Exacerbated pressor and sympathoexcitatory effects of central Elabela in spontaneously hypertensive rats.
加剧自发性高血压大鼠中枢 Elabela 的升压和交感兴奋作用。
- 作者列表："Geng Z","Ye C","Tong Y","Zhang F","Zhou YB","Xiong XQ
:Elabela (ELA) is a newly discovered peptide that acts as a novel endogenous ligand of angiotensin receptor-like 1 (APJ) receptor. This study was designed to evaluate the effects of ELA-21 in paraventricular nucleus (PVN) on blood pressure and sympathetic nerve activity in spontaneously hypertensive rats (SHR). Experiments were performed in male Wistar-Kyoto rats (WKY) and SHR. ELA expression was upregulated in PVN of SHR. PVN microinjection of ELA-21 increased renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), heart rate (HR), plasma norepinephrine, and arginine vasopressin (AVP) levels in SHR. Intravenous injection of ELA-21 significantly decreased MAP and HR in both WKY and SHR, but only induced a slight decrease in RSNA. APJ antagonist F13A in PVN abolished the effects of ELA-21 on RSNA, MAP and HR. Intravenous infusion of both ganglionic blocker hexamethonium and AVP V1a receptor antagonist SR49059 caused significant reduction in the effects of ELA-21 on RSNA, MAP and HR in SHR, while combined administration of hexamethonium and SR49059 abolished the effects of ELA-21. ELA-21 microinjection stimulated Akt and p85α subunit of phosphatidylinositol 3-kinase (PI3K) phosphorylation in PVN, whereas PI3K inhibitor LY294002 or Akt inhibitor MK-2206 almost abolished the effects of ELA-21 on RSNA, MAP, and HR. Chronic PVN infusion of ELA-21 induced sympathetic activation, hypertension, and AVP release accompanied with cardiovascular remodeling in normotensive WKY. In conclusion, ELA-21 in PVN induces exacerbated pressor and sympathoexcitatory effects in hypertensive rats via PI3K-Akt pathway.NEW & NOTEWORTHY We demonstrated that PVN microinjection of ELA-21 increases sympathetic nerve activity and blood pressure, which can be abolished by pretreatment of APJ antagonist. This is the first demonstration that central ELA can induce hypertension. The pressor effects in PVN are mediated by both sympathetic activation and vasopressin release via PI3K-Akt pathway. Our data confirm that ELA is upregulated in the PVN of SHR and so may be involved in the pressor and sympathoexcitatory effects in hypertension.
: Elabela (ELA) 是一种新发现的肽，作为血管紧张素受体样 1 (APJ) 受体的新型内源性配体。本研究旨在探讨室旁核 (PVN) ELA-21 对自发性高血压大鼠 (SHR) 血压和交感神经活动的影响。实验在雄性 Wistar-Kyoto 大鼠 (WKY) 和 SHR 中进行。在 SHR 的 PVN 中 ELA 表达上调。PVN 微量注射 ELA-21 可增加 SHR 肾交感神经活性 (RSNA) 、平均动脉压 (MAP) 、心率 (HR) 、血浆去甲肾上腺素和精氨酸加压素 (AVP) 水平。静脉注射 ELA-21 可显著降低 WKY 和 SHR 的 MAP 和 HR，但仅诱导 RSNA 轻度降低。PVN 中 APJ 拮抗剂 F13A 消除了 ELA-21 对 RSNA 、 MAP 和 HR 的影响。静脉输注神经节阻滞剂 hexamethium 和 AVP V1a 受体拮抗剂 SR49059 可显著降低 ELA-21 对 SHR RSNA 、 MAP 和 HR 的影响, 而联合应用六氨溴铵和 SR49059 消除了 ELA-21 的作用。ELA-21 显微注射刺激 PVN 中 Akt 和磷脂酰肌醇 3-激酶 (PI3K) 的 p85 α 亚基磷酸化，而 PI3K 抑制剂 LY294002 或 Akt 抑制剂几乎 MK-2206 消除 ELA-21 对 RSNA，MAP, 和 HR。慢性 PVN 输注 ELA-21 诱导交感神经激活、高血压和 AVP 释放伴随着正常血压 WKY 的心血管重塑。总之，PVN 中的 ELA-21 通过 PI3K-Akt 途径引起高血压大鼠升压和交感兴奋作用加剧。新 & 值得注意的是，我们证明 PVN 微量注射 ELA-21 可增加交感神经活性和血压，这可通过 APJ 拮抗剂预处理消除。这是首次证明中枢 ELA 可诱发高血压。PVN 中的升压效应是由交感神经激活和加压素释放通过 PI3K-Akt 途径介导的。我们的数据证实 ELA 在 SHR 的 PVN 中上调，因此可能参与高血压的升压和交感兴奋作用。
METHODS:BACKGROUND:Hypertensive disorders of pregnancy (HDP) increase cardiovascular disease (CVD) risk. Pregnancy morbidities, including preeclampsia, and CVD are common in systemic lupus erythematosus (SLE). Possible connections are important to explore. In a population-based cohort, we investigated whether HDP is associated with a higher risk of cardiovascular outcomes separately in SLE and non-SLE to examine the role of SLE. METHODS:We identified first singleton births in the Medical Birth Register (1987-2012) among mothers with SLE and a large general population comparison group. Discharge diagnoses for HDP, cardiovascular outcomes, and hypertension in the Patient Register were identified using ICD codes. We estimated adjusted hazard ratios and 95% confidence intervals (HR, 95% CI) of the association between HDP and outcomes, in separate models in women with and without SLE. We then evaluated additive and multiplicative effect modification using relative excess risk due to interaction and Cox models jointly accounting for SLE and HDP, respectively. Mediation analysis estimated the proportion of the association between SLE and outcome explained by HDP. RESULTS:HDP were more common in SLE pregnancies (20% vs 7%). In SLE, HDP were associated with a two-fold higher rate of cardiovascular outcomes and three-fold higher rate of incident hypertension. HDP mediated 20% of the latter association. In women without SLE, HDP was associated with higher hypertension incidence later in life. CONCLUSION:In women with and without SLE, HDP were associated with a three-fold higher rate of hypertension. In SLE, women with HDP developed cardiovascular outcomes twice as often as women without HDP.
METHODS:BACKGROUND:'Neuronal precursor cell expressed developmentally down-regulated 4-like' (NEDD4L) is considered a candidate gene for hypertension-both functionally and genetically-through the regulation of the ubiquitination of the epithelial sodium channel (ENaC). This study explores the relationship between genetic variation in NEDD4L and hypertension with chronic kidney disease (CKD) in the southeastern Han Chinese population. METHODS:We recruited 623 CKD patients and measured ambulatory blood pressure monitoring (ABPM), and the rs4149601 and rs2288774 polymorphisms in NEDD4L were genotyped using qPCR. RESULTS:For rs4149601, significant differences in genotype frequencies in an additive model (GG vs GA vs AA) were observed between normotensive patients and hypertensive patients when hypertension was classified into ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension (P = 0.038, 0.005 and 0.006, respectively). In a recessive model (GG+GA vs AA), the frequency of the AA genotype of rs4149601 in the hypertension groups were all higher than that in the normotensive groups. The genotype distribution of rs2288774 did not differ significantly between the normotensive and hypertensive patients. In both the full cohort and the propensity score matching (PSM) cohort, the AA genotype of rs4149601 (compared to the GG+GA genotype group) was independently correlated with ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension by multivariate logistic regression analysis. CONCLUSIONS:The present study indicates that the AA genotype of rs4149601 associates with hypertension in CKD. Consequently, the rs4149601 A allele might be a risk factor for hypertension with CKD.
METHODS:BACKGROUND:The burden of hypertension in many low-and middle-income countries is alarming and requires effective evidence-based preventative strategies that is carefully appraised and accepted by key stakeholders to ensure successful implementation and sustainability. We assessed nurses' perceptions of a recently completed Task Shifting Strategy for Hypertension control (TASSH) trial in Ghana, and facilitators and challenges to TASSH implementation. METHODS:Focus group sessions and in-depth interviews were conducted with 27 community health nurses from participating health centers and district hospitals involved in the TASSH trial implemented in the Ashanti Region, Ghana, West Africa from 2012 to 2017. TASSH evaluated the comparative effectiveness of the WHO-PEN program versus provision of health insurance for blood pressure reduction in hypertensive adults. Qualitative data were analyzed using open and axial coding techniques with emerging themes mapped onto the Consolidated Framework for Implementation Research (CFIR). RESULTS:Three themes emerged following deductive analysis using CFIR, including: (1) Patient health goal setting- relative priority and positive feedback from nurses, which motivated patients to make healthy behavior changes as a result of their health being a priority; (2) Leadership engagement (i.e., medical directors) which influenced the extent to which nurses were able to successfully implement TASSH in their various facilities, with most directors being very supportive; and (3) Availability of resources making it possible to implement the TASSH protocol, with limited space and personnel time to carry out TASSH duties, limited blood pressure (BP) monitoring equipment, and transportation, listed as barriers to effective implementation. CONCLUSION:Assessing stakeholders' perception of the TASSH implementation process guided by CFIR is crucial as it provides a platform for the nurses to thoroughly evaluate the task shifting program, while considering the local context in which the program is implemented. The feedback from the nurses informed barriers and facilitators to implementation of TASSH within the current healthcare system, and suggested system level changes needed prior to scale-up of TASSH to other regions in Ghana with potential for long-term sustainment of the task shifting intervention. TRIAL REGISTRATION:Trial registration for parent TASSH study: NCT01802372. Registered February 27, 2013.