Effects of Advanced EA on Hypertension: Role of nNOS-NO in the Dorsal Medulla

高级电针对高血压的影响：nNOS-NO 在背髓质中的作用

• 批准号: 7783868
• 负责人: SHENG-XING MA
• 金额: $ 18.23万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783868
• 关键词: Acupuncture Points; Acupuncture Therapy; Acupuncture procedure; Address; Aminobutyric Acids; Antihypertensive Agents; Area; Arginine; Attenuated; Biological Assay; Blood; Blood Pressure; Brain; Brain Stem; Capsaicin; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Cells; Chemicals; Chinese Traditional Medicine; Chloride Channels; Clinical Treatment; Clinical Trials; Conflict (Psychology); Cutaneous; Cyclic GMP; Dahl Hypertensive Rats; Dahl Salt-Resistant Rats; Depressed mood; Development; Diet; Dorsal; Electroacupuncture; Evaluation; FOS gene; Frequencies; GABA Antagonists; Generations; Genes; Goals; Gold; Guanylate Cyclase; Heart Rate; Hindlimb; Histocytochemistry; Human; Hypertension; In Situ Hybridization; Individual; Kidney; Mediating; Medical center; Mental Depression; Microinjections; Modeling; Molecular; Needles; Neonatal; Nerve; Neurons; Neurotransmitters; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nociception; Nucleus solitarius; Opioid; Opioid Receptor; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Picrotoxin; Play; Principal Investigator; Process; Production; Proteins; Public Health; Rattus; Recovery; Reflex action; Regulation; Reporting; Research; Research Personnel; Role; Science; Sensory; Signal Transduction; Signal Transduction Pathway; Site; Sodium Chloride; Spinothalamic Tracts; Stimulus; Synaptic Transmission; System; Techniques; Testing; Thalamic structure; Therapy Evaluation; Time; Transcutaneous Electric Nerve Stimulation; Up-Regulation; Visceral; Visceral pain; Western Blotting; Withdrawal; afferent nerve; base; blood pressure regulation; dorsal column; experience; extracellular; gamma-Aminobutyric Acid; hypertension control; hypertension treatment; immunocytochemistry; immunoreactivity; improved; inhibitor/antagonist; insight; midbrain central gray substance; novel; public health relevance; research study; response; salt sensitive; sciatic nerve; somatosensory

DESCRIPTION (provided by applicant): The gracile nucleus and nucleus tractus solitarius (NTS) receive somatosensory afferent inputs from the hindlimb, and low-frequency electroacupuncture (EA) stimulation of hindlimb acupoint ST36 produces long-lasting sympathoinhibition and arterial blood depressor in humans and rats. We have found that hypertension is successfully reduced by advanced EA ST36 (two phases over 2 hrs separated by an 80 min interval) in Dahl salt- sensitive (DS) rats but not significantly decreased by EA with a short stimulation period. Expression of neuronal nitric oxide (NO) synthase (nNOS) is predominantly reduced in the gracile nucleus and NTS regions in DS rats, and decreased nNOS expression in the areas is restored by advanced EA ST36. Consistently, our preliminary results show that the depressor responses to EA ST36 are facilitated by microinjection of L-arginine in the gracile nucleus in DS rats. The facilitating effects of NO donors on the hypotensive responses to EA ST36 are inhibited by microinjection of either an antagonist of GABA receptors or an ihhibitor of guanylyl cyclase into gracile nucleus. We hypothesize that impaired nNOS-NO generation in the gracile nucleus and/or NTS causes hypertension in DS rat; advanced EA ST36 induces nNOS-NO-GABA in the brain nuclei, resulting in central inhibitory regulation of cardiovascular functions for hypertension control. In view of the critical importance of NO on arterial blood pressure regulation, our major aims are: 1) Examine whether hypertension in DS rats with salt load is improved and nNOS expressions in the gracile nucleus and/or NTS are restored by advanced EA ST36; 2) Determine whether endogenous NO-GABA releases in the gracile nucleus and mNTS are induced and paralleled to cardiovascular responses to advanced EA ST36; 3) Define whether L-arginine-derived NO synthesis and NO-cGMP-GABA cascade in the gracile nucleus and/or mNTS contribute to cardiovascular responses to advanced EA ST36 in hypertensive rats. The physiological recordings of arterial blood pressure and heart rate will be incorporated with neuropharmacological manipulations, molecular examinations and histochemical studies to test the hypotheses in a DS rat model. The results should develop an effective advanced therapy to restore impaired nNOS in the gracile nucleus/NTS for hypertension control and yield new insights into central mechanisms of NO-cGMP-GABA on EA signaling and cardiovascular regulation in the dorsal medulla. PUBLIC HEALTH RELEVANCE: These studies should advance our understanding of sites and mechanisms of nitric oxide (NO) in the dorsal medulla for cardiovascular regulation and reveal a novel mechanism of NO-GABA for signal transduction of electroacupuncture (EA) ST36 in the central pathways. The results should benefit public health by providing a theraputic mechanism of acupuncture, and establish a gold-standard EA therapy based on scientific evidence of inducing NO and its synthase in the dorsal medulla for clinical treatment of hypertension and other cardiovascular diseases.

描述(申请人提供)：薄束核和孤束核(NTS)接受来自后肢的躯体感觉传入，低频电针(EA)刺激后肢穴位ST36在人类和大鼠中产生长期的交感抑制和动脉降压。我们发现，在Dahl盐敏感(DS)大鼠中，高级电针ST36(间隔80分钟的两个时相)能成功地降低高血压，但短刺激期的电针并不能显着降低高血压。DS大鼠股薄核和NTS区神经元型一氧化氮合酶(NNOS)表达明显减少，而高级电针ST36可恢复该区域nNOS的表达。我们的初步结果表明，薄束核内微量注射L-精氨酸可促进DS大鼠对电针ST36的降压反应。小核内微量注射GABA受体拮抗剂或鸟苷酸环化酶抑制剂可抑制NO供体对EA ST36降压反应的易化作用。我们推测，薄束核和/或NTS中nNOS-NO的生成受损导致了DS大鼠的高血压；高级EA ST36诱导了脑内核团中nNOS-NO-GABA的产生，从而导致心血管功能的中枢抑制调节，从而控制高血压。鉴于NO在动脉血压调节中的重要作用，我们的主要目的是：1)检测进展期电针ST36是否能改善盐负荷DS大鼠的高血压状态，恢复其在薄壁核和/或NTS内的nNOS表达；2)确定进展期电针ST36是否诱导细核和mNTs内源性NO-GABA的释放并与其心血管反应平行；3)确定L精氨酸衍生的NO合成和薄壁核和/或mNTS的NO-cGMP-GABA通路是否参与了进展期EA ST36引起的心血管反应。动脉血压和心率的生理记录将与神经药理学操作、分子检查和组织化学研究相结合，以在DS大鼠模型中验证假设。这一结果将为高血压控制开发一种有效的高级治疗方法，以恢复松质核/NTS受损的nNOS，并对NO-cGMP-GABA在电针信号和延髓背部心血管调节中的中枢机制提供新的见解。 公共卫生相关性：这些研究将促进我们对一氧化氮(NO)在延髓背部调节心血管的部位和机制的理解，并揭示NO-GABA在中枢通路电针(EA)ST36信号转导中的新机制。这一结果将通过提供针灸的治疗机制来造福公众健康，并建立基于科学证据的在延髓背侧诱导NO及其合酶的金标准电针疗法，用于临床治疗高血压和其他心血管疾病。