We have investigated the mechanisms by which acupuncture, particularly electroacupuncture (EA) regulates blood pressure (BP). EA has the capability to lower elevated BP and to alleviate demand-induced myocardial ischemia. Its actions are slow in onset but its duration of action is prolonged. Approximately 70% of experimental subjects with acute reflex-induced elevations in BP respond to EA. The most recent grant has focused on a long-loop pathway extending from the hypothalamic arcuate nucleus to the midbrain ventrolateral periaqueductal gray (vlPAG) to the medullary midline nucleus raphe'pallidus (NRP) and then the rostral ventrolateral medulla (rVLM) where the activity of premotor sympathetic neurons is inhibited by EA. We specifically identified a reinforcing reciprocating network between the arcuate and the vlPAG that serves to prolong the action of EA. We also defined an important role for the NRP as a nucleus that processes glutamatergic input from the vlPAG and through a 5-HT1A rVLM mechanism modulates sympathetic outflow. The central hypothesis of this competitive renewal is that a standardized course of acupuncture treatment and established methods convert nonresponders to responders to increase EA's efficacy in reducing elevated blood pressure (BP), particularly through its inhibitory action in the hypothalamic paraventricular nucleus (PVN). The present grant will focus on four new areas: 1) the role of the PVN modulated during EA by opioid (enkephalin and endorphinergic) inputs from the arcuate and through projections to the rVLM and IML inhibits reflex-evoked sympathetic activation, 2) the mechanism through which repetitive EA in conscious cold-induced hypertensive (CI-HTN) rats lowers BP, 3) transcriptional mechanisms regulating enkephalin and endorphin production in the rVLM and arcuate during repetitive stimulation in EA's action to lower BP in CI-HTN rats and 4) cholecystokinin neuromodulation of opioid activity in the PVN of animals unresponsive to the actions of EA. Anatomical, physiological, electrophysiological, pharmacological and molecular approaches will be used in the proposed studies that are highly relevant to patients that have the potential to benefit from clinical acupuncture.

Public Health Relevance

Hypertension, occurring more commonly in middle and older aged Americans, is a prevalent disease that causes substantial mortality and morbidity in many patients. Inconclusive data and insufficient information on the efficacy of acupuncture and its mechanisms of action deter physicians from using acupuncture to treat hypertension although this medical modality may be a viable inexpensive alternative with low incidence of side effects. The current application will provide important new information on improving efficacy and mechanisms of action in acupuncture treatment of hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VH-B (04))
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Maric-Bilkan, Christine
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University of California Irvine
Internal Medicine/Medicine
Schools of Medicine
United States
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Guo, Zhi-Ling; Fu, Liang-Wu; Su, Hou-Fen et al. (2018) Role of TRPV1 in acupuncture modulation of reflex excitatory cardiovascular responses. Am J Physiol Regul Integr Comp Physiol 314:R655-R666
Tjen-A-Looi, Stephanie C; Fu, Liang-Wu; Guo, Zhi-Ling et al. (2018) Modulation of Neurally Mediated Vasodepression and Bradycardia by Electroacupuncture through Opioids in Nucleus Tractus Solitarius. Sci Rep 8:1900
Longhurst, John C; Tjen-A-Looi, Stephanie C (2017) Evidence-based blood pressure reducing actions of electroacupuncture: mechanisms and clinical application. Sheng Li Xue Bao 69:587-597
Li, Min; Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling et al. (2016) Repetitive Electroacupuncture Attenuates Cold-Induced Hypertension through Enkephalin in the Rostral Ventral Lateral Medulla. Sci Rep 6:35791
Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling; Fu, Liang-Wu et al. (2016) Paraventricular Nucleus Modulates Excitatory Cardiovascular Reflexes during Electroacupuncture. Sci Rep 6:25910
Cheng, Ling; Li, Peng; Tjen-A-Looi, Stephanie Cheeyee et al. (2015) What do we understand from clinical and mechanistic studies on acupuncture treatment for hypertension? Chin Med 10:36
Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling; Longhurst, John C (2014) GABA in nucleus tractus solitarius participates in electroacupuncture modulation of cardiopulmonary bradycardia reflex. Am J Physiol Regul Integr Comp Physiol 307:R1313-23
Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling; Li, Min et al. (2013) Medullary GABAergic mechanisms contribute to electroacupuncture modulation of cardiovascular depressor responses during gastric distention in rats. Am J Physiol Regul Integr Comp Physiol 304:R321-32
Li, Min; Tjen-A-Looi, Stephanie C; Guo, Zhi-Ling et al. (2013) Electroacupuncture modulation of reflex hypertension in rats: role of cholecystokinin octapeptide. Am J Physiol Regul Integr Comp Physiol 305:R404-13
Longhurst, John C; Tjen-A-Looi, Stephanie (2013) Acupuncture regulation of blood pressure: two decades of research. Int Rev Neurobiol 111:257-71

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