Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Cardiovasc Res ; 116(12): 1995-2008, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31825460

RESUMO

AIMS: Activation of the angiotensin (Ang)-(1-7)/Mas receptor (R) axis protects from sympathetic overactivity. Endocytic trafficking is an essential process that regulates receptor (R) function and its ultimate cellular responses. We investigated whether the blunted responses to Ang-(1-7) in hypertensive rats are associated to an alteration in MasR trafficking. METHODS AND RESULTS: Brainstem neurons from Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHRs) were investigated for (i) Ang-(1-7) levels and binding and MasR expression, (ii) Ang-(1-7) responses (arachidonic acid and nitric oxide release and Akt and ERK1/2 phosphorylation), and (iii) MasR trafficking. Ang-(1-7) was determined by radioimmunoassay. MasR expression and functionality were evaluated by western blot and binding assays. MasR trafficking was evaluated by immunofluorescence. Ang-(1-7) treatment induced an increase in nitric oxide and arachidonic acid release and ERK1/2 and Akt phosphorylation in WKY neurons but did not have an effect in SHR neurons. Although SHR neurons showed greater MasR expression, Ang-(1-7)-elicited responses were substantially diminished presumably due to decreased Ang-(1-7) endogenous levels concomitant with impaired binding to its receptor. Through immunocolocalization studies, we evidenced that upon Ang-(1-7) stimulation MasRs were internalized through clathrin-coated pits and caveolae into early endosomes and slowly recycled back to the plasma membrane. However, the fraction of internalized MasRs into early endosomes was larger and the fraction of MasRs recycled back to the plasma membrane was smaller in SHR than in WKY neurons. Surprisingly, in SHR neurons but not in WKY neurons, Ang-(1-7) induced MasR translocation to the nucleus. Nuclear MasR expression and Ang-(1-7) levels were significantly greater in the nuclei of Ang-(1-7)-stimulated SHR neurons, indicating that the MasR is translocated with its ligand bound to it. CONCLUSION: MasRs display differential trafficking in brainstem neurons from SHRs, which may contribute to the impaired responses to Ang-(1-7).


Assuntos
Angiotensina I/farmacologia , Tronco Encefálico/efeitos dos fármacos , Hipertensão/metabolismo , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/agonistas , Receptores Acoplados a Proteínas G/agonistas , Transporte Ativo do Núcleo Celular , Animais , Animais Recém-Nascidos , Ácido Araquidônico/metabolismo , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Endocitose , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipertensão/fisiopatologia , Ligantes , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Fosforilação , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Acoplados a Proteínas G/metabolismo
2.
Pflugers Arch ; 471(8): 1103-1115, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31187260

RESUMO

The aim of this study was to determine whether exogenous administration of C-type natriuretic peptide (CNP) induces functional and morphological vascular changes in spontaneously hypertensive rats (SHR) compared with normotensive rats. Male 12-week-old normotensive Wistar and SHR were administered with saline (NaCl 0.9%) or CNP (0.75 µg/h/100 g) for 14 days (subcutaneous micro-osmotic pumps). Systolic blood pressure (SBP) was measured in awake animals and renal parameters were evaluated. After decapitation, the aorta was removed, and vascular morphology, profibrotic markers, and vascular reactivity were measured. In addition, nitric oxide (NO) system and oxidative stress were evaluated. After 14-days of treatment, CNP effectively reduced SBP in SHR without changes in renal function. CNP attenuated vascular remodeling in hypertensive rats, diminishing both profibrotic and pro-inflammatory cytokines. Also, CNP activated the vascular NO system and exerted an antioxidant effect in aortic tissue of both groups, diminishing superoxide production and thiobarbituric acid-reactive substances, and increasing glutathione content. These results show that chronic treatment with CNP attenuates the vascular damage development in a model of essential hypertension, inducing changes in fibrotic, inflammatory, oxidative, and NO pathways that could contribute to beneficial long-term effects on vascular morphology, extracellular matrix composition, and function. The knowledge of these effects of CNP could lead to improved therapeutic strategies to not only control BP but also reduce vascular damage, primarily responsible for the risk of cardiovascular events.


Assuntos
Aorta/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Natriuréticos/farmacologia , Peptídeo Natriurético Tipo C/farmacologia , Animais , Aorta/metabolismo , Pressão Sanguínea , Citocinas/metabolismo , Glutationa/metabolismo , Rim/efeitos dos fármacos , Masculino , Natriuréticos/administração & dosagem , Natriuréticos/uso terapêutico , Peptídeo Natriurético Tipo C/administração & dosagem , Peptídeo Natriurético Tipo C/uso terapêutico , Óxido Nítrico/metabolismo , Estresse Oxidativo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Superóxidos/metabolismo , Vasoconstrição
3.
PLoS One ; 11(12): e0167817, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27936197

RESUMO

Given that the role of C-type natriuretic peptide (CNP) in the regulation of vascular tone in hypertensive states is unclear, we hypothesized that impaired response of the nitric oxide system to CNP in spontaneously hypertensive rats (SHR) could affect vascular relaxation induced by the peptide in this model of hypertension, and that other endothelial systems or potassium channels opening could also be involved. We examined the effect of CNP on isolated SHR aortas, and the hindlimb vascular resistance (HVR) in response to CNP administration compared to normotensive rats. Aortas were mounted in an isometric organ bath and contracted with phenylephrine. CNP relaxed arteries in a concentration-dependent manner but was less potent in inducing relaxation in SHR. The action of CNP was diminished by removal of the endothelium, inhibition of nitric oxide synthase by Nω-nitro-L-arginine methyl ester, and inhibition of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one in both groups. In contrast, blockade of cyclooxygenase or subtype 2 bradykinin receptor increased CNP potency only in SHR. In both Wistar and SHR, CNP relaxation was blunted by tetraethylammonium and partially inhibited by BaCl2 and iberiotoxin, indicating that it was due to opening of the Kir and BKCa channels. However, SHR seem to be more sensitive to Kir channel blockade and less sensitive to BKCa channel blockade than normotensive rats. In addition, CNP decreases HVR in Wistar and SHR, but the effect of CNP increasing blood flow was more marked in SHR. We conclude that CNP induces aorta relaxation by activation of the nitric oxide system and opening of potassium channels, but the response to the peptide is impaired in conductance vessel of hypertensive rats.


Assuntos
Endotélio Vascular/fisiologia , Peptídeo Natriurético Tipo C/fisiologia , Animais , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Resistência Vascular
4.
Clin Sci (Lond) ; 127(5): 295-306, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24827941

RESUMO

The RAS (renin-angiotensin system) is composed of two arms: the pressor arm containing AngII (angiotensin II)/ACE (angiotensin-converting enzyme)/AT1Rs (AngII type 1 receptors), and the depressor arm represented by Ang-(1-7) [angiotensin-(1-7)]/ACE2/Mas receptors. All of the components of the RAS are present in the brain. Within the brain, Ang-(1-7) contributes to the regulation of BP (blood pressure) by acting at regions that control cardiovascular function such that, when Ang-(1-7) is injected into the nucleus of the solitary tract, caudal ventrolateral medulla, paraventricular nucleus or anterior hypothalamic area, a reduction in BP occurs; however, when injected into the rostral ventrolateral medulla, Ang-(1-7) stimulates an increase in BP. In contrast with AngII, Ang-(1-7) improves baroreflex sensitivity and has an inhibitory neuromodulatory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to BP regulation, but also acts as a cerebroprotective component of the RAS by reducing cerebral infarct size and neuronal apoptosis. In the present review, we provide an overview of effects elicited by Ang-(1-7) in the brain, which suggest a potential role for Ang-(1-7) in controlling the central development of hypertension.


Assuntos
Encéfalo/fisiologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/metabolismo , Angiotensina II/fisiologia , Enzima de Conversão de Angiotensina 2 , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Neurotransmissores/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/fisiologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/fisiologia , Ratos , Receptor Tipo 1 de Angiotensina/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Transdução de Sinais/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA