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1.
J Physiol ; 602(2): 317-332, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38152023

RESUMO

It has been documented that increased sympathetic activity contributes to the development of cardiovascular diseases, such as hypertension. We previously reported that ß-arrestin-1, a multifunctional cytoskeletal protein, was downregulated in the rostral ventrolateral medulla (RVLM) of the spontaneously hypertensive rat (SHR), and its overexpression elicited an inhibitory effect on sympathetic activity in hypertension. microRNA (miR)-22-3p has been reported to be associated with the pathological progress of hypertension. The purpose of this study was to determine the role of miR-22-3p in ß-arrestin-1-mediated central cardiovascular regulation in hypertension. It was observed that miR-22-3p was upregulated in the RVLM of SHRs compared with normotensive Wistar-Kyoto (WKY) rats, and it was subsequently confirmed to target the ß-arrestin-1 gene using a dual-luciferase reporter assay. miR-22-3p was downregulated in the RVLM using adeno-associated virus with 'tough decoys', which caused a significant increase of ß-arrestin-1 expression and decrease of noradrenaline and blood pressure (BP) in SHRs. However, upregulation of miR-22-3p using lentivirus in the RVLM of WKY rats significantly increased BP. In in vitro PC12 cells, enhanced oxidative stress activity induced by angiotensin II was counteracted by pretreatment with miR-22-3p inhibitor, and this effect could be abolished by ß-arrestin-1 gene knockdown. Furthermore, microglia exhaustion significantly diminished miR-22-3p expression, and enhanced ß-arrestin-1 expression in the RVLM of SHRs. Activation of BV2 cells in vitro evoked a significant increase of miR-22-3p expression, and this BV2 cell culture medium was also able to facilitate miR-22-3p expression in PC12 cells. Collectively, our findings support a critical role for microglia-derived miR-22-3p in inhibiting ß-arrestin-1 in the RVLM, which is involved in central cardiovascular regulation in hypertension. KEY POINTS: Impairment of ß-arrestin-1 function in the rostral ventrolateral medulla (RVLM) has been reported to be associated with the development of sympathetic overactivity in hypertension. However, little is known about the potential mechanisms of ß-arrestin-1 dysfunction in hypertension. miR-22-3p is implicated in multiple biological processes, but the role of miR-22-3p in central regulation of cardiovascular activity in hypertension remains unknown. We predicted that miR-22-3p could directly bind to the ß-arrestin-1 gene (Arrb1), and this hypothesis was confirmed by using a dual-luciferase reporter assay. Inhibition of ß-arrestin-1 by miR-22-3p was further verified in both in vivo and in vitro experiments. Furthermore, our results suggested miR-22-3p as a risk factor for oxidative stress in the RVLM, thus contributing to sympatho-excitation and hypertension. Our present study provides evidence that microglia-derived miR-22-3p may underlie the pathogenesis and progression of neuronal hypertension by inhibiting ß-arrestin-1 in the RVLM.


Assuntos
Hipertensão , MicroRNAs , Animais , Ratos , beta-Arrestina 1/genética , beta-Arrestina 1/metabolismo , Pressão Sanguínea/fisiologia , Luciferases/metabolismo , Bulbo/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
2.
BMC Neurol ; 24(1): 59, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336624

RESUMO

OBJECTIVES: Computed tomographic perfusion (CTP) can play an auxiliary role in the selection of patients with acute ischemic stroke for endovascular treatment. However, data on CTP in non-stroke patients with intracranial arterial stenosis are scarce. We aimed to investigate images in patients with asymptomatic intracranial arterial stenosis to determine the detection accuracy and interpretation time of large/medium-artery stenosis or occlusion when combining computed tomographic angiography (CTA) and CTP images. METHODS: We retrospectively reviewed 39 patients with asymptomatic intracranial arterial stenosis from our hospital database from January 2021 to August 2023 who underwent head CTP, head CTA, and digital subtraction angiography (DSA). Head CTA images were generated from the CTP data, and the diagnostic performance for each artery was assessed. Two readers independently interpreted the CTA images before and after CTP, and the results were analyzed. RESULTS: After adding CTP maps, the accuracy (area under the curve) of diagnosing internal carotid artery (R1: 0.847 vs. 0.907, R2: 0.776 vs. 0.887), middle cerebral artery (R1: 0.934 vs. 0.933, R2: 0.927 vs. 0.981), anterior cerebral artery (R1: 0.625 vs. 0.750, R2: 0.609 vs. 0.750), vertebral artery (R1: 0.743 vs. 0.764, R2: 0.748 vs. 0.846), and posterior cerebral artery (R1: 0.390 vs. 0.575, R2: 0.390 vs. 0.585) occlusions increased for both readers (p < 0.05). Mean interpretation time (R1: 72.4 ± 6.1 s vs. 67.7 ± 6.4 s, R2: 77.7 ± 3.8 s vs. 72.6 ± 4.7 s) decreased when using a combination of both images both readers (p < 0.001). CONCLUSIONS: The addition of CTP images improved the accuracy of interpreting CTA images and reduced the interpretation time in asymptomatic intracranial arterial stenosis. These findings support the use of CTP imaging in patients with asymptomatic intracranial arterial stenosis.


Assuntos
AVC Isquêmico , Humanos , Estudos Retrospectivos , Constrição Patológica/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Angiografia por Tomografia Computadorizada/métodos , Perfusão , Angiografia Cerebral/métodos
3.
Dig Dis ; 42(3): 221-229, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38342087

RESUMO

INTRODUCTION: The objective of our study was to develop a nomogram to predict overall survival (OS) and cancer-specific survival (CSS) in patients with gastric signet ring cell carcinoma (GSRCC). METHODS: A total of 3,408 GSRCC patients between 1975 and 2017 were screened from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into training and validation cohorts. Univariate and multivariate Cox analyses were conducted to identify independent prognostic factors for the construction of a nomogram. The performance of the model was then assessed by the concordance index (C-index), calibration plot, and area under the receiver operating characteristic curve (AUC). Then, the novel nomogram was further assessed by 64 GSRCC patients from our hospital as the external cohort. RESULTS: We identified age, tumor lymph node metastasis (TNM) staging system, surgery, and chemotherapy as significant independent elements of prognosis. On this basis, a nomogram was constructed, with a C-index of OS in the training and validation cohorts of 0.763 (95% CI: 0.751-0.774) and 0.766 (95% CI: 0.748-0.784) and a C-index of CSS of 0.765 (95% CI: 0.753-0.777) and 0.773 (95% CI: 0.755-0.791), respectively. The AUCs of the nomogram for predicting 2- and 5-year OS were 0.848 and 0.885, respectively, and those for predicting CSS were 0.854 and 0.899, respectively, demonstrating the excellent predictive value of the constructed nomogram compared to the traditional AJCC staging system. Similar results were also observed in both the internal and external validation sets. CONCLUSION: The nomogram provided an accurate tool to predict OS and CSS in patients with GSRCC, which can assist clinicians in making predictions about individual patient survival.


Assuntos
Carcinoma de Células em Anel de Sinete , Nomogramas , Programa de SEER , Neoplasias Gástricas , Humanos , Carcinoma de Células em Anel de Sinete/mortalidade , Carcinoma de Células em Anel de Sinete/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Idoso , Adulto , Estadiamento de Neoplasias , Curva ROC , Modelos de Riscos Proporcionais
4.
JAMA ; 329(24): 2135-2144, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37367978

RESUMO

Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days. Results: Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group. Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03661411.


Assuntos
Fibrinolíticos , AVC Isquêmico , Inibidores da Agregação Plaquetária , Ativador de Plasminogênio Tecidual , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hemorragia Cerebral/induzido quimicamente , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , AVC Isquêmico/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento , Quimioterapia Combinada , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Administração Intravenosa , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Seguimentos , Idoso , Recuperação de Função Fisiológica
5.
Am J Physiol Regul Integr Comp Physiol ; 323(6): R861-R874, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36222883

RESUMO

Hypertension is characterized by sympathetic hyperactivity, which is related to the overexcitation of the presympathetic neurons in the rostral ventrolateral medulla (RVLM). Nitric oxide (NO) has been reported to be a vital neuromodulator involved in central cardiovascular regulation. However, the mechanism of interleukin-enhanced binding factor 3 (ILF3) participating in blood pressure (BP) regulation is still unclear. Therefore, this study aims to clarify the role of ILF3 within the rostral ventrolateral medulla (RVLM) in regulating NO in hypertension. It was found that the expression level of ILF3 was significantly increased in the RVLM of spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto (WKY) rats through microarray gene expression analysis, Western blot, and immunofluorescence. Overexpression of ILF3 by injecting constructed adenovirus into the RVLM increased the BP and renal sympathetic nerve activity (RSNA) of the WKY rats, significantly decreasing NO production and neuronal nitric oxide synthase (nNOS) expression. Knockdown of ILF3 in the RVLM of SHR significantly reduced BP but increased NO production and the neuronal nitric oxide synthase (nNOS) expression. Furthermore, it was found that the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway was activated via Western blotting in the RVLM after overexpression of ILF3, whereas it was attenuated after knockdown of ILF3 in SHR. In addition, inhibition of PI3K by intracisternal infusion of the PI-103 attenuated the increase in Akt phosphorylation and decrease in nNOS expression and NO production caused by overexpressing ILF3, which ultimately blunted high BP induced by overexpressing ILF3. Taken together, this current study suggests that ILF3 participates in high BP via reducing NO production in the RVLM through PI3K/Akt pathway.


Assuntos
Hipertensão , Proteínas Proto-Oncogênicas c-akt , Ratos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos Endogâmicos WKY , Fosfatidilinositol 3-Quinase/metabolismo , Bulbo/metabolismo , Pressão Sanguínea , Ratos Endogâmicos SHR , Interleucinas/metabolismo , Proteínas do Fator Nuclear 90/metabolismo
6.
J Clin Monit Comput ; 35(3): 463-468, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32189165

RESUMO

We studied the application of a mobile terminal application program in endotracheal tube (ETT) cuff pressure measurement to improve the implementation rate of scientific ETT cuff pressure measurement and to ensure that the pressure falls within the recommended range. A pre-post controlled study lasting for 18 months was undertaken in a 40-bed general intensive care unit (GICU). This included a 6-month baseline period (baseline group) and a 6-month intervention period (intervention group). The mobile terminal application program was applied to monitor the cuff pressure of endotracheal intubation as an intervention measure during the intervention period. ETT pressure was the main outcome measure, while gender, age, causes for ICU admission, sedation score, duration of prior intubation, size of ETT, and number of VAP patients were secondary outcomes. ETT cuff pressure was monitored 742 times in both the baseline group and the intervention group. A total of 56.9% of the cuff pressure measurements in the baseline group were within the recommended range, while 78.4% of measurements in the intervention group were within the recommended range, reflecting a statistically significant difference (P < 0.05). The application of the mobile terminal application program used for ETT cuff pressure measurement could improve the percentage of ETT cuff pressure measurements falling within the recommended range.


Assuntos
Intubação Intratraqueal , Traqueia , Humanos , Unidades de Terapia Intensiva
7.
Nitric Oxide ; 93: 44-52, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536826

RESUMO

Persistent cardiac hypertrophy eventually leads to deterioration of heart function and changes to normal morphology. Decreased nitric oxide (NO) production plays a critical role in modulating cardiac hypertrophy. Interleukin enhancement binding factor 3 (ILF3), a member of the double-stranded RNA-binding protein family, is known to regulate the transcription and stability of mRNA. Therefore, the major aim of the present study was to determine the role of ILF3 in reduction of NO production in cardiac hypertrophy. Cardiac hypertrophy models of neonatal rat cardiomyocytes (NRCMs) and adult rats were induced by angiotensin II (Ang II) in this study. First, it was found that ILF3 expression, NO production, and nitric oxide synthase (NOS) activity was decreased in cultured cardiomyocytes and adult rats treated with Ang II, compared with NRCMs treated with vehicle and rats treated with saline infusion, respectively. These effects induced by Ang II were significantly exacerbated by specific ILF3 knockdown. Moreover, the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, was increased significantly in the Ang II-induced hypertrophic NRCMs and adult rats. Additionally, decreased protein expression and mRNA level of dimethylarginine dimethylaminohydrolases 1 (DDAH1, which degrades ADMA) were observed. Furthermore, specific ILF3 knockdown further aggravated these effects, but didn't reduce the expression level of NOS isoforms. In conclusion, our data show that ADMA accumulation-mediated decrease in NO production plays an important role in cardiomyocyte remodeling, which may be associated with ILF3-mediated DDAH1 reduction.


Assuntos
Arginina/análogos & derivados , Cardiomegalia/metabolismo , Óxido Nítrico/metabolismo , Proteínas do Fator Nuclear 90/metabolismo , Amidoidrolases/metabolismo , Angiotensina II , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Arginina/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/etiologia , Regulação para Baixo , Técnicas de Silenciamento de Genes , Losartan/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Proteínas do Fator Nuclear 90/genética , Ratos Sprague-Dawley
8.
Biomed Chromatogr ; 33(10): e4619, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31177559

RESUMO

Hypertension is a common chronic disease, and it is the strongest risk factor for cardiovascular disease. Recently, the number of patients with hypertension-related complications has increased significantly, adding a heavy burden to the public health system. It is known that chronic stress plays an important role in the pathogenesis of cardiovascular diseases such as hypertension and stroke. However, the impact of hypertension on the dysfunctions induced by chronic stress remains poorly understood. In this study, using LC-MS-based metabolomics, we established a chronic stress model to demonstrate the mechanisms of stress-induced hypertension. We found that 30 metabolites in chronically stressed rats were changed; of these metabolites, seven had been upregulated, and 23 had been downregulated, including amino acids, phospholipids, carnitines and fatty acids, many of which are involved in amino acid metabolism, cell membrane injury, ATP supply and inflammation. These metabolites are engaged in dysregulated pathways and will provide a targeted approach to study the mechanism of stress-induced hypertension.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Hipertensão/metabolismo , Espectrometria de Massas/métodos , Metabolômica/métodos , Estresse Psicológico/metabolismo , Aminoácidos/sangue , Aminoácidos/metabolismo , Animais , Pressão Sanguínea/fisiologia , Doença Crônica , Corticosterona/sangue , Corticosterona/metabolismo , Modelos Animais de Doenças , Metaboloma/fisiologia , Norepinefrina/sangue , Norepinefrina/metabolismo , Fosfolipídeos/sangue , Fosfolipídeos/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Nitric Oxide ; 67: 58-67, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28392446

RESUMO

Nitric oxide (NO) contributes to the central control of cardiovascular activity. The rostral ventrolateral medulla (RVLM) has been recognized as a pivotal region for maintaining basal blood pressure (BP) and sympathetic tone. It is reported that asymmetric dimethylarginine (ADMA), characterized as a cardiovascular risk marker, is an endogenous inhibitor of nitric oxide synthesis. The present was designed to determine the role of ADMA in the RVLM in the central control of BP in hypertensive rats. In Sprague Dawley (SD) rats, microinjection of ADMA into the RVLM dose-dependently increased BP, heart rate (HR), and renal sympathetic never activity (RSNA), but also reduced total NO production in the RVLM. In central angiotensin II (Ang II)-induced hypertensive rats and spontaneously hypertensive rat (SHR), the level of ADMA in the RVLM was increased and total NO production was decreased significantly, compared with SD rats treated vehicle infusion and WKY rats, respectively. These hypertensive rats also showed an increased protein level of protein arginine methyltransferases1 (PRMT1, which generates ADMA) and a decreased expression level of dimethylarginine dimethylaminohydrolases 1 (DDAH1, which degrades ADMA) in the RVLM. Furthermore, increased AMDA content and PRMT1 expression, and decreased levels of total NO production and DDAH1 expression in the RVLM in SHR were blunted by intracisternal infusion of the angiotensin II type 1 receptor (AT1R) blocker losartan. The current data indicate that the ADMA-mediated NO inhibition in the RVLM plays a critical role in involving in the central regulation of BP in hypertension, which may be associated with increased Ang II.


Assuntos
Arginina/análogos & derivados , Pressão Sanguínea/efeitos dos fármacos , Bulbo/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Amidoidrolases/metabolismo , Angiotensina II/farmacologia , Animais , Arginina/administração & dosagem , Arginina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Rim/inervação , Rim/metabolismo , Losartan/farmacologia , Masculino , Bulbo/metabolismo , Óxido Nítrico/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Sistema Nervoso Simpático/metabolismo , ômega-N-Metilarginina/administração & dosagem , ômega-N-Metilarginina/farmacologia
10.
Neural Plast ; 2017: 3256325, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29098089

RESUMO

It has been demonstrated that homocysteine (HCY) is a significant risk factor of hypertension, which is characterized by overactivity of sympathetic tone. Excessive oxidative stress in the rostral ventrolateral medulla (RVLM), a key region for control of sympathetic outflow, contributes to sympathetic hyperactivity in hypertension. Therefore, the goal of the present study is to determine the effect of systemic HCY on production of reactive oxygen species (ROS) in the RVLM. In the rat model of the diet-induced hyperhomocysteinemia (L-methionine, 1 g/kg/day, 8 weeks), we found that the HCY resulted in a significant increase (≈3.7-fold, P < 0.05) in ROS production in the RVLM, which was paralleled with enhanced sympathetic tone and blood pressure (BP). Compared to the vehicle group, levels of BP and basal renal sympathetic nerve activity in the HCY group were significantly (P < 0.05, n = 5) increased by an average of 27 mmHg and 31%, respectively. Furthermore, the rats treated with L-methionine (1 g/kg/day, 8 weeks) showed an upregulation of NADPHase (NOX4) protein expression and a downregulation of superoxide dismutase protein expression in the RVLM. The current data suggest that central oxidative stress induced by systemic HCY plays an important role in hypertension-associated sympathetic overactivity.


Assuntos
Hiper-Homocisteinemia/metabolismo , Bulbo/efeitos dos fármacos , Metionina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Hiper-Homocisteinemia/induzido quimicamente , Bulbo/metabolismo , NADPH Oxidase 4/metabolismo , Ratos , Superóxido Dismutase , Sistema Nervoso Simpático/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
11.
Neural Plast ; 2017: 4174010, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29158920

RESUMO

Neuropathic pain increases the risk of cardiovascular diseases including hypertension with the characteristic of sympathetic overactivity. The enhanced tonically active glutamatergic input to the rostral ventrolateral medulla (RVLM) contributes to sympathetic overactivity and blood pressure (BP) in cardiovascular diseases. We hypothesize that neuropathic pain enhances tonically active glutamatergic inputs to the RVLM, which contributes to high level of BP and sympathetic outflow. Animal model with the trigeminal neuropathic pain was induced by the infraorbital nerve-chronic constriction injury (ION-CCI). A significant increase in BP and renal sympathetic nerve activity (RSNA) was found in rats with ION-CCI (BP, n = 5, RSNA, n = 7, p < 0.05). The concentration of glutamate in the RVLM was significantly increased in the ION-CCI group (n = 4, p < 0.05). Blockade of glutamate receptors by injection of kynurenic acid into the RVLM significantly decreased BP and RSNA in the ION-CCI group (n = 5, p < 0.05). In two major sources (the paraventricular nucleus and periaqueductal gray) for glutamatergic inputs to the RVLM, the ION-CCI group (n = 5, p < 0.05) showed an increase in glutamate content and expression of glutaminase 2, vesicular glutamate transporter 2 proteins, and c-fos. Our results suggest that enhancement in tonically active glutamatergic inputs to the RVLM contributes to neuropathic pain-induced high blood pressure.


Assuntos
Ácido Glutâmico/metabolismo , Hipertensão/metabolismo , Bulbo/metabolismo , Neuralgia/metabolismo , Animais , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Glutaminase/metabolismo , Hiperalgesia/metabolismo , Hipertensão/etiologia , Masculino , Neuralgia/etiologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Ratos Sprague-Dawley , Receptores de Glutamato/metabolismo , Sistema Nervoso Simpático/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
12.
Nitric Oxide ; 52: 56-65, 2016 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-26686278

RESUMO

Angiotensin-1-7 [Ang-(1-7)], acting via the Mas receptor in the central nervous system, is involved in the regulation of cardiovascular activity. Nitric oxide (NO) is implicated as an important modulator in the nucleus tractus solitarii (NTS), a key region involved in control of cardiovascular activity. The aim of the present study was to determine the role of phosphatidylinositol 3-kinase (PI3K) signaling in mediating the effect of Ang-(1-7) on NO generation in the NTS. In Sprague-Dawley rats, acute injection of Ang-(1-7) into the NTS significantly increased NO generation and neuronal/endothelial NO synthase (n/eNOS) activity, which were abolished by the selective Mas receptor antagonist d-Alanine-[Ang-(1-7)] (A-779), the PI3K inhibitor LY294002, or the Akt inhibitor triciribine (TCN). Western blotting analysis further demonstrated that Ang-(1-7) significantly increased levels of Akt/NOS phosphorylation in the NTS, and Ang-(1-7)-induced e/nNOS phosphorylation was antagonized by LY294002 or TCN. Furthermore, gene knockdown of PI3K by lentivirus containing small hairpin RNA in the NTS prevented the Ang-(1-7)-induced increases in NOS/Akt phosphorylation and NO production. The physiological (in vivo) experiments showed that pretreatment with the NOS inhibitor l-NAME, LY294002, or TCN abolished the decreases in blood pressure, heart rate, and renal sympathetic nerve activity induced by Ang-(1-7) injected into the NTS. Our findings suggest that nitric oxide release meditated by the Mas-PI3K-NOS signaling pathway is involved in the cardiovascular effects of Ang-(1-7) in the NTS.


Assuntos
Angiotensina I/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Angiotensina I/administração & dosagem , Animais , Sistema Cardiovascular/enzimologia , Sistema Cardiovascular/metabolismo , Masculino , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/enzimologia , Núcleo Solitário/metabolismo
13.
Am J Physiol Cell Physiol ; 306(2): C132-42, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24025863

RESUMO

Chronic heart failure (CHF) is characterized by decreased cardiac parasympathetic and increased cardiac sympathetic nerve activity. This autonomic imbalance increases the risk of arrhythmias and sudden death in patients with CHF. We hypothesized that the molecular and cellular alterations of cardiac postganglionic parasympathetic (CPP) neurons located in the intracardiac ganglia and sympathetic (CPS) neurons located in the stellate ganglia (SG) possibly link to the cardiac autonomic imbalance in CHF. Rat CHF was induced by left coronary artery ligation. Single-cell real-time PCR and immunofluorescent data showed that L (Ca(v)1.2 and Ca(v)1.3), P/Q (Ca(v)2.1), N (Ca(v)2.2), and R (Ca(v)2.3) types of Ca2+ channels were expressed in CPP and CPS neurons, but CHF decreased the mRNA and protein expression of only the N-type Ca2+ channels in CPP neurons, and it did not affect mRNA and protein expression of all Ca2+ channel subtypes in the CPS neurons. Patch-clamp recording confirmed that CHF reduced N-type Ca2+ currents and cell excitability in the CPP neurons and enhanced N-type Ca2+ currents and cell excitability in the CPS neurons. N-type Ca2+ channel blocker (1 µM ω-conotoxin GVIA) lowered Ca2+ currents and cell excitability in the CPP and CPS neurons from sham-operated and CHF rats. These results suggest that CHF reduces the N-type Ca2+ channel currents and cell excitability in the CPP neurons and enhances the N-type Ca2+ currents and cell excitability in the CPS neurons, which may contribute to the cardiac autonomic imbalance in CHF.


Assuntos
Potenciais de Ação/fisiologia , Fibras Autônomas Pós-Ganglionares/fisiologia , Canais de Cálcio Tipo N/fisiologia , Insuficiência Cardíaca/fisiopatologia , Gânglio Estrelado/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Fibras Autônomas Pós-Ganglionares/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Células Cultivadas , Masculino , Ratos , Ratos Sprague-Dawley , Gânglio Estrelado/efeitos dos fármacos
14.
Am J Physiol Heart Circ Physiol ; 307(2): H182-90, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24838502

RESUMO

The rostral ventrolateral medulla (RVLM) plays a key role in cardiovascular regulation. It has been reported that tonically active glutamatergic input to the RVLM is increased in hypertensive rats, whereas angiotensin-converting enzyme 2 (ACE2) in the brain has been suggested to be beneficial to hypertension. This study was designed to determine the effect of ACE2 gene transfer into the RVLM on tonically active glutamatergic input in spontaneously hypertensive rats (SHRs). Lentiviral particles containing enhanced green fluorescent protein (lenti-GFP) or ACE2 (lenti-ACE2) were injected bilaterally into the RVLM. Both protein expression and activity of ACE2 in the RVLM were increased in SHRs after overexpression of ACE2. A significant reduction in blood pressure and heart rate in SHRs was observed 6 wk after lenti-ACE2 injected into the RVLM. The concentration of glutamate in microdialysis fluid from the RVLM was significantly reduced by an average of 61% in SHRs with lenti-ACE2 compared with lenti-GFP. ACE2 overexpression significantly attenuated the decrease in blood pressure and renal sympathetic nerve activity evoked by bilateral injection of the glutamate receptor antagonist kynurenic acid (2.7 nmol in 100 nl) into the RVLM in SHRs. Therefore, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced tonically active glutamatergic input in SHRs, which may be an important mechanism underlying the beneficial effect of central ACE2 to hypertension.


Assuntos
Ácido Glutâmico/metabolismo , Hipertensão/terapia , Bulbo/enzimologia , Peptidil Dipeptidase A/biossíntese , Enzima de Conversão de Angiotensina 2 , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Técnicas de Transferência de Genes , Vetores Genéticos , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Frequência Cardíaca , Humanos , Hipertensão/enzimologia , Hipertensão/genética , Hipertensão/fisiopatologia , Injeções , Ácido Cinurênico/administração & dosagem , Lentivirus/genética , Masculino , Bulbo/efeitos dos fármacos , Bulbo/fisiopatologia , Norepinefrina/urina , Peptidil Dipeptidase A/genética , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores de Glutamato/efeitos dos fármacos , Receptores de Glutamato/metabolismo , Fatores de Tempo , Regulação para Cima
15.
Technol Health Care ; 32(2): 719-726, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37393453

RESUMO

BACKGROUND: Providers should adjust the depth of sedation to promote lung-protective ventilation in patients with severe ARDS. This recommendation was based on the assumption that the depth of sedation could be used to assess respiratory drive. OBJECTIVE: To assess the association between respiratory drive and sedation in patients with severe ARDS by using ventilator-measured P0.1 and RASS score. METHODS: Loss of spontaneous breathing was observed within 48 h of mechanical ventilation in patients with severe ARDS, and spontaneous breathing returned after 48 hours. P0.1 was measured by ventilator every 12 ± 2 hours, and the RASS score was measured synchronously. RESULTS: The RASS score was moderately correlated with P0.1 (R𝑆𝑝𝑒𝑎𝑟𝑚𝑎𝑛, 0.570; 95% CI, 0.475 to 0.637; p= 0.00). However, only patients with a RASS score of -5 were considered to have no excessive respiratory drive, but there was a risk for loss of spontaneous breathing. A P0.1 exceeding 3.5 cm H2O in patients with other RASS scores indicated an increase in respiratory drive. CONCLUSION: RASS score has little clinical significance in evaluating respiratory drive in severe ARDS. P0.1 should be evaluated by ventilator when adjusting the depth of sedation to promote lung-protective ventilation.


Assuntos
Respiração Artificial , Síndrome do Desconforto Respiratório , Humanos , Ventiladores Mecânicos , Taxa Respiratória , Síndrome do Desconforto Respiratório/terapia
16.
Front Neurosci ; 18: 1401530, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38741786

RESUMO

Introduction: Sleep insufficiency has been linked to an increased risk of high blood pressure and cardiovascular diseases. Emerging studies have demonstrated that impaired baroreflex sensitivity (BRS) is involved in the adverse cardiovascular effects caused by sleep deprivation, however, the underlying mechanisms remain unknown. Therefore, the present study aims to clarify the role of abnormal renin-angiotensin system in the nucleus tractus solitarii (NTS) in impaired BRS induced by sleep deprivation. Methods: Rats were randomly divided into two groups: normal sleep (Ctrl) and chronic sleep deprivation (CSD) group. Rats were sleep deprived by an automated sleep deprivation system. The blood pressure, heart rate, BRS, the number of c-Fos positive cells and the expression of angiotensin (Ang) II subtype 1 receptors (AT1R) in the NTS of rats were assessed. Results: Compared to Ctrl group, CSD group exhibited a higher blood pressure, heart rate, and reduced BRS. Moreover, the number of c-Fos positive cells and local field potential in the NTS in CSD group were increased compared with the Ctrl group. It was shown that the expression of the AT1R and the content of Ang II and the ratio of Ang II to Ang-(1-7) were increased in the NTS of rats in CSD group compared to Ctrl group. In addition, microinjection of losartan into the NTS significantly improved the impaired BRS caused by sleep deprivation. Discussion: In conclusion, these data suggest that the elevated AT1R expression in the NTS mediates the reduced BRS induced by chronic sleep deprivation.

17.
Clin Res Cardiol ; 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38451260

RESUMO

This study aimed to determine the effect of supervised exercise training (SET) on cardiovascular function in patients with intermittent claudication (IC). A systematic search in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases was conducted. Primary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), rate pressure product (RPP), cardiac output (CO), peak oxygen consumption (VO2peak), and heart rate variability (HRV). Secondary outcomes were maximum walking distance (MWD) and pain-free walking distance (PFWD). Outcomes were reported as weighted mean difference (WMD) between the SET group and the control group and synthesized by using the random-effects model. Seventeen RCTs with a total of 936 patients were included in this review. SET resulted in significant improvements of SBP (WMD = - 7.40, 95% CI - 10.69 ~ - 4.11, p < 0.001, I2 = 15.2%), DBP (WMD = - 1.92, 95% CI - 3.82 ~ - 0.02, p = 0.048, I2 = 0.0%), HR (WMD = - 3.38, 95% CI - 6.30 ~ - 0.46, p = 0.023, I2 = 0.0%), RPP (WMD = - 1072.82, 95% CI - 1977.05 ~ - 168.59, p = 0.020, I2 = 42.7%), and VO2peak with plantar flexion ergometer exercise (WMD = 5.57, 95% CI 1.66 ~ 9.49, p = 0.005, I2 = 62.4%), whereas CO and HRV remained statistically unaltered. SET also improved MWD (WMD = 139.04, 95% CI 48.64 ~ 229.44, p = 0.003, I2 = 79.3%) and PFWD (WMD = 40.02, 95% CI 23.85 ~ 56.18, p < 0.001, I2 = 0.0%). In conclusion, SET is effective in improving cardiovascular function in patients with IC, which was confirmed on outcomes of cardiovascular function associated with exercise ability. The findings hold out that the standard therapy of SET can improve not only walking distance but also cardiovascular function in patients with IC.

18.
JAMA Neurol ; 81(5): 450-460, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38466274

RESUMO

Importance: Dual antiplatelet therapy has been demonstrated to be superior to single antiplatelet in reducing recurrent stroke among patients with transient ischemic attack or minor stroke, but robust evidence for its effect in patients with mild to moderate ischemic stroke is lacking. Objective: To evaluate whether dual antiplatelet therapy is superior to single antiplatelet among patients with mild to moderate ischemic stroke. Design, Setting, and Participants: This was a multicenter, open-label, blinded end point, randomized clinical trial conducted at 66 hospitals in China from December 20, 2016, through August 9, 2022. The date of final follow-up was October 30, 2022. The analysis was reported on March 12, 2023. Of 3065 patients with ischemic stroke, 3000 patients with acute mild to moderate stroke within 48 hours of symptom onset were enrolled, after excluding 65 patients who did not meet eligibility criteria or had no randomization outcome. Interventions: Within 48 hours after symptom onset, patients were randomly assigned to receive clopidogrel plus aspirin (n = 1541) or aspirin alone (n = 1459) in a 1:1 ratio. Main Outcomes and Measures: The primary end point was early neurologic deterioration at 7 days, defined as an increase of 2 or more points in National Institutes of Health Stroke Scale (NIHSS) score, but not as a result of cerebral hemorrhage, compared with baseline. The superiority of clopidogrel plus aspirin to aspirin alone was assessed based on a modified intention-to-treat population, which included all randomized participants with at least 1 efficacy evaluation regardless of treatment allocation. Bleeding events were safety end points. Results: Of the 3000 randomized patients, 1942 (64.6%) were men, the mean (SD) age was 65.9 (10.6) years, median (IQR) NIHSS score at admission was 5 (4-6), and 1830 (61.0%) had a stroke of undetermined cause. A total of 2915 patients were included in the modified intention-to-treat analysis. Early neurologic deterioration occurred in 72 of 1502 (4.8%) in the dual antiplatelet therapy group vs 95 of 1413 (6.7%) in the aspirin alone group (risk difference -1.9%; 95% CI, -3.6 to -0.2; P = .03). Similar bleeding events were found between 2 groups. Conclusions and Relevance: Among Chinese patients with acute mild to moderate ischemic stroke, clopidogrel plus aspirin was superior to aspirin alone with regard to reducing early neurologic deterioration at 7 days with similar safety profile. These findings indicate that dual antiplatelet therapy may be a superior choice to aspirin alone in treating patients with acute mild to moderate stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT02869009.


Assuntos
Aspirina , Clopidogrel , Quimioterapia Combinada , AVC Isquêmico , Inibidores da Agregação Plaquetária , Humanos , Clopidogrel/uso terapêutico , Aspirina/uso terapêutico , Aspirina/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/administração & dosagem , AVC Isquêmico/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico
19.
World J Gastroenterol ; 29(43): 5818-5833, 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-38074915

RESUMO

BACKGROUND: Patients with inflammatory bowel diseases (IBDs) generally have poor knowledge, attitude, and practice of their disease, while the data from China are lacking. AIM: To address this knowledge disparity among Chinese patients with IBD. METHODS: This web-based, cross-sectional study was conducted on a cohort of IBD patients who visited the Second Affiliated Hospital of Wenzhou Medical University between December 2022 and February 2023. Their socio-demographic information and the knowledge, attitude, and practice scores were collected and estimated using a self-designed questionnaire. Pearson's correlation analysis was used to determine the pairwise correlations among knowledge, attitude, and practice scores. A multivariate logistic regression analysis was further performed to determine the independent factors associated with their knowledge, attitude, and practice scores. RESULTS: A total of 353 patients (224 males) with IBD completed the questionnaires. The mean knowledge, attitude, and practice scores were 10.05 ± 3.46 (possible range: 0-14), 41.58 ± 5.23 (possible range: 0-56), 44.20 ± 7.39 (possible range: 0-56), respectively, indicating good knowledge, positive attitude, and proactive practice toward IBD. Pearson's correlation analysis showed that the knowledge score had significant positive correlations with the attitude score (r = 0.371, P < 0.001) and practice score (r = 0.100, P < 0.001). The attitude score had a significant positive correlation with the practice score (r = 0.452, P < 0.001). Moreover, multivariate logistic regression analysis showed that aged 30-40 years [odds ratio (OR) = 4.06, 95% confidence interval (CI): 1.04-15.82, P = 0.043], middle school education (OR = 3.98, 95%CI: 1.29-12.33, P = 0.017), high school/technical secondary school education (OR = 14.06, 95%CI: 3.92-50.38, P < 0.001), and junior college/bachelor's degree and above education (OR = 15.20, 95%CI: 4.15-55.650, P < 0.001) were independently associated with good knowledge. The higher knowledge score was independently associated with a positive attitude (OR = 1.23, 95%CI: 1.11-1.36, P < 0.001). The higher attitude score was independently associated with proactive practice (OR = 1.20, 95%CI: 1.11-1.30, P < 0.001). CONCLUSION: Chinese patients with IBD might have good knowledge, a positive attitude, and proactive practice toward their disease. However, a small number of specific items require education.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Doenças Inflamatórias Intestinais , Masculino , Humanos , Estudos Transversais , Doenças Inflamatórias Intestinais/terapia , Escolaridade , Inquéritos e Questionários
20.
Nutrients ; 15(3)2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36771313

RESUMO

Gut microbiota is the largest and most complex microflora in the human body, which plays a crucial role in human health and disease. Over the past 20 years, the bidirectional communication between gut microbiota and extra-intestinal organs has been extensively studied. A better comprehension of the alternative mechanisms for physiological and pathophysiological processes could pave the way for health. Cardiovascular disease (CVD) is one of the most common diseases that seriously threatens human health. Although previous studies have shown that cardiovascular diseases, such as heart failure, hypertension, and coronary atherosclerosis, are closely related to gut microbiota, limited understanding of the complex pathogenesis leads to poor effectiveness of clinical treatment. Dysregulation of inflammation always accounts for the damaged gastrointestinal function and deranged interaction with the cardiovascular system. This review focuses on the characteristics of gut microbiota in CVD and the significance of inflammation regulation during the whole process. In addition, strategies to prevent and treat CVD through proper regulation of gut microbiota and its metabolites are also discussed.


Assuntos
Doenças Cardiovasculares , Microbioma Gastrointestinal , Hipertensão , Probióticos , Humanos , Doenças Cardiovasculares/prevenção & controle , Probióticos/uso terapêutico , Hipertensão/etiologia , Inflamação/complicações , Prebióticos
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