Diabetes, which is characterized by elevated plasma glucose, can have a devastating effect on peripheral nerves frequently leading to the clinical symptoms of neuropathy. Diabetic autonomic neuropathy (DAN) results from damage to autonomic nerves, and the most troubling forms of DAN often lead to cardiovascular abnormalities and premature death. Despite the prevalence of DAN and the impact to quality and life expectancy, the precise mechanisms underlying these pathologies are poorly understood. Recently, a new model for the onset of DAN was proposed where hyperglycemia-induced oxidative stress inactivates nicotinic acetylcholine receptors (nAChRs), the main receptor driving autonomic synaptic transmission at sympathetic ganglia. This inactivation leads to the depression of synaptic transmission, and consequently triggers the onset of autonomic neuropathy in diabetic mice. However, the source and pathways contributing to the elevation of reactive oxygen species (ROS) and oxidative stress remained unclear. In recent years it has been shown that the accelerated formation of advanced glycation end products (AGEs) and activation of their receptor (RAGE) in diabetes play a major role in the induction of oxidative stress in sensory nerve damage. Thus we hypothesized that the activation and up-regulation of RAGE during high glucose conditions is a major source of ROS production in sympathetic neurons leading to the inactivation of nAChRs and autonomic malfunction. In this thesis we show for the first time that RAGE is expressed in cultured sympathetic neurons and is also up-regulated during high glucose conditions. Our results further demonstrate that direct RAGE activation by its natural ligands leads to an increase in cytoplasmic ROS which in turn induces the inactivation of nAChRs in sympathetic neurons. We also report that high glucose-induced ROS generation and subsequent inactivation of nAChRs is prevented in sympathetic neurons from RAGE knock-out mice. The results of this dissertation suggest RAGE to be a pivotal source of ROS production leading to the functional deficits observed in sympathetic neurons during high glucose conditions.

UA Open Access Publishing Fund / Resistant hypertension is associated with chronic activation of the sympathetic nervous system resulting in various comorbidities. The prevalence of resistant hypertension is often under estimated due to various reasons. Activation of sympathetic nervous system at the renal- as well as systemic- level contributes to the increased level of catecholamines and resulting increase in the blood pressure. This increased activity was demonstrated by increased muscle sympathetic nerve activity and renal and total body noradrenaline spillover. Apart from the hypertension, it is hypothesized to be associated with insulin resistance, congestive heart failure and obstructive sleep apnea. Renal denervation is a novel procedure where the sympathetic afferent and efferent activity is reduced by various techniques and has been used successfully to treat drug-resistant hypertension improvement of various metabolic derangements. Renal denervation has the unique advantage of offering the denervation at the renal level, thus mitigating the systemic side effects. Renal denervation can be done by various techniques including radiofrequency ablation, ultrasound guided ablation and chemical ablation. Various trials evaluated the role of renal denervation in the management of resistant hypertension and have found promising results. More studies are underway to evaluate the role of renal denervation in patients presenting with resistant hypertension in different scenarios. Appropriate patient selection might be the key in determining the effectiveness of the procedure.

Obesity is associated with increased sympathoactivation that elevates arterial pressure. However, the mechanism linking sympathetic activation to arterial pressure is unclear. Specifically, it has never been demonstrated unequivocally that sympathetically mediated vasoconstriction is increased in obesity. This project tested the hypothesis that sympathetic vascular tone is increased in obese normotensive and hypertensive subjects. The effect of weight loss on sympathetic vascular tone was also assessed. Sympathetic vascular tone was assessed as forearm vasodilatation to intra-arterial phentolamine (?1/2-adrenergic receptor antagonist). Pharmacological responses were correlated with skeletal muscle sympathetic nerve activity (mSNA). Obese subjects with and without hypertension had increased mSNA. However, the vasodilatator response to phentolamine was not augmented in obese normotensive and hypertensive subjects versus lean controls. Additionally, weight loss did not alter phentolamine's vasodilatator response, despite reducing mSNA and arterial pressure in obese groups. These results indicate that sympathetic vascular tone is not increased in obesity despite higher mSNA. These studies also assessed forearm resistance vessel function using intra-arterial nitroprusside (nitric oxide donor) and isoproterenol (?2-adrenergic receptor agonist). The effects of weight loss on these responses were studied in the obese groups. The response to both vasodilators was blunted, but only in obese hypertensive subjects. Weight loss normalized the response to nitroprusside but not to isoproterenol. This result suggests that obesity-related hypertension is associated with vascular smooth muscle dysfunction, which can be improved by weight loss. Blunted vasodilatation to isoproterenol suggests an abnormality on ?2-adrenergic receptor-dependent mechanisms that may or may not depend on the endothelium. Also, mental stress-induced forearm vasodilatation was blunted in obese normotensive subjects, which was not normalized by weight loss. In conclusion, increased sympathetic nerve activity does not augment forearm sympathetic vascular tone. This dissociation could be due to opposing local factors (e.g. insulin, leptin) or to a different target of limb sympathoactivation (e.g. adipocytes vs. vascular). Sympathetic drive to tissues other than the peripheral circulation may play a more important role in arterial pressure elevation in obesity, either directly or indirectly.

A. INTRODUCTION A.1. The sympathetic nervous system. A.1.1. General considerations and historical perspective. A.1.1.1. Historical perspective A.1.1.2. Reflex regulation of the autonomic nervous system A.1.1.3. Central control of the autonomic nervous system A.1.1.4. Sympathetic and parasympathetic components of the autonomic nervous system A.1.1.5. Organisation of the sympathetic nervous system A.1.1.6. Functions of the sympathetic nervous system A.1.1.7. Neurotransmitters of the sympathetic nervous system A.1.1.8. Neurotransmitter secretion at effectors organ synapse A.1.1.9. Adrenoreceptors A.1.2. Control mechanisms A.1.2.1. Aortic arch and carotid baroreceptors A.1.2.2. Low pressure baroreceptors A.1.2.3. Chemoreceptors A.1.2.4. Effects of exercise on sympathetic nervous system activation A.1.2.5. Effects of left ventricular dysfunction on sympathetic nervous system activation A.1.2.6. Effects of right ventricular dysfunction and heart transplantation on sympathetic nervous system activity A.2. Methodological considerations. A.2.1. Assessment of sympathetic activity in humans A.2.2. Circulating catecholamines A.2.3. Microneurography A.3. Ergospirometry A.3.1. Several aspects of physiology of exercise A.3.2. Principles of exercise testing A.3.3. Exercise ventilation A.4. Assessment of chemoreceptor regulation in humans A.4.1. Peripheral chemoreceptor inhibition A.4.2. Peripheral and central chemoreceptor activation A.5. Brief summary of still unresolved questions A.5.1. Pulmonary arterial hypertension A.5.2. Heart transplantation B. SYMPATHETIC CONTROL IN PULMONARY ARTERIAL HYPERTENSION B.1. Hypothesis tested B.2. Study populations B.2.1. Study investigating sympathetic activity in PAH patients B.2.2. Study investigating the effects of atrial septostomy on MSNA in PAH patients B.3. Material, methods and study protocols B.3.1. Particular measurements in the study investigating sympathetic activity in PAH patients B.3.2. Particular measurements in the study investigating effects of atrial septostomy on MSNA in PAH patients B.4. Sympathetic nervous activity in PAH and effects of disease severity B.5. Effects of chemoreflex activation B.6. Effects of atrial septostomy C. SYMPATHETIC CONTROL AFTER HEART TRANSPLANTATION C.1. Hypothesis tested C.2. Patient population C.3. Material and methods C.4. Effects of chemoreflex activation on sympathetic activity and blood pressure C.5. Effects of chemoreflex activation on exercise intolerance D. DISCUSSION D.1. Sympathetic nervous system activation in patients with pulmonary arterial hypertension D.2. Effects of atrial septostomy on sympathetic nervous system activation D.3. Chemoreceptors in heart transplant recipients D.3.1. Peripheral chemoreceptors deactivation D.3.2. Peripheral and central chemoreceptors sensitivity E. CONCLUSIONS F. REFERENCE LIST G. ANNEXES G.1. Publications G.1.1. Velez-Roa and Ciarka et al, Increased sympathetic nerve activity in pulmonary artery hypertension, Circulation. 2004 Sep 7;110(10):1308- 12. G.1.2. Ciarka et al, Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension, Chest. 2007 Jun;131(6):1831-7. G.1.3. Ciarka et al, Effects of peripheral chemoreceptors deactivation on sympathetic activity in heart transplant recipients. Hypertension. 2005 May;45(5):894-900. G.1.4. Ciarka et al, Increased peripheral chemoreceptors sensitivity and exercise ventilation in heart transplant recipients. Circulation. 2006 Jan 17;113(2):252-7. G.2. Annexe thesis title. G.3. Brief summary in French of described research

Neck-shoulder pain (NSP) is a highly prevalent musculoskeletal disorder with unclear causes, and effective prevention and treatment require a further understanding of the underlying mechanisms. Aberrant autonomic nervous system (ANS) regulation is a hypothesized causal element in the development and maintenance of chronic muscle pain. The overall aim of this thesis was to investigate possible differences in ANS regulation between chronic NSP and healthy control (CON) groups using both laboratory assessment and ambulatory monitoring in daily life. Four papers are included in this thesis, based on data from three groups with chronic NSP. Autonomic responses to laboratory stressors were assessed using heart rate variability (HRV), blood pressure, trapezius muscle activity and blood flow measurements (Study І) in NSP and CON. Long-term ambulatory monitoring of HRV, physical activity and perceived symptoms were assessed in Studies ІІ and IV to investigate group differences in real-life conditions. Finally, the effects of a ten-week intervention (using individually adjusted HRV biofeedback) to reinstating ANS balance in subjects with chronic NSP were evaluated using self-reported symptoms and health ratings, as well as autonomic regulation testing (i.e., evaluating HRV at rest and in response to stress) (Study ІІІ). The main findings from the four studies demonstrated aberrant ANS regulation in the NSP group compared to CON, which was predominantly characterized by diminished parasympathetic cardiac activity during rest and sleep, and altered sympathetic reactivity to laboratory stressors (Studies І, ІІ and IV). Different patterns in physical activity were observed between the NSP and CON groups, with reduced physical activity during leisure time in the NSP group (Studies ІІ and IV). Physical activity was found to be positively associated with HRV. Positive effects of HRV-biofeedback were found on perceived health, including social function, vitality and bodily pain, and improved HRV (Study ІІІ). In conclusion, imbalanced ANS regulation was demonstrated among persons with chronic NSP at both the systemic and local levels. Diminished parasympathetic activity in NSP was modulated by lower levels of physical activity in leisure time. Interventions targeting ANS functions might benefit persons with chronic NSP.

A detailed investigation of ion crystals produced by laser and sympathetic cooling in a linear RF trap has been conducted. The laser cooling methods were examined and applied to the trapped ^24Mg^(positive) ions. The crystals produced by the laser cooling were studied, including the dependence on RF voltage, end cap DC voltage, laser power and laser frequency. By manipulating the different RF voltages and endcap DC voltages, the structure phase transition of the ion crystals was observed. In addition, the sympathetic cooling of different ion species with the laser cooled 24Mg^(positive) was carried out. In this process, the mixed Mg^(positive) and He^(positive) crystals were created andidentified, and mixed Mg^(positive) and H2^(positive) crystals were produced. The effect of an unwanted chemical reaction of Mg^(positive) and H2 was observed and minimized. After sympathetic cooling of light ion species, the sympathetic cooling of heavy molecular ions such as fullerene ions was also carried out. The efficiencies and final temperature in both cases are very different. Theoretically to interpret the results, molecular dynamics simulations of the laser cooling and sympathetic cooling were implemented. And the simulations were compared with the experimental results. In the process of carrying out this research, the optics were rebuilt to provide reliable UV sources for the photoionization and laser cooling of Mg ions. The imaging system was reconfigured to take the images of ion crystals. New elements were added tin the ion trap to improve the ability to manipulate ions.

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Die chronisch obstruktive Lungenerkrankung geht mit einer nachweislich erhöhten sympathischen Aktivität einher. Von Erkrankungen, wie der Herzinsuffizienz, die ebenfalls mit einer erhöhten sympathischen Aktivierung einhergehen, lässt sich ein die Prognose verschlechternder Effekt der erhöhten sympathischen Aktivierung annehmen. Auf dieser Annahme beruhend war das Ziel dieser Studie einen möglichen Zusammenhang zwischen sympathischer Aktivierung und Morbidität sowie Mortalität bei COPD zu untersuchen. In dieser Studie wurde in einem Follow-Up 20 Herzinsuffizienz-Patienten, 20 COPD-Patienten und 23 Kontrollpersonen, die mikroneurographisch untersucht wurden, telefonisch nach Krankenhausaufenthalten aufgrund ihrer Grunderkrankung befragt, beziehungsweise der Todeszeitpunkt ermittelt. Nach erfolgter statistischer Auswertung wurden die entsprechenden Kollektive nach klinischen Endpunkten in Subgruppen unterteilt und der Grad der initial mikroneurographisch gemessenen sympathischen Aktivierung verglichen. Sowohl Herzinsuffizienz- als auch COPD-Patienten, die aufgrund ihrer Erkrankung einen Krankenhausaufenthalt hatten oder verstarben, wiesen gegenüber Patienten, die keinen Krankenhausaufenthalt hatten, eine signifikant erhöhte sympathische Aktivierung auf. Durch diese Studie konnte bei COPD-Patienten erstmalig eine signifikante Assoziation einer erhöhten sympathischen Aktivierung mit einer gesteigerten Morbidität und Mortalität nachgewiesen werden. Nach ausführlicheren Untersuchungen bietet dieses noch junge Forschungsfeld perspektivisch eventuell die Möglichkeit, die bisherigen COPD-Therapien um eine kausalere, die Prognose potentiell verbessernde Therapie zu ergänzen.

To track evolution of autonomic responses during orthostasis in men and women, we used discrete pseudo-Wigner distribution based time-frequency analysis to compute dominant frequencies and spectral powers in RR intervals and Systolic Blood Pressure (SBP). Data were collected from 38 healthy volunteers (22 men, 16 women) during 10 min supine posture followed by 30 min of 700 head up tilt. The RR intervals were computed from ECG and systolic blood pressure was and spectral amplitudes of RR intervals were integrated in two regions viz., Low Frequency (LF) region defined between 0.05-0.15 Hz and High Frequency region (HF), sometimes referred to as respiratory frequency region, defined as mean breathing frequency of the individual +/- one standard deviation. Dominant frequencies of RR intervals in the LF region decreased in both men and women. There were no significant differences between men and women as far as the SBP data were concerned for the dominant frequencies, however women had higher values than men. Dominant frequencies of RR intervals in the HF region increased both in men and women from supine to tilt. No significant differences in dominant frequencies were found between men and women. Also there were no significant differences even for the SBP data, however men had higher values than women Integrated powers within the auto spectra of RR showed that in the HF region, power decreased significantly for both men (pandlt;0.005), and women (pandlt;0.001) during tilt compared to supine. However, the HF power in women was significantly higher for men during both supine (pandlt;0.001), and tilt (pandlt;0.005). In LF region integrated power spectrum showed no significant difference between men and women although women showed a slight increase from supine to tilt. These results suggest that men have a higher sympathetic control while women have greater para-sympathetic influence.