Adenosine A2A receptors in the rostral ventrolateral medulla participate in blood pressure decrease with electroacupuncture in hypertensive rats.

Acupuncture is increasingly used to manage high blood pressure (BP) as a complementary therapy. However, the mechanisms underlying its hypotensive effects remain unclear. Our previous studies have shown that electroacupuncture (EA) at the ST36-37 acupoints, overlying the deep peroneal nerve, attenuates pressor responses through adenosine A2A receptors (A2AR) in the rostral ventrolateral medulla (rVLM). However, it is uncertain whether rVLM A2AR contributes to EA's BP-lowering effect in sustained hypertension. We hypothesized that a course of EA treatment lowers BP, in part, through the activation of adenosine A2AR in the rVLM in hypertensive rats. To mimic essential hypertension in the clinic, we performed EA in conscious Dahl salt-sensitive hypertensive rats (DSHRs). EA (0.1-0.4 mA, 2 Hz) was applied at ST36-37 for 30 min twice weekly for four weeks, while sham-EA was conducted in a similar manner but without electrical input. In hypertensive rats, BP was reduced by EA (n = 14) but neither by sham-EA (n = 14) nor in the absence of needling (n = 8). Following four weeks of eight treatments and then under anesthesia, EA's modulatory effect on elevated BP was reversed by unilateral rVLM microinjection of SCH 58261 (1 mM in 50 nl; an A2AR antagonist; n = 7; P < 0.05) but not the vehicle (n = 5) in EA-treated DSHRs. Activation of rVLM A2AR in DSHRs treated with sham-EA by an A2AR agonist, CGS-21680 (0.4 mM in 50 nl; n = 8), decreased BP. Unilateral administration of SCH 58261 or CGS-21680 into the rVLM did not alter basal BP in Dahl salt-sensitive rats fed a regular diet with normal BP. The A2AR level in the rVLM after EA was increased compared to the sham-EA and untreated DSHRs (n = 5 in each group; all P < 0.05). These data suggest that a 4-week twice weekly EA treatment reduced BP in salt-sensitive hypertensive rats likely through adenosine-mediated A2AR in the rVLM.

Sympathoinhibitory electroacupuncture (EA) interacts positively with anti-inflammatory EA alleviating blood pressure in hypertensive rats.

Elevated sympathetic activity and chronic inflammation are known contributory factors observed in hypertension. We have observed that sympathoinhibitory electroacupuncture (SI-EA) at acupoints ST36-37 alleviates sympathetic activity and hypertension. Additionally, EA at acupoints SP6-7 exerts anti-inflammatory (AI-EA) effects. However, it is not known whether simultaneous stimulation of this combination of acupoints attenuates or enhances individual effects. A 2 × 2 factorial design was used to test the hypothesis that combining SI-EA and AI-EA (cEA) leads to greater reduction of hypertension by decreasing sympathetic activity and inflammation in hypertensive rats than either set of acupoints alone. Dahl salt-sensitive hypertensive (DSSH) rats were treated with four EA regimens including cEA, SI-EA, AI-EA, and sham-EA twice weekly for five weeks. A group of normotensive (NTN) rats served as control. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were measured non-invasively by tail-cuff. Plasma norepinephrine (NE), high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) concentrations were determined with ELISA at the completion of treatments. DSSH rats on high salt diet progressively developed moderate hypertension within five weeks. DSSH rats treated with sham-EA showed continuous increase in SBP and DBP and elevations in plasma NE, hs-CRP, and IL-6 levels relative to NTN control. Both SI-EA and cEA decreased SBP and DBP, and had corresponding changes in biomarkers (NE, hs-CRP, and IL-6) compared with sham-EA. AI-EA prevented SBP and DBP elevation and decreased IL-6 and hs-CRP relative to sham-EA. Importantly in DSSH rats that received repetitive cEA treatment, SI-EA interacted positively with AI-EA leading to greater reduction of SBP, DBP, NE, hs-CRP, and IL-6 than SI-EA or AI-EA alone. These data suggest that by targeting both elevated sympathetic activity and chronic inflammation, cEA regimen results in a greater reduction of BP effects in treating hypertension compared to using individual SI-EA or AI-EA alone.

Lipid-Lowering Nutraceuticals for an Integrative Approach to Dyslipidemia.

Dyslipidemia is a treatable risk factor for atherosclerotic cardiovascular disease that can be addressed through lifestyle changes and/or lipid-lowering therapies. Adherence to statins can be a clinical challenge in some patients due to statin-associated muscle symptoms and other side effects. There is a growing interest in integrative cardiology and nutraceuticals in the management of dyslipidemia, as some patients desire or are actively seeking a more natural approach. These agents have been used in patients with and without established atherosclerotic cardiovascular disease. We provide an updated review of the evidence on many new and emerging nutraceuticals. We describe the mechanism of action, lipid-lowering effects, and side effects of many nutraceuticals, including red yeast rice, bergamot and others.

Electroacupuncture for the management of symptom clusters in cancer patients and survivors (EAST).

BACKGROUND: Neuropsychiatric symptoms, comprising cognitive impairment, fatigue, insomnia, depression, and anxiety, are prevalent and may co-occur during and after chemotherapy treatment for cancer. Electroacupuncture (EA), which involves mild electrical stimulation with acupuncture, holds great potential in addressing the management of individual symptoms. However, there is a lack of studies evaluating if EA can manage concurrent neuropsychiatric symptoms in cancer (i.e., symptom cluster). Hence, we designed a trial to evaluate the efficacy, safety, and feasibility of administering EA as an intervention to mitigate neuropsychiatric symptom clusters amongst cancer patients and survivors. METHODS: The EAST study is a randomized, sham-controlled, patient- and assessor-blinded clinical trial. Sixty-four cancer patients and survivors with complaints of one or more neuropsychiatric symptom(s) in the seven days prior to enrollment are recruited from the University of California Irvine (UCI) and Children's Hospital of Orange County (CHOC). Individuals with needle phobia, metastases, bleeding disorders, electronic implants, epilepsy, exposure to acupuncture in the three months prior to enrollment, and who are breastfeeding, pregnant, or planning to get pregnant during the duration of the study will be excluded. Screening for metal fragments and claustrophobia are performed prior to the optional neuroimaging procedures. Recruited patients will be randomized (1:1) in random blocks of four or six to receive either ten weekly verum EA (treatment arm, vEA) or weekly sham EA (control arm, sEA) treatment visits with a follow-up appointment four to twelve weeks after their last treatment visit. The treatment arm will receive EA at 13 acupuncture points (acupoints) chosen for their therapeutic effects, while the control arm receives minimal EA at 7 non-disease-related acupoints. Questionnaires and cognitive assessments are administered, and blood drawn to assess changes in symptom clusters and biomarkers, respectively. CONCLUSION: The EAST study can provide insight into the efficacy of EA, an integrative medicine modality, in the management of cancer symptom clusters in routine clinical practice. TRIAL REGISTRATION: This trial is registered with clinicaltrials.gov NCT05283577.

Neurogenic Hypotension and Bradycardia Modulated by Electroacupuncture in Hypothalamic Paraventricular Nucleus.

Electroacupuncture (EA) stimulates somatic median afferents underlying P5-6 acupoints and modulates parasympathoexcitatory reflex responses through central processing in the brainstem. Although decreases in blood pressure and heart rate by the neural-mediated Bezold-Jarisch reflex responses are modulated by EA through opioid actions in the nucleus tractus solitarius and nucleus ambiguus, the role of the hypothalamus is unclear. The hypothalamic paraventricular nucleus (PVN) is activated by sympathetic afferents and regulates sympathetic outflow and sympathoexcitatory cardiovascular responses. In addition, the PVN is activated by vagal afferents, but little is known about its regulation of cardiopulmonary inhibitory hemodynamic responses. We hypothesized that the PVN participates in the Bezold-Jarisch reflex responses and EA inhibits these cardiopulmonary responses through the PVN opioid system. Rats were anesthetized and ventilated, and their heart rate and blood pressures were monitored. Application of phenylbiguanide every 10 min close to the right atrium induced consistent depressor and bradycardia reflex responses. Unilateral microinjection of the depolarization blockade agent kainic acid or glutamate receptor antagonist kynurenic acid in the PVN reduced these reflex responses. In at least 70% of the rats, 30 min of bilateral EA at P5-6 acupoints reduced the depressor and bradycardia responses for at least 60 min. Blockade of the CCK-1 receptors converted the non-responders into EA-responders. Unilateral PVN-microinjection with naloxone reversed the EA inhibition. Vagal-evoked activity of the PVN cardiovascular neurons was reduced by 30 min EA (P5-6) through opioid receptor activation. These data indicate that PVN processes inhibitory cardiopulmonary reflexes and participates in EA-modulation of the neural-mediated vasodepression and bradycardia.

Dietary potassium intake, kidney function, and survival in a nationally representative cohort.

BACKGROUND: In healthy adults, higher dietary potassium intake is recommended given that potassium-rich foods are major sources of micronutrients, antioxidants, and fiber. Yet among patients with advanced kidney dysfunction, guidelines recommend dietary potassium restriction given concerns about hyperkalemia leading to malignant arrhythmias and mortality. OBJECTIVES: Given sparse data informing these recommendations, we examined associations of dietary potassium intake with mortality in a nationally representative cohort of adults from the NHANES. METHODS: We examined associations between daily dietary potassium intake scaled to energy intake (mg/1000 kcal), ascertained by 24-h dietary recall, and all-cause mortality among 37,893 continuous NHANES (1999-2014) participants stratified according to impaired and normal kidney function (estimated glomerular filtration rates <60 and ≥60 mL · min-1 · 1.73 m-2, respectively) using multivariable Cox models. We also examined the impact of the interplay between dietary potassium, source of potassium intake (animal- compared with plant-based sources), and coexisting macronutrient and mineral consumption upon mortality. RESULTS: Among participants with impaired and normal kidney function, the lowest tertile of dietary potassium scaled to energy intake was associated with higher mortality (ref: highest tertile) [adjusted HR (aHR): 1.18; 95% CI: 1.02, 1.38 and aHR: 1.17; 95% CI: 1.06, 1.28, respectively]. Compared with high potassium intake from plant-dominant sources, participants with low potassium intake from animal-dominant sources had higher mortality irrespective of kidney function. Among participants with impaired kidney function, pairings of low potassium intake with high protein, low fiber, or high phosphorus consumption were each associated with higher death risk. CONCLUSIONS: Lower dietary potassium scaled to energy intake was associated with higher mortality, irrespective of kidney function. There was also a synergistic relation of higher potassium intake, plant-based sources, and macronutrient/mineral consumption with survival. Further studies are needed to elucidate pathways linking potassium intake and coexisting dietary factors with survival in populations with and without chronic kidney disease.

Fos-CreER-based genetic mapping of forebrain regions activated by acupuncture.

Acupuncture increasingly is accepted as a potential therapy for many diseases in the Western world. However, the mechanism of acupuncture is not well understood mechanistically. We have established that manual acupuncture (MA) at the Neiguan (P6) acupoint inhibits excitatory cardiovascular reflex responses through modulation of the autonomic nervous system in the brainstem. It is unclear whether P6 MA activates neurons in the brain regions beyond the brainstem. Thus, we mapped P6 specific neural activation by MA in the forebrain using the Fos-CreER; Ai9 mice model, which allows for enhanced sensitivity and efficiency compared to conventional immunohistochemical staining. Compared to sham-MA control without manual stimulation, we find that MA at P6 markedly increases c-Fos positive neurons in a number of the forebrain regions (n = 5 in each group). These activated regions include accumbens nucleus, caudate putamen, claustrum, bed nucleus of the stria terminalis, amygdaloid nucleus, ventral posterior division of the thalamic nucleus, paraventricular hypothalamic nucleus, arcuate hypothalamic nucleus, primary and secondary somatosensory cortex, ectorhinal cortex, and dorsolateral entorhinal cortex. As MA at P6 activates neurons in relatively broad brain networks beyond the brainstem, our data suggest that acupuncture at this acupoint has the potential to influence physiological functions associated with autonomic and non-autonomic nervous systems through its effects on multiple brain regions.

Adenosine Receptor A2a, but Not A1 in the rVLM Participates Along With Opioids in Acupuncture-Mediated Inhibition of Excitatory Cardiovascular Reflexes.

Electroacupuncture (EA) can be used to lower high blood pressure (BP) in clinical practice. However, precise mechanisms underlying its effects on elevated BP remain unclear. Our previous studies have shown that EA at the P5-6 acupoints, overlying the median nerve, attenuates elevated BP induced by gastric distension (GD) through influence on rostral ventrolateral medulla (rVLM). Although adenosine is released during neuronal activation in the rVLM, its role in acupuncture-cardiovascular regulation is unknown. The purinergic system is involved in cardiovascular pressor and depressor responses, including via selective activation of A1 and A2 a rVLM receptors, respectively. The action of A2 a receptor stimulation in the central nervous system may be further regulated through an endogenous opioid mechanism. However, it is uncertain whether this putative action occurs in the rVLM. We hypothesized that adenosine in the rVLM contributes to EA modulation of sympathoexcitatory reflexes through an A2 a but not an A1 adenosine receptor-opioid mechanism. EA or sham-EA was applied at the P5-6 acupoints in Sprague-Dawley male rats subjected to repeated GD under anesthesia. We found that EA (n = 6) but not sham-EA (n = 5) at P5-6 significantly (P < 0.05) attenuated GD-induced elevations in BP. EA modulation of sympathoexcitatory cardiovascular reflexes was reversed significantly after rVLM microinjection (50 nl) of 8-SPT (10 mM; non-selective adenosine receptor antagonist; n = 7) or SCH 58261 (1 mM; A2 a receptor antagonist; n = 8; both P < 0.05), but not by DPCPX (3 mM; A1 receptor antagonist; n = 6) or the vehicle (5% dimethylsulfoxide; n = 6). Moreover, microinjection of an A2 a receptor agonist, CGS-21680 (0.4 mM; n = 8) into the rVLM attenuated GD-induced pressor responses without EA, which mimicked EA's inhibitory effects (P < 0.05). After blockade of opioid receptors with naloxone (1 mM) in the rVLM, SCH 58261's reversal of EA's effect on GD-induced pressor responses was blunted, and CGS-21680-mediated inhibitory effect on pressor responses was not observed. Furthermore, neurons labeled with adenosine A2 a receptors were anatomically co-localized with neurons stained with enkephalin in the rVLM. These data suggest that the involvement of rVLM adenosine A2 a receptors in EA modulation of GD-induced pressor reflexes is, at least in part, dependent on the presence of endogenous opioids.

Acupuncture activates a direct pathway from the nucleus tractus solitarii to the rostral ventrolateral medulla.

Our previous studies have shown that electroacupuncture (EA) at the Jianshi-Neiguan acupoints (P5-6, overlying the median nerve) attenuates sympathoexcitatory responses through its influence on neuronal activity in the rostral ventrolateral medulla (rVLM). The nucleus tractus solitarii (NTS) receives input from somatic nerve stimulation. Connections between the NTS and the rVLM during EA stimulation have not been investigated and thus were the focus of the present study. Seven to ten days after unilateral microinjection of a rhodamine-conjugated microsphere retrograde tracer (100 nl) into the rVLM, rats were subjected to EA or sham-EA without electrical stimulation. EA was performed for 30 min at the P5-6 acupoints bilaterally. Perikarya containing the microsphere tracer were found in the NTS of both groups. Compared to controls (needle placement without electrical stimulation, n = 7), c-Fos immunoreactivity and neurons double-labeled with c-Fos, an immediate early gene, and the tracer were significantly increased in the NTS of EA-treated rats (all P < 0.05; n = 8), particularly, in the medial and lateral subdivisions of NTS at subpostremal and obex levels. These results suggest that EA at the P5-6 acupoints activates NTS neurons. Furthermore, EA-activated NTS neurons directly project to the rVLM and likely influence the rVLM activity.

Integrative Medicine as a Vital Component of Patient Care.

The landscape of medicine in the United States has been slowly progressing toward a more holistic and individualized approach to healing. Part of this progress has been the integration between western and alternative forms of medicine, a concept that has been described as "integrative medicine." This approach to healthcare incorporates a patient's mind, spirituality, and sense of community into the healing process. Integrative medicine has been typically well received and the demand has been steadily increasing in primary US hospitals. Here we cover a number of topics that include the definition of integrative medicine, its potential benefits, current examples of successful implementations, and potential barriers to its expansion. The aim was to give a primary on integrative medicine and its current state for healthcare providers.

A novel integrative healing services approach for neurosurgery inpatients: Preliminary experiences and cost calculations.

BACKGROUND: Neurosurgery inpatients are oftentimes critically ill, and face significant stress, post-operative pain, and/or emotional distress. As a result, the use of non-pharmacologic, alternative therapies as adjuncts in surgical care may benefit this patient population. Hospital economics related to integrative services may also provide additional incentive to providing alternative therapies. This study characterizes and evaluates how Integrative Healing Services (IHS) affects patient pain levels and length of stay. We also performed a literature review to examine national trends in inpatient integrative healing. METHODS: An IHS team (e.g. acupuncture, healing touch, music therapy, pet therapy, and counseling) was incorporated into the treatment regimen of neurosurgery inpatients (with >4days of stay) with chronic or intractable pain, stress or depression, and/or patients intolerant to or who failed physical or occupational therapy. RESULTS: 34 charts were retrospectively reviewed, with 17 patients receiving IHS (11 cranial and 6 spine cases), and 17 age and gender matched controls receiving routine care (11 cranial and 6 spine patients). Overall, 71% (12/17) of patients had a reduction in pain medication consumption, with 55% (6/11) of cranial and 100% (6/6) of spine patients reporting a reduction compared to baseline. The average pre-treatment pain-scale score was 5.5 out of 10 across all patients, while the average post-treatment pain-scale score was 3 out of 10 (p<0.01). 59% of patients had improved mobility. The average length of stay in the IHS group was 12.6days, and 19.6days in the routine care group (range 4-45) (p<0.01). CONCLUSIONS: IHS intervention may be an effective option for treating pain and decreasing hospital length of stay. National trends support the use of integrative healing and will likely continue to increase as further studies are performed.

Moxibustion Modulates Sympathoexcitatory Cardiovascular Reflex Responses Through Paraventricular Nucleus.

Electroacupuncture (EA) point specific (ST36-37) stimulation decreases cardiovascular reflex responses through supraspinal regions such as the hypothalamic paraventricular nucleus (PVN) while mechanical stimulation of acupoints decreases pressor responses through peripheral thermal transient receptor potential vanilloid type-1 (TRPV1). Moxibustion generating heat applied at acupoint in combination with antihypertensive drugs decreases elevated blood pressure. We hypothesized that moxibustion modulates sympathoexcitatory cardiovascular responses through the hypothalamic PVN and peripheral heat sensitive TRPV1 in the absence of antihypertensive drugs. Rats were anesthetized, ventilated, and heart rate and mean blood pressure were monitored. Gastric distention induced consistent pressor reflex responses every 10-min. Thirty-minutes of bilateral moxibustion at the acupoint ST36, overlying the deep peroneal nerves, reduced the gastric distention evoked elevation in blood pressure. Blood pressure reflex responses were not reduced by both EA and moxibustion at G39. The moxibustion inhibition but not EA inhibition of the cardiovascular responses was reversed with blockade of local heat sensitive TRPV1 at ST36. Accordingly, activation of thermal TRPV1 by moxibustion at an average of 44.2°C in contrast to 40°C reduced the pressor responses. Naloxone, an opioid receptor antagonist, microinjected into PVN inhibited transiently the effect of moxibustion. Thus, activation of peripheral heat sensitive TRPV1 mediated the moxibustion-inhibition, but not EA-inhibition, of sympathoexcitatory cardiovascular reflex responses through hypothalamic PVN opioid system.

Systems healthcare: a holistic paradigm for tomorrow.

Systems healthcare is a holistic approach to health premised on systems biology and medicine. The approach integrates data from molecules, cells, organs, the individual, families, communities, and the natural and man-made environment. Both extrinsic and intrinsic influences constantly challenge the biological networks associated with wellness. Such influences may dysregulate networks and allow pathobiology to evolve, resulting in early clinical presentation that requires astute assessment and timely intervention for successful mitigation. Herein, we describe the components of relevant biological systems and the nature of progression from at-risk to manifest disease. We illustrate the systems approach by examining two relevant clinical examples: Alzheimer's and cardiovascular diseases. The implications of systems healthcare management are examined through the lens of economics, ethics, policy and the law. Finally, we propose the need to develop new educational paradigms to enhance the training of the health professional in an era of systems medicine.