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Sympathetic vasomotor changes induced by manual and electrical acupuncture of the Hoku point visualized by thermography.

Considerable evidence implicates sympathetic neural activity in acupuncture analgesia. However, the exact nature of these effects has not been specified in detail, and many experimental findings are contradictory. This study evaluated in normal conditions the specific sympathetic effects of both manual and electrical acupuncture applied to the same hand (Hoku) point. Thermographic measures of superficial skin temperature were used to assess sympathetic vasomotor tone in the face, hand and foot of 19 normal subjects. Baseline assessment, manual acupuncture and electrical acupuncture were performed in 3 separate sessions in a well controlled, 23 degrees C environment. Superficial skin temperature decreased slowly in the control condition. Both manual and electrical acupuncture produced a generalized long-lasting warming effect, indicating reduced sympathetic activity (sympatholytic effect). In addition, electrical acupuncture induced a localized short-term cooling effect, indicating a transient segmental increase in sympathetic activity (sympathomimetic effect).

Acupuncture Therapy↗

Intravenous phentolamine test: diagnostic and prognostic use in reflex sympathetic dystrophy.

In some patients, ongoing and evoked neurogenic pain is relieved by pharmacological or destructive block of the sympathetic innervation of the affected part. In others, sympatholysis is ineffective. The present report shows that these two groups of patients can be distinguished by a safe and simple diagnostic test. Individuals in whom the pain was transiently relieved by intravenous phentolamine (Regitine) were very likely to respond favourably to subsequent sympatholytic treatment with i.v. regional guanethidine. Individuals in whom the phentolamine test was negative did not enjoy pain relief from this type of sympatholysis.

Adolescent↗

Central catecholaminergic responses in hypoxic moderation of spontaneous hypertension.

Exposure to hypobaric hypoxia (H; simulated altitude = 3658 m) was initiated in 5-week-old, male spontaneously hypertensive (SHR) and Wistar-Kyoto (WKy) normotensive rats while normoxic controls (N) for both groups were maintained under laboratory conditions. Significant attenuation of systolic arterial blood pressure was evident in SHR-H relative to SHR-N (125 +/- 6 vs. 145 +/- 5, mmHg; p less than 0.05) while blood pressure in the normotensive, Wistar-Kyoto rat was not affected by 20 days of exposure to hypoxia (WKy-H, 116 +/- 2 vs. WKy-N, 117 +/- 5, mmHg). Increased contents of norepinephrine and dopamine in brain stem, striatum, hypothalamus, and frontal cortex in SHR versus WKy indicated a possible involvement of central catecholaminergic mechanisms with spontaneous hypertension. Hypoxia significantly decreased neuronal contents of both neurotransmitters, typically on both days studied (days 4 and 21 of altitude treatment). In striatum and hypothalamus, dihydroxyphenylacetic acid to dopamine ratios indicated that dopamine turnover was decreased with hypoxia. Hypoxia elicits catecholaminergic responses consistent with profiles found following ICV administration of 6-hydroxydopamine, a sympatholytic agent that also prevents the development of spontaneous hypertension. Hypoxic mitigation of spontaneous hypertension may occur via mechanisms initiated at the level of the CNS.

Animals↗

High-performance liquid chromatography of deacetylmetipranolol in plasma.

A sensitive high-performance liquid chromatographic method with electro-chemical detection is developed for the determination of deacetylmetipranolol (DMP), an active metabolite of beta-sympatholytic drug metipranolol (MP). DMP is extracted from the plasma after basifying with dichloromethane. After evaporation, the residue is reconstituted in the mobile phase, injected onto the reversed-phase ODS column and chromatographed at 50 degrees C. The sensitivity of the method is 2 ng of DMP in 1 ml plasma. Pindolol, another beta-blocking agent is used as internal standard. The method is used for a pharmacokinetic investigation of MP in healthy volunteers and in the patients with liver cirrhosis.

Adrenergic beta-Antagonists↗

Adrenergic control of lipolysis in swine adipose tissue.

Most potential adrenergic compounds did not stimulate lipolysis in swine adipose tissue slices. Most of the sympatholytic agents antagonized lipolysis. Most beta 1- and beta 2-adrenergic agonists were not active but many were active with rat adipose tissue. Catecholamines (epinephrine, norepinephrine and isoproterenol), the resorcinol containing beta 2-agonists (terbutaline, metaproterenol and fenoterol) and the beta 1-agonist, dobutamine were active. The beta 1-antagonists were generally more potent and efficacious than the beta 2-antagonists. The swine adipose tissue adrenoceptor was not readily classified as either beta 1- or beta 2-specific.

Adipose Tissue↗

Do synthetic adrenergic agents interfere with the measurement of endogenous plasma catecholamine concentrations?

PURPOSE: It is common to administer synthetic sympathomimetic and sympatholytic agents in the intensive care unit and operating room. The present study examines whether such agents, as well as the products of catecholamine metabolism, interfere with the quantitation of endogenous catecholamines by high-performance liquid chromatography. METHODS: Samples of drugs and metabolites were assayed before and after alumina extraction and their relative retention times were compared with dopamine, norepinephrine, and epinephrine relative retention times. Blood samples from patients receiving these drugs were also assayed for their interferences with catecholamine determination. RESULTS: Phenylephrine interfered with the quantitation of epinephrine. Isoproterenol's peak was so delayed it appeared in the following chromatogram. Dobutamine had two small peaks in vitro, whereas in the patient samples only one peak was identified; the other was probably masked by the dopamine peak. Labetalol had one peak when the pure drug was assayed but multiple peaks in patient samples, that were probably caused by metabolites of labetalol. CONCLUSION: Synthetic adrenergic agents and catecholamine metabolites can potentially interfere with the quantitation of the endogenous catecholamines. Thus, it is important to examine whether such interference occurs when conducting high-performance liquid chromatography assays.

Adrenergic Agents↗

Electromotive administration of guanethidine for treatment of reflex sympathetic dystrophy: a pilot study in eight patients.

Persistent neuropathic pain is associated with diagnostic and therapeutic challenges that may be very difficult to resolve. This report describes eight patients with incapacitating, posttraumatic neuropathic pain characteristic of reflex sympathetic dystrophy (RSD) who were treated by electromotive administration of guanethidine into affected areas of skin. Following 1-5 treatments, six patients experienced complete resolution of all superficial symptoms of hyperalgesia, pain, pallor, coolness, and sweating of the affected areas. One patient demonstrated partial relief of these symptoms, and one patient failed to respond. The results of this preliminary study suggest that electromotive administration of the the sympatholytic agent, guanethidine, may be useful in the treatment of some types of neuropathic pain. These findings justify the implementation of further controlled studies.

Adult↗

Effect of amlodipine and felodipine on sympathetic activity and baroreflex function in normal humans.

Baroreflex sensitization and direct sympatholytic effects have been suggested as contributing mechanisms to the effects of dihydropyridine calcium channel blockers in hypertension and heart failure. In this study, we tested the hypothesis that either amlodipine or felodipine would decrease norepinephrine levels and enhance cardiac, peripheral vascular, or sympathetic responses to baroreflex perturbation in healthy humans. Six healthy male volunteers aged 21 to 40 participated. Heart rate, forearm blood flow, arterial pressure, and norepinephrine kinetics were assessed in the supine position, after 15 min of 60 degrees head-up tilt, after 15 min of 30 degrees head-down tilt, and after 15 min head-down tilt with phenylephrine infused to raise mean arterial pressure 10 to 15 mm Hg. Studies were conducted double-blind on 3 different days 8 to 12 h after placebo, 5 mg amlodipine, and 10 mg felodipine. Resting heart rate, mean arterial pressure, forearm vascular resistance, plasma norepinephrine, and norepinephrine spillover were not affected by amlodipine or felodipine. During upright tilt, head-down tilt, and phenylephrine, each variable increased and decreased as expected after placebo. There was no effect of either amlodipine or felodipine on any response to any maneuver. Baseline sympathetic activity as reflected by plasma norepinephrine and norepinephrine spillover are not altered by either amlodipine or felodipine. Neither drug acutely sensitizes baroreflex function in normal humans over the degree of perturbation produced in these protocols.

Adult↗

Special cases: ketamine, nitrous oxide and xenon.

Most general anaesthetic agents produce anaesthesia by increasing the activity of inhibitory gamma-aminobutyric acid type A receptors. The effects of ketamine, xenon and nitrous oxide on these receptors are, however, negligible. These anaesthetic agents potently inhibit excitatory N-methyl-D-aspartate receptors. Although these anaesthetic agents display some similar clinical features, such as potent analgesic effects, there are some important differences. Ketamine and nitrous oxide produce sympathomimetic effects, whereas xenon produces a sympatholytic effect. In addition, these anaesthetic agents return differential signals on clinical available anaesthetic depth monitors such as the bispectral index and mid-latency auditory evoked potential. Ketamine and nitrous oxide do not per se decrease the bispectral index. However, xenon decreases the bispectral index in a concentration-dependent manner. Similarly, ketamine and nitrous oxide do not suppress the mid-latency auditory evoked potential whereas xenon does. Thus, anaesthetic depth monitors fail to describe consciousness accurately when ketamine and nitrous oxide are used.

Anesthesia, General↗

Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects.

BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment. Studies in healthy subjects suggested that sibutramine might have opposing effects on peripheral and central sympathetic activity; an increase in blood pressure has been claimed. Direct measurements of muscle sympathetic nerve activity (MSNA) in sibutramine-treated patients have not been conducted. METHODS AND RESULTS: Twenty nondiabetic obese men and women completed the study (mean body mass index, 35 +/- 3 kg/m2; mean age, 42 +/- 8 years). They were treated for 5 days with 15 mg sibutramine per day or matching placebo in a randomized, double-blind, crossover fashion. At the end of each intervention, heart rate, blood pressure, and MSNA were recorded. Patients underwent cold pressor testing and phenylephrine and nitroprusside infusions. RESULTS: The mean blood pressure (systolic/diastolic) was 118 +/- 13 mm Hg/70 +/- 9 mm Hg with placebo and 120 +/- 13 mm Hg/69 +/- 8 mm Hg with sibutramine (P = .29). The mean resting MSNA was 28 +/- 14 bursts/min with placebo and 12 +/- 10 bursts/min with sibutramine (P < .0001). Sibutramine attenuated the rise in blood pressure (25 +/- 9 mm Hg/9 +/- 9 mm Hg versus 31 +/- 12 mm Hg/14 +/- 9 mm Hg, P < .01) and MSNA (0.3 +/- 0.5 arbitrary units/min versus 1.0 +/- 1.1 arbitrary units/min, P = .01) in response to cold pressor testing. Baroreflex heart rate control was similar with sibutramine and with placebo. The sympathetic baroreflex was shifted such that at a given blood pressure, MSNA was substantially decreased (top, 44 +/- 1.23 bursts/min versus 58 +/- 2.99 bursts/min [P < .001]; center point, 65 +/- 0.32 mm Hg versus 67 +/- 0.81 mm Hg [P < .05]). CONCLUSIONS: Sibutramine treatment profoundly and selectively reduces sympathetic nerve traffic at rest and attenuates the responsiveness to sympathetic stimuli. Our data support the idea that sibutramine's peripheral sympathomimetic effect is counteracted by a central sympatholytic mechanism.

Adult↗

Receptors involved in moxonidine-stimulated atrial natriuretic peptide release from isolated normotensive rat hearts.

Imidazoline I1-receptors are present in the heart and may be involved in atrial natriuretic peptide (ANP) release. The following studies investigated whether moxonidine (an antihypertensive imidazoline I1-receptor and alpha2-adrenoceptor agonist) acts directly on the heart to stimulate ANP release, and to characterize the receptor type involved in this action. Perfusion of rat (200-225 g) isolated hearts with moxonidine (10(-6) and 10(-5) M), for 30 min, resulted in ANP release (83+/-29 and 277+/-70 ng/30 min, above basal, respectively), significantly (P<0.01) different from perfusion with buffer (-6+/-31 ng/30 min). ANP release stimulated by moxonidine (10(-6) M) was inhibited by co-perfusion with the antagonists, AGN192403 (imidazoline I1-receptor), phenoxybenzamine (alpha2>alpha1-adrenoceptors), and prazosin (alpha1>alpha2-adrenoceptors), but increased by rauwolscine (alpha2-adrenoceptors). Perfusion with 10(-5) M brimonidine (full alpha2-adrenoceptor agonist) inhibited moxonidine-stimulated ANP release. Similarly, moxonidine (10(-6) M) tended to reduce coronary flow, but significantly increased coronary flow in the presence of brimonidine, which was vasoconstrictive when perfused alone. Coronary flow was reduced by 10(-5) M each, brimonidine>clonidine>moxonidine; while similar bradycardia was observed with clonidine and moxonidine, but not with brimonidine. In conclusion, these results argue in favor of moxonidine acting primarily on imidazoline I1-receptors to release ANP, with both alpha2-adrenoceptor and imidazoline I1-receptors exerting inhibitory inter-relation. In contrast, the coronary vasodilatory effect of moxonidine requires full activation of alpha2-adrenoceptor. The sympatholytic and ANP-releasing effects of moxonidine appear to be mediated by cardiac imidazoline receptors that may be differentially localized. Most importantly, moxonidine can stimulate ANP release from the heart without contribution of the central nervous system.

Adrenergic alpha-2 Receptor Agonists↗

Intrathecal clonidine reduces the incidence of ischemia-provoked ventricular arrhythmias in a canine postinfarction heart failure model.

BACKGROUND: Intrathecal clonidine (ITC) is used clinically to manage neuropathic pain but frequently causes hypotension and bradycardia due to centrally mediated sympatholytic effects. OBJECTIVES: The purpose of this study was to evaluate the cardiac electrophysiologic effects of thoracic ITC and its effects on ischemia-provoked ventricular arrhythmias. METHODS: Twelve mongrel dogs with healed myocardial infarctions and heart failure were evaluated. ITC was delivered locally via catheter to the T2-T4 spinal segments and was dosed to reduce heart rate (HR) by >20% to 25%. Electrophysiologic testing was performed before and after ITC. Transient (4-minute) myocardial ischemia was induced via left circumflex coronary artery occlusion on two separate occasions to provoke ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]). Ischemic episodes were separated by 1 to 2 days, and dogs were randomly assigned to receive ITC or intrathecal saline flush (control) prior to the first or the second ischemic episode. RESULTS: ITC produced significant decrease in HR (31%) and increases in PR interval (22%), Wenckebach cycle length (122%), and atrial and ventricular effective refractory periods (19% and 9%, respectively) but had no significant effect on systemic blood pressure. The occurrence of VT/VF was reduced from 9 of 12 to 3 of 12 dogs when ITC was administered prior to transient myocardial ischemia (P = .04). ITC also blunted ischemia-induced HR increase by 74%. CONCLUSION: ITC reduced ischemia-induced VT/VF in a canine model of healed myocardial infarction with superimposed heart failure and acute ischemia. Results from electrophysiologic testing were consistent with a clonidine-induced reduction in cardiac sympathetic activity from the spinal cord. These data suggest that ITC administration may be a novel approach to treating ventricular arrhythmias.

Adrenergic alpha-Agonists↗

Comparison of the effects of propofol and midazolam on the cardiovascular autonomic nervous system during combined spinal and epidural anesthesia.

STUDY OBJECTIVE: To investigate the effect of propofol and midazolam on cardiac autonomic nervous system (CANS) activity during combined spinal-epidural anesthesia. DESIGN: Prospective, clinical study. SETTING: Operating room of a university hospital. PATIENTS: Forty ASA physical status I and II patients scheduled for knee surgery. INTERVENTION: Patients were randomized to receive sedation with either propofol or midazolam. MEASUREMENTS: Heart rate (HR), HR variability (HRV), systolic arterial pressure (SAP), and SAP variability (SAPV) were used for the analysis. These values were measured at the preanesthetic period, after intrathecal injection for spinal anesthesia, after sedation with propofol or midazolam, and just before the end of surgery with sedation. Cross-spectral analyses of the HR and SAP data were assessed to quantify the frequency-related coherence spectra and phase spectra. MAIN RESULTS: Spinal anesthesia itself had no effect on power spectral changes in both groups. After sedation, as for HRV, high-frequency (HF) power (HF, 0.15-0.40 Hz) did not change, whereas low-frequency (LF) power (LF, 0.04-0.15 Hz) and LF/HF, an indicator of CANS balance, significantly decreased with propofol. Further, coherence in cross-spectra presented depression in the LF band area after sedation with propofol. Before the end of surgery with sedation, LF and LF/HF in both HRV and SAPV were correlated with age in those with propofol; however, scarce relation was observed in those who received midazolam. CONCLUSIONS: Propofol was more potent than midazolam in causing CANS activity to be sympatholytic during combined spinal and epidural anesthesia and which was correlated with age only with propofol.

Adult↗

Adjuvant analgesics.

Chronic pain, whether arising from viscera, bone, or any other tissue or structure, is, more often than commonly thought, the result of a mixture of pain mechanisms, and therefore there is no simple formula available to manage chronic complex pain states. Box 1 summarizes a pharmacological algorithm for difficult-to-treat chronic pain, which merely introduces the medication aspect of the treatment. In effect, any comprehensive algorithm should call for an interdisciplinary approach that would include rehabilitation, as well as psychosocial, and when indicated, interventional techniques. Box 1 Analgesic algorithm for difficult-to-treat pain syndromes. Pharmacological Interventions. Moderate to severe pain/functional impairment; pain with a score of >4 on the brief pain inventory. 1. Gabapentinoid (gabapentin, pregabalin)+/-Opioid/opioid rotation or 2. Antidepressant (TCA, duloxetine, venlafaxine)+/-Opioid/opioid rotation or 3. Gabapentinoid+antidepressant+Opioid/opioid rotation; in addition, may consider trials of one or more of the following adjuvants when clinically appropriate: Topical therapies for cutaneous allodynia/hyperalgesia. Anti-inflammatory drugs (corticosteroids for acute inflammatory neuropathic pain)IV bisphosphonates for cancer bone pain or CRPS/RSDNon-gabapentinoid AEDs such as carbamazepine or oxcarbazepine or lamotrigine+/-baclofen for intermittent lancinating pain due to cranial neuralgiasNMDA antagonists Mexiletine On a compassionate basis, according to the patient's clinical condition and pain mechanism, the physician may want to consider an empirical trial of one or more of the emergent topical, oral or parenteral/intrathecal therapies as discussed in the text. If SMP, consider topical clonidine and sympatholytic interventions; if clinically feasible, trials of topical therapies, eg, lidocaine 5% patch, may be considered for a variety of pain states and features.The major rationale for introducing adjuvants is to better balance efficacy and adverse effects. The following scenarios should prompt the use of adjuvants in clinical practice: The toxic limit of a primary analgesic has been reached. The therapeutic benefit of a primary analgesic has plateaued, eg, treatment has reached its true efficacy limit or pharmachodynamic tolerance has developed. The primary analgesic is contraindicated, eg, substance abuse, aberrant behavior, organ failure, allergy, and so forth. Subjective and qualitative symptoms demand broader coverage. Patients often convey that different medications will impart distinct analgesic benefits. Presence of disabling nonpainful complaints and need to manage symptoms such as insomnia, depression, anxiety, and fatigue that all cause worsening of the patient's quality of life and function. Physicians have also been drawn to the adjuvants secondary to new realities of clinical practice. Moreover, aversion to addiction and diversion remains a potent force that shapes prescribing profiles.

Adjuvants, Pharmaceutic↗

A new wrinkle: skin manifestations of aging may relate to autonomic dysfunction.

Various mechanisms have been argued for skin wrinkling, one of the hallmarks of aging. We hypothesize that chronic sympathetic bias is a previously unrecognized mechanism for wrinkling. In the acute setting of water immersion, reversible skin wrinkling is a well-known reflex mediated by the autonomic nervous system. We postulate that skin wrinkling results as a local maladaptive manifestation of a global chronic sympathetic bias that emerges during aging. The persistence of such changes may induce additional compensatory remodeling to cause permanent alteration of the skin. Sympatholytic agents may prove beneficial for arresting or ameliorating the development of wrinkles. Conditions that amplify sympathetic bias such as stress, smoking, amphetamine abuse, HIV, heart failure, and transplantation may accelerate wrinkling. Other common diseases of the skin may also arise as particular manifestations of aberrant autonomic activity through induction of vascular and immune dysfunctions. The temporal and spatial distribution of these dermatologic conditions may reflect variation of autonomic balance, which also regulates T helper immune balance. For all of these dermatologic conditions, local and systemic administration of drugs and medical devices that pharmacologically or electrically modulate autonomic nervous system activity may yield benefits as well.

Aging↗

Effects of dexmedetomidine on respiratory mechanics and control of breathing in normal rats.

Dexmedetomidine is a highly selective and specific alpha(2)-adrenergic agonist, with sedative, analgesic, and sympatholytic activities. The aim of the present study was to define the effects of DMED in respiratory mechanics in normal rats. In addition, lung morphometry was studied to determine whether the physiological changes reflected underlying morphological changes defining the sites of action of dexmedetomidine. Arterial blood gases were also determined. Twelve adult Wistar rats were randomly assigned to two groups of six animals each: PENTO and DMED. In PENTO group animals were sedated (diazepam, 5mg, i.p.) and anaesthetised with pentobarbital sodium (20mgkg(-1) i.p.). The rats of the DMED group received dexmedetomidine (250mugkg(-1) i.p. followed by intravenous infusion of 0.5mugkg(-1)h(-1)). In spontaneously breathing rats, minute ventilation, respiratory frequency, and neuromuscular inspiratory drive were lower in dexmedetomidine group, which also presented hypercapnia, whereas tidal volume, inspiratory, expiratory, and total respiratory cycle times were higher in dexmedetomidine group compared to the PENTO group. During mechanical ventilation, respiratory mechanical parameters were similar in both groups. These findings were supported by the absence of histological changes. In conclusion, under the conditions studied, dexmedetomidine did not change respiratory mechanical parameters and lung histology, but induced ventilatory depression.

Adrenergic alpha-Agonists↗

Selenoproteins, cholesterol-lowering drugs, and the consequences: revisiting of the mevalonate pathway.

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and peroxisome proliferator-activated receptor alpha activators (fibrates) are the backbone of pharmacologic hypercholesterolemia and dyslipidemia treatment. Many of their clinical effects, however, are still enigmatic. This article describes how a side road of the mevalonate pathway, characterized in recent years, can rationalize a major fraction of these unexplained observations. This side road is the enzymatic isopentenylation of selenocysteine-tRNA([Ser]Sec) (Sec-tRNA), the singular tRNA to decode the unusual amino acid selenocysteine. The functionally indispensable isopentenylation of Sec-tRNA requires a unique intermediate from the mevalonate pathway, isopentenyl pyrophosphate, which concomitantly constitutes the central building block for cholesterol biosynthesis, and whose formation is suppressed by statins and fibrates. The resultant inhibition of Sec-tRNA isopentenylation profoundly decreases selenoprotein expression. This effect might seamlessly explain the immunosuppressive, redox, endothelial, sympatholytic, and thyroidal effects of statins and fibrates as well as their common side effects and drug interactions.

Animals↗