Adrenergic Function Research Articles

Su1555 - In Experimental Ascitic Cirrhosis Reduction of Adrenergic Function has Considerable Aquaretic Effects: Pathophysiological and Clinical Consequences

Su1555 - In Experimental Ascitic Cirrhosis Reduction of Adrenergic Function has Considerable Aquaretic Effects: Pathophysiological and Clinical Consequences

Evaluation of Adrenergic Function: Tilt-Table and Valsalva Test

Evaluation of Adrenergic Function: Tilt-Table and Valsalva Test

Impact of Racial Discrimination and Hostility on Adrenergic Receptor Responsiveness in African American Adults.

Racial discrimination is increasingly recognized as a contributor to increased cardiovascular disease (CVD) risk among African Americans. Previous research has shown significant overlap between racial discrimination and hostility, an established predictor of CVD risk including alterations in adrenergic receptor functioning. The present study examined the associations of racial discrimination and hostility with adrenergic receptor responsiveness. In a sample (N = 57) of young to middle-aged African American adults (51% female) with normal and mildly elevated blood pressure, a standardized isoproterenol sensitivity test (CD25) was used to evaluate β-AR responsiveness, whereas the dose of phenylephrine required to increase mean arterial pressure by 25 mm Hg (PD25) was used to assess α1-AR responsiveness. Racial discrimination was measured using the Perceived Racism Scale and hostility was assessed using the Cook-Medley Hostility Scale. In hierarchical regression models, greater racial discrimination, but not hostility, emerged as a significant predictor of decreased β-adrenergic receptor responsiveness (β = .38, p = .004). However, moderation analysis revealed that the association between racial discrimination and blunted β-adrenergic receptor responsiveness was strongest among those with higher hostility (β = .49, 95% confidence interval = .17-.82, p = .004). In addition, hostility, but not racial discrimination, significantly predicted α1-AR responsiveness. These findings suggest racial discrimination was associated with blunted β-adrenergic receptor responsiveness, providing further evidence of the potential contribution of racial discrimination to increased CVD risk among African Americans. The adverse effects of discrimination on cardiovascular health may be enhanced in individuals with higher levels of hostility.

Clinical Practice Guidelines for management of Sexual Disorders in Elderly.

Clinical Practice Guidelines for management of Sexual Disorders in Elderly.

<sup>123</sup>I-MIBG in Latin America

Heart Failure (HF) is a life-threatening disease which incidence is growing over the years, leading to a considerable increase in disability, mortality and healthcare costs. The actual treatment of HF, includes, beside optimal medical treatment, use of resynchronization therapy and implantable cardiac defibrillator. In some developing countries, the cost of these two devices is extremely high, being mandatory the adequate selection of the patients whose will benefit more from these measures. 123I-MIBG scintigraphy is the only technique approved to provide information of the adrenergic function of the heart, being a powerful risk stratification tool in patients with HF. Multiple studies have shown that the evaluation of cardiac sympathetic nerve activity using 123I-MIBG imaging, especially the heart-to-mediastinum ratio, can differentiate high-risk from low-risk patients. Cardiac MIBG imaging has still poor availability in Latin America. It is mostly performed in Brazil, where some studies showed the possible benefits and potential uses for MIBG.

The PPARγ agonist rosiglitazone promotes the induction of brite adipocytes, increasing β-adrenoceptor-mediated mitochondrial function and glucose uptake

Recruitment and activation of brite (or beige) adipocytes has been advocated as a potential avenue for manipulating whole-body energy expenditure. Despite numerous studies illustrating the differences in gene and protein markers between brown, brite and white adipocytes, there is very little information on the adrenergic regulation and function of these brite adipocytes. We have compared the functional (cyclic AMP accumulation, oxygen consumption rates, mitochondrial function, glucose uptake, extracellular acidification rates, calcium influx) profiles of mouse adipocytes cultured from three contrasting depots, namely interscapular brown adipose tissue, and inguinal or epididymal white adipose tissues, following chronic treatment with the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone. Prototypical brown adipocytes readily express β3-adrenoceptors, and β3-adrenoceptor stimulation increases cyclic AMP accumulation, oxygen consumption rates, mitochondrial function, glucose uptake, and extracellular acidification rates. Treatment of brown adipocytes with rosiglitazone increases uncoupling protein 1 (UCP1) levels, and increases β3-adrenoceptor mitochondrial function but does not affect glucose uptake responses. In contrast, inguinal white adipocytes only express UCP1 and β3-adrenoceptors following rosiglitazone treatment, which results in an increase in all β3-adrenoceptor-mediated functions. The effect of rosiglitazone in epididymal white adipocytes, was much lower compared to inguinal white adipocytes. Rosiglitazone also increased α1-adrenoceptor mediated increases in calcium influx and glucose uptake (but not mitochondrial function) in inguinal and epididymal white adipocytes. In conclusion, the PPARγ agonist rosiglitazone promotes the induction and function of brite adipocytes cultured from inguinal and epididymal white adipose depots.

Patients with Orthostatic Intolerance: Relationship to Autonomic Function Tests results and Reproducibility of Symptoms on Tilt

This study was designed to investigate the frequency and pattern of orthostatic symptoms during head-up tilt (HUT) in patients with orthostatic intolerance during daily life, and to identify the relationship between the orthostatic symptoms during HUT and autonomic parameters. We prospectively collected autonomic data from 464 patients with orthostatic symptoms. Adrenergic and cardiovagal function tests including HUT were performed. Based on HUT results, we divided patients into orthostatic hypotension (OH), postural tachycardia syndrome (POTS), or normal HUT groups. We also investigated orthostatic symptoms during HUT. Only 25% of the patients reported orthostatic symptoms during HUT and 75% were asymptomatic. Typical orthostatic symptoms such as orthostatic dizziness and blurred vision, and atypical symptoms like chest tightness and headache occurred in 86% and 66%, respectively. Patients with POTS had symptoms more frequently than patients with OH during HUT. There were no differences in degrees of BP or HR changes between symptomatic and asymptomatic groups within the OH and POTS groups. HUT fails to reproduce symptoms of orthostatic intolerance in the majority of patients. Clinicians need to be aware that most patients with OH are asymptomatic during HUT and patients with POTS are more likely to be symptomatic than patients with OH.

Autonomic Function Impairment and Brain Perfusion Deficit in Parkinson's Disease.

Autonomic disorders have been recognized as important Parkinson's disease (PD) components. Some vulnerable structures are related to the central autonomic network and have also been linked to autonomic function alterations. The aims of the study are to evaluate the severity of the autonomic dysfunction and the cortical hypoperfusion using arterial spin labeling (ASL) MRI. And then, possible relationships of significant between-group differences in perfusion pattern to clinical variables and autonomic functions were examined to determine the pharmaceutical effects of dopaminergic treatment on cerebral blood flow (CBF) in patients with PD. Brain ASL MRI was carried out in 20 patients with PD (6 men and 14 women, mean age: 63.3 ± 6.4 years) and 22 sex- and age-matched healthy volunteers to assess whole-brain CBF and the effects of dopaminergic therapy on perfusion. All subjects underwent a standardized evaluation of cardiovagal and adrenergic function including a deep breathing, Valsalva maneuver, and 5-min head-up tilt test. Perfusion MRI data were acquired on a 3.0 T scanner with a pulsed continuous ASL technique. The CBF, autonomic parameters, and clinical data were analyzed after adjusting for age and sex. Patients exhibited a decline in autonomic function (rapid heart rate in response to deep breathing, low baroreflex sensitivity, high systolic and diastolic pressure, and altered tilting test response), widespread low CBF, and robust response to dopaminergic therapy. Lower perfusion in the middle frontal gyrus was associated with increased clinical disease severity (Unified Parkinson's Disease Rating Scale I score, P < 0.001). Lower perfusion in autonomic control areas, such as the frontal lobe and insula, were significantly associated with autonomic impairment (P < 0.001). Our study indicates that PD is a progressive neurodegenerative disorder that changes the perfusion of central nervous system and is associated with variable autonomic dysfunctions. Neuronal loss and sympathetic activation may explain the interaction between cortical autonomic region perfusion and cardiovascular autonomic function.

123 I-MIBG imaging for detection of anthracycline-induced cardiomyopathy.

Due to improvements in early detection and treatment of malignant disease, the population of cancer survivors is constantly expanding. Cancer survivors are faced with chemotherapy-related long-term side effects, including irreversible cardiac injury with risk of heart failure (HF). Numerous antineoplastic regimens are associated with risk of cardiac side effects, but anthracyclines in particular carry a severe risk of cardiotoxicity. Currently, serial echocardiographic evaluation of resting left ventricular ejection fraction (LVEF) is the gold standard for monitoring anthracycline-induced cardiac side effects from chemotherapy. LVEF measurements are, however, limited by their low sensitivity. A normal LVEF does not exclude cardiotoxicity and declines in LVEF are usually not observed before the occurrence of irreversible cardiomyopathy. Hence, a clinically applicable high-sensitivity diagnostic tool for early detection of chemotherapy-related cardiotoxicity is still lacking and alternative non-invasive imaging modalities are therefore being investigated. 123 I-MIBG is a noradrenaline (NA) analogue used for evaluation of cardiac adrenergic function, including assessment of HF prognosis and evaluation of HF treatment response. However, the role of 123 I-MIBG for monitoring chemotherapy-related cardiotoxicity is still unclear. Here, we review the value of 123 I-MIBG imaging for early detection and prevention of anthracycline-induced cardiomyopathy.

Preliminary evidence for a role of the adrenergic nervous system in generalized anxiety disorder

Generalized anxiety disorder (GAD) is a common chronic condition that is understudied compared to other psychiatric disorders. An altered adrenergic function has been reported in GAD, however direct evidence for genetic susceptibility is missing. This study evaluated the associations of gene variants in adrenergic receptors (ADRs) with GAD, with the involvement of stressful events. Data were obtained from 844 French community-dwelling elderly aged 65 or over. Anxiety disorders were assessed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. Eight single-nucleotide polymorphisms (SNPs) involved with adrenergic function were genotyped; adrenergic receptors alpha(1A) (ADRA1A), alpha(2A) (ADRA2A), and beta2 (ADRB2) and transcription factor TCF7L2. Questionnaires evaluated recent stressful life events as well as early environment during childhood and adolescence. Using multivariate logistic regression analyses four SNPs were significantly associated with GAD. A 4-fold modified risk was found with ADRA1A rs17426222 and rs573514, and ADRB2 rs1042713 which remained significant after Bonferroni correction. Certain variants may moderate the effect of adverse life events on the risk of GAD. Replication in larger samples is needed due to the small case number. This is the first study showing that ADR variants are susceptibility factors for GAD, further highlighting the critical role of the adrenergic nervous system in this disorder.

Altered distribution of adrenergic constrictor responses contributes to skeletal muscle perfusion abnormalities in metabolic syndrome.

Although studies suggest elevated adrenergic activity paralleling metabolic syndrome in OZRs, the moderate hypertension and modest impact on organ perfusion question the multi-scale validity of these data. To understand how adrenergic function contributes to vascular reactivity in OZR, we utilized a multi-scale approach to investigate pressure responses, skeletal muscle blood flow, and vascular reactivity following adrenergic challenge. For OZR, adrenergic challenge resulted in increased pressor responses vs LZRs, mediated via α1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted functional hyperemia, partially restored with α1 inhibition, although improved muscle performance and VO2 required combined treatment with TEMPOL. Within OZR in situ cremaster muscle, proximal arterioles exhibited a more heterogeneous constriction to adrenergic challenge, biased toward hyperresponsiveness, vs LZR. This increasingly heterogeneous pattern was mirrored in ex vivo arterioles, mediated via α1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only. These results support the central role of the α1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity in OZR that is presently of unclear purpose.

In experimental ascitic cirrhosis reduction of adrenergic function by means of α2A adrenergic receptor agonists has considerable aquaretic effects

In experimental ascitic cirrhosis reduction of adrenergic function by means of α2A adrenergic receptor agonists has considerable aquaretic effects

Amelioration of Aggression and Echolalia With Propranolol in Autism Spectrum Disorder

Amelioration of Aggression and Echolalia With Propranolol in Autism Spectrum Disorder

FRI-064 - Considerable aquaretic effects in experimental ascitic cirrhosis achieved through blunting of adrenergic function with α2A adrenergic receptor agonists

FRI-064 - Considerable aquaretic effects in experimental ascitic cirrhosis achieved through blunting of adrenergic function with α2A adrenergic receptor agonists

Endogenous α2A-Adrenoceptor-Operated Sympathoadrenergic Tones Attenuate Insulin Secretion via cAMP/TRPM2 Signaling.

In pancreatic β-cells, pharmacological concentrations of catecholamines, including adrenaline, have been used to inhibit insulin release and explore the multiple mechanisms involved. However, the significance of these signaling pathways for physiological adrenergic functions in β-cells is largely unknown. In the process of glucose-induced insulin secretion, opening of background current through nonselective cation channels (NSCCs) might facilitate membrane depolarization by closure of the ATP-sensitive K+ channels. Here, we examined whether physiological insulinostatic adrenaline action is mediated via the transient receptor potential melastatin 2 (TRPM2) channel, a type of NSCC, in β-cells. Results showed that physiological concentrations of adrenaline strongly suppressed glucose-induced and incretin-potentiated cAMP production and insulin secretion and inhibited NSCCs current and membrane excitability via the α2A-adrenoceptor in wild-type mice; however, insulin secretion was not attenuated in TRPM2-knockout (KO) mice. Administration of yohimbine, an α2-adrenoceptor antagonist, failed to affect glucose tolerance in TRPM2-KO mice, in contrast to an improved glucose tolerance in wild-type mice receiving the antagonist. The current study demonstrated that a physiological concentration of adrenaline attenuates insulin release via coupling of α2A-adrenoceptor to cAMP/TRPM2 signaling, thereby providing a potential therapeutic tool to treat patients with type 2 diabetes.

The natural history of takotsubo syndrome: a two-year follow-up study with myocardial sympathetic and perfusion G-SPECT imaging.

To investigate changes in sympathetic activity, perfusion, and left ventricular (LV) functionality in takotsubo cardiomyopathy (TTC) patients from onset (T0) to post-onset conditions at 1month (T1), 1-2 years (T2, T3). Twenty-two patients (70 ± 11 years) underwent serial gated single photon emission tomography (G-SPECT) studies with 123I-mIBG and 99mTc-Sestamibi. Statistics were performed using ANOVA/Sheffé post-hoc, correlation test, and receiver operating characteristic (ROC) curve analysis (p < 0.05). Patients presented at T0 with LV ballooning and reduced early-late mIBG uptake (95%, 100%), left ventricular ejection fraction (LVEF)G-SPECT (86%) and perfusion (77 %). Adrenergic dysfunction was greater in apex, it overlaps with contractile impairment, and both were more severe than perfusion defect. During follow-up, LVEFG-SPECT, contractility, and perfusion were normal, while 82% and 90% of patients at T1 and 50% at T2 and T3 continued to show a reduced apical early-late mIBG distribution. These patients presented at T0-T1 with greater impairment of adrenergic function, contractility, and perfusion. A relationship was present within innervation and both perfusion and contractile parameters at T0 and T1, and between the extent of adrenergic defect at T3 and both the defect extent and age at T0 (cut-off point 42.5%, 72 years). Outcome for TTC is not limited to a reversible contractile and perfusion abnormalities, but it includes residual adrenergic dysfunction, depending on the level of adrenergic impairment and age of patients at onset. The number of patients, as well as degree of perfusion abnormalities were found to be higher than those previously reported possibly depending on the time-interval between hospital admission and perfusion scan.

The impact of paclitaxel and carboplatin chemotherapy on the autonomous nervous system of patients with ovarian cancer.

BackgroundPaclitaxel-based regimens are frequently associated with the development of peripheral neuropathy. The autonomous nervous system (ANS) effects, however, of this chemotherapeutic agent remain unexplored.MethodsWe investigated a group of 31 female patients with ovarian cancer receiving treatment with paclitaxel and carboplatin, as well as a group of 16 healthy age- and gender-matched healthy volunteers. All study participants completed a questionnaire and were assessed neurophysiologically at three time points (baseline, 3–4 months and 6–8 months following the onset of chemotherapy). The evaluation of the ANS included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (30/15 ratio) and sympathetic skin response (SSR).ResultsAt the 3–4 months ANS assessment, 19.2 % of the patients had systolic OH and the same percentage had diastolic OH, but at the 6–8 months evaluation no patient had systolic OH and only 13.8 % had diastolic OH. The values of the 30/15 ratio were significantly reduced at both time points, whereas the SSR was not affected.ConclusionsCombined paclitaxel and carboplatin chemotherapy is associated with significant effects on the parasympathetic heart innervation and occasionally with effects on the adrenergic cardiovascular reaction. The SSR remained unaffected. Physicians should be alert to the possibility of these treatment-emergent side effects, so as to monitor ANS parameters and introduce treatment modifications accordingly. Our findings however, should be validated in larger cohorts.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0710-4) contains supplementary material, which is available to authorized users.

Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation?

Norepinephrine (NE) is synthesized in the Locus Coeruleus (LC) of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system (CNS) and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework. Since three main families of NE receptors are represented—in order of decreasing affinity for the catecholamine—by: α2 adrenoceptors (α2Rs, high affinity), α1 adrenoceptors (α1Rs, intermediate affinity), and β adrenoceptors (βRs, low affinity), on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: (1) sleep: virtual absence of NE, (2) quiet wake: activation of α2Rs, (3) active wake/physiological stress: activation of α2- and α1-Rs, (4) distress: activation of α2-, α1-, and β-Rs. We postulate that excess intensity and/or duration of states (3) and (4) may lead to maladaptive plasticity, causing—in turn—a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the CNS. While the model has the potential to explain a large number of experimental and clinical findings, a major challenge will be to adapt this hypothesis to integrate the role of other neurotransmitters released during stress in a centralized fashion, like serotonin, acetylcholine, and histamine, as well as those released in a non-centralized fashion, like purines and cytokines.

Pilomotor function is impaired in patients with Parkinson's disease: A study of the adrenergic axon-reflex response and autonomic functions

IntroductionAutonomic nervous system disturbances including sweating abnormalities and cardiovascular symptoms are frequent in Parkinson's disease (PD) and often precede motor involvement. Cholinergic vasomotor and sudomotor skin nerves are impaired in patients with PD even at early disease stages. We hypothesized that adrenergic pilomotor nerve function is similarly impaired in early PD and might constitute a novel diagnostic target. MethodsWe conducted a study in 12 PD patients (Hoehn&Yahr 1–2) and 12 healthy control subjects. Pilomotor function was evaluated after iontophoresis of phenylephrine on the dorsal forearm to elicit axon-reflex mediated pilomotor erection (goose bumps). Silicone impressions were obtained, scanned and quantified for pilomotor muscle impressions by number, area and axon-reflex spread. Vasomotor function was evaluated using laser Doppler flowmetry and sudomotor function via sympathetic skin response. Cardiac autonomic function was assessed via heart rate variability. Severity of autonomic symptoms was evaluated using the Scales for Outcomes in Parkinson's disease–Autonomic questionnaire. ResultsPilomotor response was reduced in PD patients compared to control subjects (impression number: 12.2 ± 8.2 vs. 16.5 ± 5.9, p < 0.05; impression area: 10.8 ± 2.2 mm2 vs. 24.8 ± 3.1 mm2, p < 0.01; axon-reflex spread: 89.0 ± 10.6 mm2 vs. 185.9 ± 10.8 mm2, p < 0.01) and correlated negatively with severity of autonomic symptoms (p < 0.01). Similarly, sudomotor (p < 0.01) and vasomotor (p < 0.05) but not cardiac autonomic (p = n.s.) function were reduced in PD patients versus control subjects. ConclusionPilomotor function is impaired in early stages of PD. Pilomotor axon-reflex assessment might be useful in the investigation of disease related pathology and supplement other clinical markers of autonomic neuropathy in PD.

Protein Restriction During the Last Third of Pregnancy Malprograms the Neuroendocrine Axes to Induce Metabolic Syndrome in Adult Male Rat Offspring.

Metabolic malprogramming has been associated with low birth weight; however, the interplay between insulin secretion disruption and adrenal function upon lipid metabolism is unclear in adult offspring from protein-malnourished mothers during the last third of gestation. Thus, we aimed to study the effects of a maternal low-protein diet during the last third of pregnancy on adult offspring metabolism, including pancreatic islet function and morphophysiological aspects of the liver, adrenal gland, white adipose tissue, and pancreas. Virgin female Wistar rats (age 70 d) were mated and fed a protein-restricted diet (4%, intrauterine protein restricted [IUPR]) from day 14 of pregnancy until delivery, whereas control dams were fed a 20.5% protein diet. At age 91 d, their body composition, glucose-insulin homeostasis, ACTH, corticosterone, leptin, adiponectin, lipid profile, pancreatic islet function and liver, adrenal gland, and pancreas morphology were assessed. The birth weights of the IUPR rats were 20% lower than the control rats (P < .001). Adult IUPR rats were heavier, hyperphagic, hyperglycemic, hyperinsulinemic, hyperleptinemic, and hypercorticosteronemic (P < .05) with higher low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol, adiponectin, ACTH, and insulin sensitivity index levels (P < .01). The insulinotropic action of glucose and acetylcholine as well as muscarinic and adrenergic receptor function were impaired in the IUPR rats (P < .05). Maternal undernutrition during the last third of gestation disrupts the pancreatic islet insulinotropic response and induces obesity-associated complications. Such alterations lead to a high risk of metabolic syndrome, characterized by insulin resistance, visceral obesity, and lower high-density lipoprotein cholesterol.