%; 1 +/- 0.4%; 3 +/- 0.6%; 4 +/- 0.8% and 6 +/- 1%, respectively, n = 6, and 7 +/- 2%; 12 +/- 5%; 15 +/- 2%, 17 +/- 2% and 25 +/- 3%, respectively). The anaesthesia with sodium thiopental did not affect the AFSC-induced responses when compared with those induced in non-anaesthetized rats (data not showed). In conclusion, the results obtained so far show that AFSC produce hypotension and bradycardia, mainly due to a direct stimulation of the endothelial vascular muscarinic receptor and indirect cardiac muscarinic activation, respectively.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Malvaceae/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Anestesia , Animais , Bradicardia/induzido quimicamente , Eletrocardiografia/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , VagotomiaRESUMO
Male and female rats were treated daily for 13 weeks with an ethanol extract of Cissampelos sympodialis leaves (9, 45 and 225 mg[sol ]kg). The food consumption, body weight and behavioural effects in the open-field test were evaluated by weekly monitoring. The results showed that the extract chronic treatment in female rats (45 and 225 mg[sol ]kg) reduced significantly the food intake and the body weight, and produced several alterations in the open-field test. These findings indicate that repeated oral administration of the extract may produce a sex-dependent difference in anoretic and behavioural effects.