Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder
Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder
批准号:
9891297
负责人:
Jeanie Park
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-07-01 至 2024-06-30
关键词:
AcuteAddressAdrenergic AgentsAdrenergic AgonistsAdrenergic ReceptorAfghanistanAnti-CholinergicsAnti-Inflammatory AgentsBaroreflexBiological MarkersBlood Flow VelocityBlood PressureBlood VesselsBrain StemCardiovascular DiseasesCervicalChronic DiseaseDataDevelopmentDevicesDiseaseDoppler UltrasoundDoseEfferent NeuronsElectrocardiogramFutureGeneral PopulationGoalsGoldHealthHumanHypertensionImpairmentInflammationInflammatoryInterventionIraqKidneyMeasuresMediatingMental disordersMilitary PersonnelMuscleNerveNerve FibersNervous System PhysiologyNucleus solitariusOrganOutputParasympathetic Nervous SystemPathogenesisPatientsPeripheral ResistancePharmacologyPhenylephrinePhysiologyPlasmaPost-Traumatic Stress DisordersPsyche structureRegulationRenal Blood FlowReninRenin-Angiotensin SystemResearchRestRiskRisk FactorsRoleSodiumStressSympathetic Nervous SystemTechniquesTestingTherapeuticTimeVagus nerve structureVascular resistanceVeteransWorkafferent nervealpha-1 adrenergic receptorsblood pressure regulationcardiovascular disorder riskcardiovascular risk factordisorder controlexperimental studyhemodynamicshigh risk populationimprovedinsightkidney vascular structureneurovascularnovelpatient populationperipheral bloodpreventprogramsreceptor sensitivityresponsetherapeutic targettime usevagus nerve stimulationvascular abnormalityvasoconstrictionyoung manyoung woman
中文摘要
创伤后应激障碍(PTSD)是一种非常普遍且使人衰弱的心理健康问题。
与心血管疾病风险增加独立相关的疾病
还有高血压。鉴于9·11事件后大批退伍军人遭受创伤后应激障碍的困扰,
解决创伤后应激障碍这一未被充分认识但意义重大的后果是至关重要的
保护这些年轻退伍军人未来健康的重要性。我们已经证明了
9/11事件后患有创伤后应激障碍的退伍军人交感神经系统(SNS)过度激活
在精神应激和动脉压力反射敏感性(BRS)受损期间,这可能导致
这些患者的高血压和心血管疾病的发病机制。虽然我们现在有
证实了中枢交感神经输出在创伤后应激障碍中得到增强,
SNS对创伤后应激障碍患者血压(BP)调节的输出仍不清楚,这是PSD的主要目标
这项提议。我们假设创伤后应激障碍患者交感神经活动增强导致
增强SNS介导的肾内血管收缩,这是一个在BP中起关键作用的器官
监管。交感神经介导的肾血管收缩的夸大增加可能
通过肾脏对钠的重吸收和激活,使血压随时间持续上升
肾素-血管紧张素系统(RAS)。为了验证这一假设,我们将测量肾脏血流量。
多普勒超声测速、持续血流动力学、肌交感神经
应用显微神经学、血浆肾素活性和炎症生物标记物测定活动(MSNA
9·11事件后退伍军人和配对对照组的休息和精神应激。我们进一步
假设SNS激活导致夸大的血管收缩反应(即
异常血管介导的SNS活动的神经血管转导增强
创伤后应激障碍患者的肾上腺素能受体敏感性。为了验证这一假设,我们将确定血管
α-1肾上腺素能受体(α1AR)敏感性的测定
选择性α1AR激动剂苯肾上腺素的剂量呈指数级增加
创伤后应激障碍和对照中的可变差动变压器。最后,先前的研究表明,
经皮迷走神经刺激(TVNS)可降低SNS活性,改善BRS,并
降低健康人类的炎症和一些慢性病;然而,
TVNS对创伤后应激障碍患者SNS功能和调节的潜在好处以前从未
调查过了。我们假设tVNS显著降低了sns的活性并提高了交感神经。
创伤后应激障碍患者的心脏迷走神经BRS。为了验证这一假设,我们将测量MSNA、EKG、
静息和静息状态下药物处理血压的血流动力学、炎症和BRS
在创伤后应激障碍患者的TVNS期间(与假刺激相比)。TVNS可能是一部小说
降低这些患者的SNS活性和恢复BRS的非药物方法。
改善社交网络过度活动和BRS可能对降低创伤后应激障碍的心血管风险有长期好处
病人。
英文摘要
Post-traumatic stress disorder (PTSD) is a highly prevalent and debilitating mental health
disorder that is independently associated with an increased risk of cardiovascular (CV) disease
and hypertension. Given the large numbers of post-9/11 Veterans afflicted with PTSD,
addressing this under-recognized but highly significant consequence of PTSD is of paramount
importance to protect the future health of these young Veterans. We have shown that
post-9/11 Veterans with PTSD have overactivation of the sympathetic nervous system (SNS)
during mental stress and impaired arterial baroreflex sensitivity (BRS) that could contribute to
the pathogenesis of hypertension and CV disease in these patients. While we have now
established that central sympathetic output is augmented in PTSD, the downstream effects of
SNS output on blood pressure (BP) regulation in PTSD remain unknown and is a major goal of
this proposal. We hypothesize that augmented sympathetic nerve activity in PTSD leads to
augmented SNS-mediated vasoconstriction within the kidney, an organ with a critical role in BP
regulation. Exaggerated increases in sympathetically mediated renal vasoconstriction could
perpetuate sustained increases in BP over time via renal sodium reabsorption and activation of
the renin-angiotensin system (RAS). To test this hypothesis, we will measure renal blood flow
velocity using Doppler ultrasound, continuous hemodynamics, muscle sympathetic nerve
activity (MSNA) using microneurography, plasma renin activity and inflammatory biomarkers at
rest and during mental stress in post 9/11 Veterans and matched controls. We further
hypothesize that SNS activation leads to an exaggerated vasoconstrictive response (i.e.
heightened neurovascular transduction of SNS activity) mediated by abnormal vascular
adrenergic receptor sensitivity in PTSD. To test this hypothesis, we will determine vascular
alpha-1 adrenergic receptor (α1AR) sensitivity by measuring vasoconstriction in response to
exponentially increasing doses of the selective α1AR agonist phenylephrine using a linear
variable differential transformer in PTSD and controls. Finally, prior studies have shown that
transcutaneous vagus nerve stimulation (tVNS) reduces SNS activity, improves BRS, and
lowers inflammation in healthy humans and a number of chronic diseases; however, the
potential benefits of tVNS on SNS function and regulation in PTSD have never previously been
investigated. We hypothesize that tVNS acutely lowers SNS activity and improves sympathetic
and cardiovagal BRS in PTSD. To test this hypothesis, we will measure MSNA, EKG,
hemodynamics, inflammation, and BRS using pharmacologic manipulation of BP at rest and
during tVNS (versus sham stimulation) in PTSD patients. tVNS could be a novel
nonpharmacologic approach to reducing SNS activity and restoring BRS in these patients.
Improving SNS overactivity and BRS may have long term benefits on reducing CV risk in PTSD
patients.
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