Effects Of Sympathetic Stimulation Research Articles

Nanodomain cAMP signalling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.

3', 5'-cyclic adenosine monophosphate (cAMP) mediates the effects of sympathetic stimulation on the rate and strength of cardiac contraction. Beyond this pivotal role, in cardiac myocytes cAMP also orchestrates a diverse array of reactions to various stimuli. To ensure specificity of response, the cAMP signaling pathway is intricately organized into multiple, spatially confined, subcellular domains, each governing a distinct cellular function. In this review, we describe the molecular components of the cAMP signalling pathway, how they organized are inside the intracellular space and how they achieve exquisite regulation of signalling within nanometer-size domains. We delineate the key experimental findings that lead to the current model of compartmentalised cAMP signaling and we offer an overview of our present understanding of how cAMP nanodomains are structured and regulated within cardiac myocytes. Furthermore, we discuss how compartmentalized cAMP signaling is affected in cardiac disease and consider the potential therapeutic opportunities arising from understanding such organization. By exploiting the nuances of compartmentalized cAMP signaling, novel and more effective therapeutic strategies for managing cardiac conditions may emerge. Finally, we highlight the unresolved questions and hurdles that must be addressed to translate these insights into interventions that may benefit patients.

B-PO03-025 AUTONOMIC MODULATION OF HUMAN RIGHT VENTRICULAR OUTFLOW TRACT: IMPLICATIONS FOR ARRHYTHMOGENESIS

Right ventricle outflow tract (RVOT) is a common source of ventricular arrhythmias, however, the mechanisms underlying the region’s arrhythmia susceptibility remain poorly understood. Electrophysiological studies in the RVOT are needed to better characterize the arrhythmogenic nature of this region. To establish the sympathetic and parasympathetic stimulatory response profile and assess susceptibility to arrhythmias and the corresponding epi/endo arrhythmia dynamics. We conducted optical mapping studies in 17 donor human heart right ventricular wedge preparations subjected to sympathetic and/or parasympathetic stimulation. We used another 15 donor hearts for transcriptomics (N=10), and immunohistology (N=5) studies. We found that isoproterenol (100nM) shortened action potential duration (APD80) and increased incidents of premature ventricular contractions (PVCs), whereas acetylcholine (100μM) alone did not produce statistically significant effect on APD80 or PVCs, compared to baseline conditions. Interestingly, acetylcholine treatment post isoproterenol stimulation, reduced the incidents of PVCs (p<0.05) and induced recovery of APD80 (p<0.03) approaching baseline. Immunolabeling of RVOT tissue confirmed the presence of vesicular acetylcholine transporter (vAChT) in the region, which suggests structural evidence to the anti-arrhythmic functional response. Transcriptome analysis to profile differentially expressed genes (DEGs) revealed sex-specific differences in the RVOT. Here we describe unique electrophysiological, immunohistological, and transcriptomic profile of the donor human RV and report sex specific differences in the RVOT region. We also report that parasympathetic stimulation attenuates the arrhythmogenic effect of sympathetic stimulation by reducing the incidence of PVC and also lengthening APD in the RV.

Targeting the β‐adrenergic receptor in the clinical management of congenital long QT syndrome

The long QT syndrome (LQTS) is largely treated pharmacologically with β-blockers, despite the role of sympathetic activity in LQTS being poorly understood. Using the trigger-substrate model of cardiac arrhythmias in this review, we amalgamate current experimental and clinical data from both animal and human studies to explain the mechanism of adrenergic stimulation and blockade on LQT arrhythmic risk and hence assess the efficacy of β-adrenoceptor blockade in the management of LQTS. In LQTS1 and LQTS2, sympathetic stimulation increases arrhythmic risk by enhancing early afterdepolarizations and transmural dispersion of repolarization. β-Blockers successfully reduce cardiac events by reducing these triggers and substrates; however, these effects are less marked in LQTS2 compared with LQTS1. In LQTS3, clinical and experimental investigations of the effects of sympathetic stimulation and β-blocker use have produced contradictory findings, resulting in significant clinical uncertainty. We offer explanations for these contradicting results relating to study sample size, the dose of the β-blocker administered associated with its off-target Na+ channel effects, as well as the type of β-blocker used. We conclude that the antiarrhythmic efficacy of β-blockers is a genotype-specific phenomenon, and hence the use of β-blockers in clinical practice should be genotype dependent.

Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y

The sympathetic nervous system plays an important role in the occurrence of ventricular tachycardia (VT). Many patients, however, experience VT despite maximal doses of beta blocker therapy, possibly due to the effects of sympathetic cotransmitters such as neuropeptide Y (NPY). The purpose of this study was to determine, in a porcine model, whether propranolol at doses higher than clinically recommended could block ventricular electrophysiological effects of sympathoexcitation via stellate ganglia stimulation, and if any residual effects are mediated by NPY. Greater release of cardiac NPY was observed at higher sympathetic stimulation frequencies (10 and 20 vs. 4 Hz). Despite treatment with even higher doses of propranolol (1.0 mg/kg), electrophysiological effects of sympathetic stimulation remained, with residual shortening of activation recovery interval (ARI), a surrogate of action potential duration (APD). Adjuvant treatment with the NPY Y1 receptor antagonist BIBO 3304, however, reduced these electrophysiological effects while augmenting inotropy. These data demonstrate that high-dose beta blocker therapy is insufficient to block electrophysiological effects of sympathoexcitation, and a portion of these electrical effects in vivo are mediated by NPY. Y1 receptor blockade may represent a promising adjuvant therapy to beta-adrenergic receptor blockade.

Stellate ganglion stimulation causes spatiotemporal changes in ventricular repolarization in pig

Dispersion in ventricular repolarization is relevant for arrhythmogenesis. The purpose of this study was to determine the spatiotemporal effects of sympathetic stimulation on ventricular repolarization. In 5 anesthetized female open-chest pigs, ventricular repolarization was measured from the anterior, lateral, and posterior walls of the left ventricle (LV) and right ventricle using up to 40 transmural plunge needles (4 electrodes each) before and after left stellate ganglion stimulation (LSGS) and right stellate ganglion stimulation. In addition, LSGS was performed in 3 pigs (2 male, 1 female) before and after verapamil (5-10 mg/h) administration. LSGS yielded a biphasic response in repolarization in the lateral and posterior walls of the LV, with prolongation at ∼5 seconds (10 ± 1.5 ms) and shortening at 20-30 seconds of stimulation (-28.9 ± 4.4 ms) during a monotonic pressure increase. While the initial prolongation was abolished by verapamil, late shortening was augmented. Sequential transections of the vagal nerve and stellate ganglia augmented repolarization dispersion responses to LSGS in 2of 5 hearts. An equal pressure increase by aortic occlusion resulted in a homogeneous shortening of repolarization in the LV, and the effects were smaller than those during LSGS. Right stellate stimulation shortened repolarization mainly in the anterior LV wall, but the effects were smaller than those of LSGS. LSGS first prolongs (through the L-type calcium current) and then shortens repolarization. The effect of LSGS was prominent in the posterior and lateral, not the anterior, LV walls.

Effect of Purine Co-Transmitters on Automatic Activity Caused by Norepinephrine in Myocardial Sleeves of Pulmonary Veins.

We studied the effect of extracellular purine nucleotides (NAD+ and ATP) on spontaneous arrhythmogenic activity caused by norepinephrine in myocardial sleeves of pulmonary veins. In pulmonary veins, NAD+ and ATP reduced the frequency of action potentials and their duration at regular type of spontaneous activity caused by norepinephrine. NAD+ and ATP lengthened the intervals between spike bursts at periodic (burst) type of spontaneous activity. In addition, ATP shortened the duration of spike bursts and the number of action potentials in the "bursts" caused by norepinephrine in the pulmonary veins. It was hypothesized that NAD+ and ATP attenuate the effects of sympathetic stimulation and when released together with norepinephrine from sympathetic endings in vivo, probably, reduce arrhythmogenic activity in myocardial sleeves of pulmonary veins.

The role of diadenosine pentaphosphate and nicotinamide adenine dinucleotide (NAD+) as potential nucleotide comediators in the adrenergic regulation of cardiac function

The functioning of the heart is under the tight control of the sympathetic division of the autonomous nervous system. The terminals of the postganglionary fibers release both noradrenaline (NA), which is the major sympathetic neurotransmitter, and comediators that can contribute to the fine “tuning” of the adrenergic control of cardiac function. Purine compounds, such as diadenosine pentaphosphate (Ар5А), as well as nicotinamide adenine dinucleotide (NAD+), can act as comediators. The distinctive features of the effects of these compounds on the heart have been incompletely characterized. It is not clear whether these compounds can act as comediators, i.e., to modulate the sympathetic (adrenergic) activity in the heart. Exogenous extracellular Ар5А was shown to reduce the contractility of the ventricular myocardium and to suppress conduction in the atrioventricular (AV) junction in a Langendorff-perfused isolated rat heart. Extracellular NAD+ had a weak effect on inotropy but induced a negative dromotropic effect in the AV junction, similarly to Ар5А. We found that Ар5А and NAD+ suppress both the positive inotropic effect of noradrenaline in the ventricular myocardium and the positive dromotropic effect of NA in the AV junction. The “inhibitory” effects of both purine compounds were more pronounced in the case of combined application with NA. In addition, the influence of Ар5А and NAD+ on the effects of noradrenaline was shown to depend on the timing of the application of these compounds. Our results suggest that the role of the sympathetic comediators NAD+ and Ар5А may consist of the limitation of noradrenaline effects and/or the effects of sympathetic stimulation in the heart.

Abstract 11917: Muscarinic Stimulation Facilitates SR Ca +2 Release by Increasing PKG Phosphorylation of RyR2 at Ser-2808 and Decreasing CaMKII Phosphorylation at Ser-2814

Autonomic regulation of SR Ca +2 release is critical for modulating cardiac performance to match physiologic demand. During heart failure (HF), autonomic balanced shifts to a dominant sympathetic state to increase fractional SR Ca +2 release. Although intended to be compensatory, this increase in sympathetic input causes increases in the frequency of proarrhythmic spontaneous SR Ca +2 release events. Interestingly, parasympathetic augmentation was recently shown to alleviate HF phenotypes by shifting autonomic balance away from sympathetic dominance. While the effects of sympathetic stimulation and mechanism behind their action on cardiomyocyte Ca +2 handling are relatively well established in health and disease, the modes of action and mechanisms of parasympathetic modulation of SR Ca +2 release are poorly defined. To address this question, we investigated the effects of the cholinergic agonist, carbachol (CCH), on Ca +2 handling (Fluo-4 FF AM) and protein phosphorylation levels in cardiomyocytes using a combination of pharmacological approaches and genetic mouse models. In settings of reduced SR Ca +2 load, exposure to the parasympathetic agonist CCH increased fractional Ca +2 release without affecting Ca +2 spark frequency in cardiomyocytes. Immunoblot measurements showed that this “efficient” mode of excitation-contraction (EC) coupling involves reciprocal changes in the phosphorylation state of RyR2. Specifically, CCH treatment of cardiomyocytes increased Ser-2808 phosphorylation, mediated by muscarinic receptor subtype 2 and activation of PKG. Conversely, CCH treatment was associated with dephosphorylation at Ser-2814 through activation of muscarinic receptor subtype 3 and decreased ROS-dependent activation of CaMKII. We further demonstrate that parasympathetic stimulation improved Ca +2 cycling efficiency in cardiomyocytes isolated from failing hearts by restoring altered RyR2 phosphorylation balance. These results suggest that parasympathetic stimulation initiates a novel mode of EC coupling in cardiomyocytes that enhances the efficiency of cardiac SR Ca +2 store mobilization during systolic Ca +2 release, while inhibiting pathologic diastolic Ca +2 leak.

Sympathetic stimulation facilitates thrombopoiesis by promoting megakaryocyte adhesion, migration, and proplatelet formation

AbstractThe effect of sympathetic stimulation on thrombopoiesis is not well understood. Here, we demonstrate that both continual noise and exhaustive exercise elevate peripheral platelet levels in normal and splenectomized mice, but not in dopamine β-hydroxylase–deficient (Dbh−/−) mice that lack norepinephrine (NE) and epinephrine (EPI). Further investigation demonstrates that sympathetic stimulation via NE or EPI injection markedly promotes platelet recovery in mice with thrombocytopenia induced by 6.0 Gy of total-body irradiation and in mice that received bone marrow transplants after 10.0 Gy of lethal irradiation. Unfavorably, sympathetic stress-stimulated thrombopoiesis may also contribute to the pathogenesis of atherosclerosis by increasing both the amount and activity of platelets in apolipoprotein E–deficient (ApoE−/−) mice. In vitro studies reveal that both NE and EPI promote megakaryocyte adhesion, migration, and proplatelet formation (PPF) in addition to the expansion of CD34+ cells, thereby facilitating platelet production. It is found that α2-adrenoceptor–mediated extracellular signal-regulated kinase 1/2 (ERK1/2) activation is involved in NE- and EPI-induced megakaryocyte adhesion and migration, and PPF is regulated by ERK1/2 activation-mediated RhoA GTPase signaling. Our data deeply characterize the role of sympathetic stimulation in the regulation of thrombopoiesis and reevaluate its physiopathological implications.

Molecular Mechanisms of Sympathetic Remodeling and Arrhythmias.

A variety of pathological conditions can increase risk for development of ventricular arrhythmias in humans including diabetes mellitus, obesity, myocardial infarction (MI), and heart failure. Many of these diseases involve global disruption of the autonomic nervous system, including increased sympathetic drive and parasympathetic withdrawal, but another common factor among these disorders is sympathetic dysfunction within the heart. Treatments that target cardiac sympathetic transmission, including β-blockers and ganglionectomy, prolong life and decrease arrhythmias.1–5 Sympathetic control of the heart under normal conditions occurs primarily via norepinephrine acting on β adrenergic receptors (β-AR) to stimulate increases in heart rate (chronotropy), conduction velocity (dromotropy), and contractility (inotropy). These positive effects of sympathetic stimulation allow myocytes to meet increased cardiac demands during stress or exercise, serving to maintain homeostasis. The nervous system adapts to changing conditions, however, and sympathetic neurons undergo structural and functional alterations in response to injury and disease. There are at least 4 types of sympathetic remodeling that occur during conditions of increased arrhythmia susceptibility: hyperinnervation (increased nerve density), denervation (decreased nerve density), altered neurotransmitter or neuropeptide production and increased neuronal excitability. Rubart and Zipes6 proposed a model to explain how these diverse changes in sympathetic transmission might contribute to arrhythmia generation, suggesting that inappropriate heterogeneity of norepinephrine release within the heart leads to differential electric remodeling of cardiac myocytes and predisposes the heart to electric instability. Many studies now support the hypothesis that heterogeneity of noradrenergic transmission increases the risk of arrhythmia and have identified some of the mechanisms that underlie neuronal remodeling. This review will examine the mechanisms of sympathetic remodeling and will connect neural changes to increased arrhythmia susceptibility. We will focus on ventricular arrhythmias because atrial arrhythmias were reviewed recently.7 Regional hyperinnervation was the first type of neural remodeling linked to arrhythmia generation …

Effect of fingolimod on cardiac autonomic regulation in patients with multiple sclerosis

Background: Fingolimod modulates sphingosine-1-phosphate receptors that are also found in cardiovascular tissue. Objective: To investigate the effects of fingolimod on cardiac autonomic regulation prospectively. Methods: Twenty-seven relapsing–remitting multiple sclerosis patients underwent 24-hour electrocardiogram recording before, at the first day of fingolimod treatment (1d) and after three months of continuous dosing (3mo). The time interval between two consecutive R-peaks (RR-interval) was measured. Cardiac autonomic regulation was assessed by the various parameters of heart rate variability. Parasympathetic stimulation prolongs the RR-interval and increases heart rate variability while the effects of sympathetic stimulation are mainly the opposite. The low frequency/high frequency ratio reflects sympathovagal balance. Results: From baseline to 1d, a prolongation of the RR-interval (P<0.001), an increase in the values of various heart rate variability parameters (P<0.05 to P<0.001) and a decrease in the low frequency/high frequency ratio (P<0.05) were demonstrated. At 3mo, although the RR-interval remained longer (P<0.01), the values of various heart rate variability parameters were lower (P<0.01 to P<0.001) as compared to baseline. At 3mo, the low frequency/high frequency ratio (P<0.05) was higher in men than in women although no such difference was found at baseline or at 1d. Conclusions: After an initial increase in parasympathetic regulation, continuous fingolimod dosing shifts cardiac autonomic regulation towards sympathetic predominance, especially in men. Careful follow-up of fingolimod-treated relapsing–remitting multiple sclerosis patients is warranted as sympathetic predominance associates generally with impaired outcome. ClinicalTrials.cov: NCT01704183

Atrioventricular nodal function during atrial fibrillation: Model building and robust estimation

Statistical modeling of atrioventricular (AV) nodal function during atrial fibrillation (AF) is revisited for the purpose of defining model properties and improving parameter estimation. The characterization of AV nodal pathways is made more detailed and the number of pathways is now determined by the Bayesian information criterion, rather than just producing a probability as was previously done. Robust estimation of the shorter refractory period (i.e., of the slow pathway) is accomplished by a Hough-based technique which is applied to a Poincaré plot of RR intervals. The performance is evaluated on simulated data as well as on ECG data acquired from AF patients during rest and head-up tilt test. The simulation results suggest that the refractory period of the slow pathway can be accurately estimated even in the presence of many artifacts. They also show that the number of pathways can be accurately determined. The results from ECG data show that the refined AV node model provides significantly better fit than did the original model, increasing from 85±5% to 88±4% during rest, and from 86±5% to 87±3% during tilt. When assessing the effect of sympathetic stimulation, the AF frequency increased significantly during tilt (6.25±0.58 Hz vs. 6.32±0.61 Hz, p<0.05, rest vs. tilt) and the prolongation of the refractory periods of both pathways decreased significantly (slow pathway: 0.23±0.20 s vs. 0.11±0.10 s, p<0.001, rest vs. tilt; fast pathway: 0.24±0.31 s vs. 0.16±0.19 s, p<0.05, rest vs. tilt). The results show that AV node characteristics can be assessed noninvasively for the purpose of quantifying changes induced by autonomic stimulation.

Passive Smoking, Endothelial Dysfunction and Related Markers in Healthy Individuals: An Update

By the analysis of previous studies, functional and biochemical markers related to environmental tobacco smoke (ETS) exposure are discussed. 18 healthy never smokers, 12 men (67%) and 6 women (33%) aged from 21 to 55 years (mean: 34+/-9 ys.) underwent experimental procedures twice. in a smoking free environment and in the same environment polluted by 35 ppm carbon monoxide derived from smoked cigarettes. Brachial artery ultrasonography, exercise stress testing, heart rate (HR) and blood pressure (BP) monitoring, and carboxyhaemoglobin (COHb) concentrations were examined. Five markers related to ETS exposure of healthy individuals could be demonstrated: l. Impaired FMD as an effect of endothelial dysfunction, 2. Transient increase in systolic BP; 3. HR increase; 4. Diminished tolerance to exercise; 5. Increased COHb blood concentrations. Some of these feel the effects of sympathetic stimulation induced by both nicotine and carbon monoxide. Since both active and passive smoking are believed to be a chemical toxicosis, avoiding ETS exposure of healthy nonsmokers must be a categorical imperative.

Sympathetic stimulation increases dispersion of repolarization in humans with myocardial infarction

The sympathetic nervous system is thought to play a key role in genesis and maintenance of ventricular arrhythmias. The myocardial effect of sympathetic stimulation on myocardial repolarization in humans is poorly understood. The purpose of this study was to evaluate the effects of direct and reflex sympathetic stimulation on ventricular repolarization in patients with postinfarct cardiomyopathy (ICM). The effects of direct sympathetic stimulation were assessed using isoproterenol, while those of reflex sympathetic stimulation were assessed with nitroprusside infusion in ICM patients (n = 5). Five patients without cardiomyopathy were also studied. Local repolarization was measured from intracardiac electrograms that were used to calculate the activation recovery interval (ARI), a surrogate of action potential duration. Isoproterenol significantly increased heterogeneity in repolarization in patients with ICM; the decrease in ARI from baseline was 72.9 ± 9.1 ms in more viable regions, 64.5 ± 8.9 ms in the scar, and 54.9 ± 9.1 ms in border zones (P = 0.0002 and 0.014 comparing normal and scar to border zones, respectively). In response to nitroprusside, the ARI at the border zones decreased significantly more than either scar or surrounding viable myocardium, which showed an increase in ARI (P = 0.014 and 0.08 comparing normal tissue and scar to border zones, respectively). Furthermore, isoproterenol increased ARI dispersion by 70%, while nitroprusside increased ARI dispersion by 230% when ICM patients were compared to those with structurally normal hearts (P = 0.0015 and P < 0.001, respectively). In humans, both direct and reflex sympathetic stimulations increase regional differences in repolarization. The normal tissue surrounding the scar appears denervated. Dispersion of ARI in response to sympathetic stimulation is significantly increased in patients with ICM.

A new electrocardiographic marker for sympathetic nerve stimulation: modulation of repolarization by stimulation of stellate ganglia

Activation of cardiac sympathetic nerves alters ventricular repolarization; however, these changes remain poorly characterized. The goal of this study was to examine effects of sympathetic stimulation on repolarization to identify electrocardiographic markers of sympathetic activation. Pigs underwent median sternotomy and bilateral thoracotomy to expose the stellate ganglia. Changes in T-wave duration, amplitude, repolarization vector, and time from peak to end (Tp-Te) were continuously monitored. Within 15 seconds of unilateral left or right stellate ganglion (LSG/RSG) stimulation, T-wave amplitude increased 6- and 4.5-fold, respectively, in lead aVF. T-wave duration and Tp-Te both increased 200% during LSG stimulation but only 50% and 30%, respectively, with RSG stimulation. During LSG stimulation, frontal and horizontal T-wave vectors, respectively, changed from 1.9° ± 22.8° and 333.8° ± 9.7° at baseline to 83.4° ± 3.9° (inferiorly) and 306.7° ± 1.8° (posteriorly). During RSG stimulation, frontal and horizontal T-wave vectors changed from 348.2° ± 21.6° and 333.8° ± 10.3° before stimulation to 280.7° ± 4.6° (superiorly) and 118.1° ± 5.6° (anteriorly). During stellate stimulation, T-wave vectors are displaced to angles specific for LSG activation (posteroinferiorly) or RSG activation (anterosuperiorly); T-wave amplitude, duration, and Tp-Te increase; and ST-duration decreases. Displaced repolarization vector and changes in T-wave morphometrics provide a novel marker of unilateral sympathetic nerve stimulation.

Anchored PKA and regulation of calcium handling in cardiomyocytes

Sympathetic stimulation of the heart elevates cAMP levels leading to the rapid phosphorylation of several protein targets by protein kinase A (PKA). Immediate consequences of this phosphorylation include increased Ca2+ entry through voltage‐gated Ca2+ channels (CaV1.2), Ca2+ release from sarcoplasmic reticulum (SR) ryanodine receptors, and Ca2+ reuptake into the SR by the calcium ATPase (SERCA). Enhanced Ca2+ cycling amplifies the force of contraction and rate of relaxation, substantially improving cardiac performance. Timely and specific phosphorylation of PKA substrates is made possible by scaffolding molecules called A Kinase Anchoring Proteins (AKAPs) which bind directly to PKA, phosphatases, ion channels, and other proteins and membranes to coordinate discrete molecular signaling complexes. Several AKAPs are expressed in the heart. Disruption of all AKAP‐PKA binding abolishes the effect of sympathetic stimulation on Ca2+ cycling. Our work utilizes AKAP knockout/mutant mice to identify specific AKAP(s) that are essential for CaV1.2 and PLB/SERCA regulation. Genetically targeted AKAPs include AKAP7 (15/18), AKAP5 (79/150), and AKAP1.

Electrical stimulation of sympathetic neurons induces autocrine/paracrine effects of NGF mediated by TrkA

Neuronal remodeling with increased sympathetic innervation density has been implicated in the pathogenesis of atrial fibrillation (AF). Recently, increased transcardiac nerve growth factor (NGF) levels were observed in a canine model of AF. Whether atrial myocytes or cardiac sympathetic neurons are the source of neurotrophins, and whether NGF is the main neurotrophic factor contributing to sympathetic nerve sprouting (SNS) in AF still remains unclear. Therefore, neonatal rat atrial myocytes were cultured under conditions of high frequency electrical field stimulation (HFES) to mimic rapid atrial depolarization. Likewise, sympathetic neurons from the superior cervical ganglia of neonatal rats were exposed to HFES to simulate the physiological effect of sympathetic stimulation. Real-time PCR, ELISA and Western blots were performed to analyze the expression pattern of NGF and neurotrophin-3 (NT-3). Baseline NGF and NT-3 content was 3-fold higher in sympathetic neurons than in atrial myocytes (relative NGF protein expression: 1±0.0 vs. 0.37±0.11, all n=5, p<0.05). HFES of sympathetic neurons induced a frequency dependent NGF and NT-3 gene and protein up-regulation (relative NGF protein expression: 0Hz=1±0.0 vs. 5Hz=1.13±0.19 vs. 50Hz=1.77±0.08, all n=5, 0Hz/5Hz vs. 50Hz p<0.05), with a subsequent increase of growth associated protein 43 (GAP-43) expression and morphological SNS. Moreover, HFES of sympathetic neurons increased the tyrosine kinase A (TrkA) receptor expression. HFES induced neurotrophic effects could be abolished by lidocaine, TrkA blockade or NGF neutralizing antibodies, while NT-3 neutralizing antibodies had no significant effect on SNS. In neonatal rat atrial myocytes, HFES resulted in myocyte hypertrophy accompanied by an increase in NT-3 and a decrease in NGF expression. In summary, this study provides evidence that high-rate electrical stimulation of sympathetic neurons mediates nerve sprouting by an increase in NGF expression that targets the TrkA receptor in an autocrine/paracrine manner.

Counterpoint: Sympathetic nerve activity does not influence cerebral blood flow

It is intuitively clear that the cerebral circulation cannot take part in general cardiovascular regulation. During states of shock, where the sympathetic nervous system is activated, leading to a decrease in the perfusion of kidneys and mesenteric vascular bed, the cerebral circulation is kept

Going to cAMP just got more complicated

Going to cAMP just got more complicated

Effects of sympathetic stimulation during cooling on hypothermic as well as posthypothermic hemodynamic function

This experimental study was performed to explore hemodynamic effects of a moderate dose epinephrine (Epi) during hypothermia and to test the hypothesis whether sympathetic stimulation during cooling affects myocardial function following rewarming. Two groups of male Wistar rats (each, n=7) were cooled to 15 degrees C, maintained at this temperature for 1 h, and then rewarmed. Group 1 received 1 microg/min Epi, i.v., for 1 h during cooling to 28 degrees C, a dose known to elevate cardiac output (CO) by approximately 25% at 37 degrees C. Group 2 served a saline solution control. At 37 degrees C, Epi infusion elevated CO, left ventricular systolic pressure, maximum rate of left ventricle pressure rise, and mean arterial pressure. During cooling to 28 degrees C, these variables, with the exception of mean arterial pressure, decreased in parallel to those in the saline solution group. In contrast, in the Epi group, mean arterial pressure remained increased and total peripheral resistance was significantly elevated at 28 degrees C. Compared with corresponding prehypothermic values, most hemodynamic variables were lowered after 1 h at 15 degrees C in both groups (except for stroke volume). After rewarming, alterations in hemodynamic variables in the Epi-treated group were more prominent than in saline solution controls. Thus, before cooling, continuous Epi infusion predominantly stimulates myocardial mechanical function, materialized as elevation of CO, left ventricular systolic pressure, and maximum rate of left ventricle pressure rise. Cooling, on the other hand, apparently eradicates central hemodynamic effects of Epi and during stable hypothermia, elevation of peripheral vascular vasopressor effects seem to take over. In contrast to temperature-matched, non-Epi stimulated control rats, a significant depression of myocardial mechanical function occurs during rewarming following a moderate sympathetic stimulus during initial cooling.