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1.
Front Immunol ; 13: 814334, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572602

RESUMO

NKG2C+ natural killer (NK) cell plays a vital role in CMV infection control after hematopoietic stem cell transplantation (HSCT). However, the modulation on NKG2C+ NK cell reconstitution is still unclear. NK cell education is affected by the interactions of HLA-I/killer immunoglobulin receptor (KIR). Our aim is to figure out which HLA-I/KIR interaction plays a dominant role in NKG2C+ NK education. Based on allogeneic haploidentical HSCT, we investigated the expansion and function of single KIR positive NKG2C+ NK cells via the interaction of KIR with both donor HLA and recipient HLA at days 30, 90, and 180 after HSCT. KIR2DL2/L3 single-positive/NKG2C+ cells were significantly expanded compared with KIR2DL1 or KIR3DL1 single-positive/NKG2C+ cells when donors and recipients were both HLA-C1/C1 or HLA-C1C1BW4 (p < 0.05), with higher NKp30 expression (p < 0.05). Moreover, the proportion of single KIR positive NK cells increased in both NKG2C+/NKG2A- NK cells and conventional NKG2C-/NKG2A- NK cells over time. We also observed that increased proportion of KIR2DL2/L3 single-positive/NKG2C+ NK cells correlated with higher incidence of acute graft-versus-host disease (aGVHD). Our study allows a better understanding of HLA-I/KIR interaction in the NKG2C+ NK cell education after HSCT.

2.
Am J Hematol ; 97(6): 762-769, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35293011

RESUMO

Adoptive therapy with cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has emerged as an effective method for CMV infection. However, the efficacy reportedly ranges from 50% to 90%, and factors affecting anti-CMV efficacy have not been established. We investigated the safety and efficacy of adoptive therapy with CMV-CTLs for CMV infection in 190 patients after haploidentical stem cell transplantation (haplo-SCT), and importantly, we analyzed the main factors affecting antiviral efficacy. The CMV peak titer decreased from 19 (range, 1.0-503.0) × 103 copies/mL to 3.9 (range, 0-112) × 103 copies/mL after CMV-CTL infusion. The cumulative complete response (CR) rates in the first, fourth, and sixth weeks after the first CMV-CTL infusion were 37.9% (95% CI 35.0-40.8), 76.8% (95% CI 70.7-82.9), and 89.5% (95% CI 85.2-93.8), respectively. In multivariate analysis, persistent CMV infection prior to CMV-CTL infusion (hazard ratio [HR] 2.29, 95% CI 1.29-4.06, p = .005) and basiliximab treatment within 2 weeks of CMV-CTL infusion (HR 1.87, 95% CI 1.06-3.81, p = .031) were independent predictors of poor antiviral efficacy of CMV-CTL therapy. Our data showed that adoptive therapy with CMV-CTLs is a safe and effective treatment for CMV infection after haplo-SCT. Persistent CMV infection and basiliximab treatment are correlated with poor anti-CMV efficacy of CMV-CTL therapy.


Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Antivirais/uso terapêutico , Basiliximab/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transplante de Células-Tronco , Linfócitos T Citotóxicos
3.
JCI Insight ; 7(3)2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-34990406

RESUMO

CMV infection remains an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several investigators have reported that adaptive NKG2C+ NK cells persistently expand during CMV reactivation. In our study, 2 cohorts were enrolled to explore the relationships among the NKG2C genotype, NKG2C+ NK cell reconstitution, and CMV infection. Multivariate analysis showed that donor NKG2C gene deletion was an independent prognostic factor for CMV reactivation and refractory CMV reactivation. Furthermore, adaptive NKG2C+ NK cells' quantitative and qualitative reconstitution, along with their anti-CMV function after transplantation, was significantly lower in patients grafted with NKG2Cwt/del donor cells than in those grafted with NKG2Cwt/wt donor cells. At day 30 after transplantation, quantitative reconstitution of NKG2C+ NK cells was significantly lower in patients with treatment-refractory CMV reactivation than in patients without CMV reactivation and those with nonrefractory CMV reactivation. In humanized CMV-infected mice, we found that, compared with those from NKG2Cwt/del donors, adaptive NKG2C+ NK cells from NKG2Cwt/wt donors induced earlier and stronger expansion of NKG2C+ NK cells as well as earlier and stronger CMV clearance in vivo. In conclusion, donor NKG2C homozygosity contributes to CMV clearance by promoting the quantitative and qualitative reconstruction of adaptive NKG2C+ NK cells after haploidentical allo-HSCT.


Assuntos
Infecções por Citomegalovirus/genética , Rejeição de Enxerto/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células Matadoras Naturais/patologia , Mutação , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Doadores de Tecidos , Adolescente , Adulto , Animais , Linhagem Celular , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/virologia , DNA/genética , Análise Mutacional de DNA , Feminino , Seguimentos , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Homozigoto , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Masculino , Camundongos , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Estudos Prospectivos , Transplante Haploidêntico , Ativação Viral , Adulto Jovem
4.
Cell Mol Immunol ; 19(4): 482-491, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35017718

RESUMO

Adoptive transfer of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation (allo-SCT), but the antiviral activity of CMV-CTL types has not been compared. To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs, we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity, and analyzed the underlying mechanisms driving sustained antiviral immunity. The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion. The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups. A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups. Our clinical study, which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection, further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8+ tetramer+ T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion, which were associated with a reduced or cleared viral load. Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.


Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Animais , Citomegalovirus , Humanos , Camundongos , Transplante de Células-Tronco , Linfócitos T Citotóxicos , Doadores de Tecidos
5.
Br J Haematol ; 196(4): 1007-1017, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34787307

RESUMO

Natural killer (NK) cells exert anti-viral effects after haematopoietic stem cell transplantation (HSCT). The balance between inhibition and activation of NK cells determined by the inherited repertoire of killer cell immunoglobulin-like receptors (KIR) genes may influence Epstein-Barr virus (EBV) reactivation after transplantation. To evaluate the relative contributions of KIR genotypes to EBV reactivation, we prospectively enrolled 300 patients with malignant haematological disease who were suitable for haploidentical HSCT. Univariate analysis showed that donors with KIR2DS1, KIR2DS3 or KIR3DS1 genes were associated with an increased risk of EBV reactivation [hazard ratio (HR) 1·86, 95% confidence interval (CI) 1·19-2·9, P = 0·0067; HR 1·78, 95% CI 1·07-2·97, P = 0·027; HR 1·86, 95% CI 1·19-2·91, P = 0·0065 respectively]. Multivariate analysis revealed that the presence of KIR2DS1, KIR2DS3 or KIR3DS1 genes was associated with increased EBV reactivation after HSCT. This effect was more evident in the absence of the cognate ligands for the corresponding activating receptors. Our present data firstly showed that donors with activating KIR genes, specifically activating KIR2DS1, KIR2DS3 and KIR3DS1, had an increased risk of EBV reactivation. Precaution for patients whose donors carry activating genes will help prevent EBV reactivation and improve patient prognosis after HSCT.


Assuntos
Infecções por Vírus Epstein-Barr/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Receptores KIR/genética , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Influenza Other Respir Viruses ; 16(3): 395-401, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34796652

RESUMO

BACKGROUND: The pandemic of COVID-19 has a persistent impact on global health, yet its sequelae need to be addressed at a wide scale around the globe. This study aims to investigate the characteristics, prevalence, and risk factors for mid-term (>6 months) clinical sequelae in a cohort of COVID-19 survivors. METHODS: Totally 715 COVID-19 survivors discharged before April 1, 2020, from three medical centers in Wuhan, China, were included. The longitudinal study was conducted by telephone interviews based on a questionnaire including the clinical sequelae of general, respiratory, and cardiovascular systems. Demographics and some characteristics of clinical sequelae of the survivors were recorded and analyzed. Multivariate logistic regression analysis was applied to explore the risk factors for the sequelae. RESULTS: The median time interval from discharge to telephone interview was 225.0 days. The COVID-19 survivors' median ages were 69 years, and 51.3% were male. Among them, 29.9% had at least one clinical sequela. There were 19.2%, 22.7%, and 5.0% of the survivors reporting fatigue, respiratory symptoms, and cardiovascular symptoms, respectively. Comorbidities, disease severity, the application of mechanical ventilation and high-flow oxygen therapy, and the history of re-admission were associated with the presence of clinical sequelae. CONCLUSIONS: Our study provides further evidence for the prevalence and characteristics of clinical sequelae of COVID-19 survivors, suggesting long-term monitoring and management is needed for their full recovery.


Assuntos
COVID-19 , Idoso , COVID-19/complicações , COVID-19/epidemiologia , China/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Pandemias , SARS-CoV-2 , Sobreviventes
7.
J Immunol ; 208(2): 492-500, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34937746

RESUMO

The interaction of inhibitory receptors with self-MHC class I (MHC-I) molecules is responsible for NK cell education. The intensity of DNAM-1 expression correlates with NK cell education. However, whether DNAM-1 expression directly influences the functional competence of NK cells via the KIR/MHC-I interaction remains unclear. Based on allogeneic haploidentical hematopoietic stem cell transplantation, we investigated the intensity of DNAM-1 expression on reconstituted NK cells via the interaction of KIR with both donor HLA and recipient HLA at days 30, 90, and 180 after hematopoietic stem cell transplantation. The reconstituted NK cells educated by donor and recipient HLA molecules showed the highest DNAM-1 expression, whereas DNAM-1 expression on educated NK cells with only recipient HLA molecules was higher than that on educated NK cells with only donor HLA molecules, indicating that NK cells with donor or recipient HLA molecules regulate DNAM-1 expression and thereby affect NK cell education. Additionally, the effects of recipient cells on NK cell education were greater than those of donor cells. However, only when the DNAM-1, NKP30, and NKG2D receptors were blocked simultaneously was the function of educated and uneducated NK cells similar. Therefore, activating receptors may collaborate with DNAM-1 to induce educated NK cell hyperresponsiveness. Our data, based on in vitro and in vivo studies, demonstrate that the functional competence of NK cells via the KIR/MHC-I interaction correlates with DNAM-1 expression in human NK cells.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/imunologia , Antígenos de Diferenciação de Linfócitos T/biossíntese , Estudos de Casos e Controles , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Linfoide/terapia , Leucemia Mieloide/terapia , Síndromes Mielodisplásicas/terapia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor 3 Desencadeador da Citotoxicidade Natural/metabolismo , Estudos Prospectivos
8.
Mol Neurodegener ; 16(1): 48, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281568

RESUMO

BACKGROUND: Understanding the long-term effects of coronavirus disease 2019 (COVID-19) on cognitive function is essential for monitoring the cognitive decline in the elderly population. This study aims to assess the current cognitive status and the longitudinal cognitive decline in elderly patients recovered from COVID-19. METHODS: This cross-sectional study recruited 1539 COVID-19 inpatients aged over 60 years who were discharged from three COVID-19-designated hospitals in Wuhan, China, from February 10 to April 10, 2020. In total, 466 uninfected spouses of COVID-19 patients were selected as controls. The current cognitive status was assessed using a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) and the longitudinal cognitive decline was assessed using an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Cognitive assessments were performed 6 months after patient discharge. RESULTS: Compared with controls, COVID-19 patients had lower TICS-40 scores and higher IQCODE scores [TICS-40 median (IQR): 29 (25 to 32) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.19 (3.00 to 3.63) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had lower TICS-40 scores and higher IQCODE scores than non-severe COVID-19 patients [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.63 (3.13 to 4.31) vs. 3.13 (3.00 to 3.56), p < 0.001] and controls [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR) 3.63 (3.13 to 4.31) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had a higher proportion of cases with current cognitive impairment and longitudinal cognitive decline than non-severe COVID-19 patients [dementia: 25 (10.50 %) vs. 9 (0.69 %), p < 0.001; Mild cognitive impairment (MCI): 60 (25.21 %) vs. 63 (4.84 %), p < 0.001] and controls [dementia: 25 (10.50 %) vs. 0 (0 %), p < 0.001; MCI: 60 (25.21 %) vs. 20 (4.29 %), p < 0.001)]. COVID-19 severity, delirium and COPD were risk factors of current cognitive impairment. Low education level, severe COVID-19, delirium, hypertension and COPD were risk factors of longitudinal cognitive decline. CONCLUSIONS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with an increased risk of long-term cognitive decline in elderly population. COVID-19 patients, especially severe patients, should be intensively monitored for post-infection cognitive decline.


Assuntos
COVID-19/complicações , Disfunção Cognitiva/virologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , China , Disfunção Cognitiva/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2
12.
Sci Rep ; 6: 26711, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27384759

RESUMO

During the process of embryonic development in mammals, epigenetic modifications must be erased and reconstructed. In particular, the trimethylation of histone 3 lysine 27 (H3K27me3) is associated with gene-specific transcriptional repression and contributes to the maintenance of the pluripotent embryos. In this study, we determined that the global levels of the H3K27me3 marker were elevated in MII oocyte chromatin and decrease to minimal levels at the 8-cell and morula stages. When the blastocyst hatched, H3K27me3 was re-established in the inner cell mass. We also determined that H3K27me3-specific demethylases, UTX and JMJD3, were observed at high transcript and protein levels in mouse preimplantation embryos. In the activated oocytes, when the H3K27me3 disappeared at the 8-cell stage, the UTX (but not JMJD3) protein levels were undetectable. Using RNA interference, we suppressed UTX and JMJD3 gene expression in the embryos and determined that the functions of UTX and JMJD3 were complementary. When JMJD3 levels were decreased by RNA interference, the embryo development rate and quality were improved, but the knockdown of UTX produced the opposite results. Understanding the epigenetic mechanisms controlling preimplantation development is critical to comprehending the basis of embryonic development and to devise methods and approaches to treat infertility.


Assuntos
Blastocisto/enzimologia , Desenvolvimento Embrionário/fisiologia , Histona Desmetilases/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Animais , Blastocisto/citologia , Feminino , Histona Desmetilases/genética , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos
13.
World J Microbiol Biotechnol ; 31(5): 795-803, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25737203

RESUMO

Acute gastroenteritis caused by pathogenic Vibrio parahaemolyticus is one of the major factors affecting the development of aquaculture and the safety of seafood. Using the antagonism of probiotics against pathogens is an alternative strategy to antibiotics and a common trend to control food-borne pathogenic bacteria. In this study, a total of 249 isolates were isolated from four types of seafood (Litopenaeus vannamei, Oratosquilla oratoria, Mactra veneriformis and Portunus trituberculatus) and coastal sediment from Liaodong Bay in the Bohai Sea, China with five different separation agars. The most isolates came from the sample of coastal sediment and on agar of 2216E, which accounted for 36.14 and 54.62 % respectively. Twenty-four among 249 isolates displayed direct antimicrobial activity to V. parahaemolyticus with spot inoculation. Sixteen active isolates were selected for extracellular antimicrobial activity using the Oxford cup method. Only strains of B16 and J7 showed extracellular antimicrobial activity and were identified as Bacillus pumilus and Bacillus mojavensis respectively based on the physiological identification and 16S rRNA sequence analysis. Both of the strains B16 and J7 exhibited extracellular hydrolytic enzyme activity and antagonism against more than one indicator bacteria in vitro, which indicates that the two strains have broad potential application as suitable probiotic candidates in aquaculture while B. mojavensis was first reported to inhibit pathogenic Vibrio spp. in vitro. There is no particular trait as to antagonism of B. pumilus B16 or B. mojavensis J7 to Gram-positive or Gram-negative indicator bacteria.


Assuntos
Antibiose , Bacillus/crescimento & desenvolvimento , Bacillus/isolamento & purificação , Probióticos/isolamento & purificação , Vibrio parahaemolyticus/crescimento & desenvolvimento , Aquicultura/métodos , Bacillus/classificação , Bacillus/genética , Técnicas de Tipagem Bacteriana , China , Análise por Conglomerados , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Sedimentos Geológicos/microbiologia , Filogenia , RNA Ribossômico 16S/genética , Alimentos Marinhos/microbiologia , Análise de Sequência de DNA
14.
FEBS Lett ; 579(21): 4843-50, 2005 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-16107252

RESUMO

Myocyte-specific enhancer factor 2A (MEF2A) regulates a broad range of fundamental cellular processes including cell division, differentiation and death. Here, we tested the hypothesis that MEF2A is required in cardiac contractility employing zebrafish as a model organism. MEF2A is highly expressed in heart as well as somites during zebrafish embryogenesis. Knock-down of MEF2A in zebrafish impaires the cardiac contractility and results in sarcomere assembly defects. Dysregulation of cardiac genes in MEF2A morphants suggests that sarcomere assembly disturbances account for the cardiac contractile deficiency. Our studies suggested that MEF2A is essential in cardiac contractility.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Fatores de Transcrição/metabolismo , Peixe-Zebra/embriologia , Animais , Proteínas de Ligação a DNA/genética , Expressão Gênica , Humanos , Proteínas de Domínio MADS , Fatores de Transcrição MEF2 , Microinjeções , Morfogênese , Miocárdio/ultraestrutura , Fatores de Regulação Miogênica , Oligonucleotídeos Antissenso , Fenótipo , Regiões Promotoras Genéticas , Splicing de RNA , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Transcrição/genética , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
15.
Am J Physiol Heart Circ Physiol ; 288(1): H205-13, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15331368

RESUMO

Using neuronal NO synthase (nNOS)-specific antisense oligonucleotides, we examined the role of nitric oxide (NO) in the paraventricular nucleus (PVN) on control of blood pressure and heart rate (HR) in conscious sham rats and rats with chronic heart failure (CHF). After 6-8 wk, rats with chronic coronary ligation showed hemodynamic and echocardiographic signs of CHF. In sham rats, we found that microinjection of sodium nitroprusside (SNP, 20 nmol, 100 nl) into the PVN induced a significant decrease in mean arterial pressure (MAP). SNP also induced a significant decrease in HR over the next 10 min. In contrast, the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 200 pmol, 100 nl) significantly increased MAP and HR over the next 18-20 min. After injection of nNOS antisense, MAP was significantly increased in sham rats over the next 7 h. The peak response was 27.6 +/- 4.1% above baseline pressure. However, in the CHF rats, only MAP was significantly increased. The peak magnitude was 12.9 +/- 5.4% of baseline, which was significantly attenuated compared with sham rats (P < 0.01). In sham rats, the pressor response was completely abolished by alpha-receptor blockade. HR was significantly increased from hour 1 to hour 7 in sham and CHF rats. There was no difference in magnitude of HR responses. The tachycardia could not be abolished by the beta(1)-blocker metoprolol. However, the muscarinic receptor antagonist atropine did not further augment the tachycardia. We conclude that NO induces a significant depressor and bradycardiac response in normal rats. The pressor response is mediated by an elevated sympathetic tone, whereas the tachycardia is mediated by withdrawal of parasympathetic tone in sham rats. These data are consistent with a downregulation of nNOS within the PVN in CHF.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Baixo Débito Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Óxido Nítrico Sintase/genética , Oligonucleotídeos Antissenso/administração & dosagem , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Atropina/farmacologia , Northern Blotting , Doença Crônica , Hemodinâmica , Imuno-Histoquímica , Masculino , Metoprolol/administração & dosagem , Metoprolol/farmacologia , Microinjeções , Proteínas do Tecido Nervoso/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Nitroprussiato/administração & dosagem , Nitroprussiato/farmacologia , Oligonucleotídeos Antissenso/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Fentolamina/administração & dosagem , Fentolamina/farmacologia , Ratos , Ratos Sprague-Dawley , ômega-N-Metilarginina/administração & dosagem , ômega-N-Metilarginina/farmacologia
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