Thesis (M.A.)--Kutztown University of Pennsylvania, 1996. / Source: Masters Abstracts International, Volume: 45-06, page: 3324. Typescript. Untitled abstract follows first title page. Includes bibliographical references (leaves 24-26).

Inaug.-Diss.--Königsberg. / Vita. Bibliography: p. 30.

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Master of Science / Department of Kinesiology / Steven Copp / Hindlimb skeletal muscle stretch (i.e., selective activation of the muscle mechanoreflex) in decerebrate rats evokes reflex increases in blood pressure and sympathetic nerve activity. Bradykinin has been found to sensitize mechano-gated channels through a bradykinin B2 receptor-dependent mechanism. Moreover, bradykinin B2 receptor expression on sensory neurons is increased following chronic femoral artery ligation in the rat (a model of simulated peripheral artery disease). We tested the hypothesis that, in decerebrate, unanesthetized rats, the injection of bradykinin into the arterial supply of a hindlimb would acutely augment (i.e., sensitize) the increase in blood pressure and renal sympathetic nerve activity (RSNA) during hindlimb muscle stretch to a greater extent in rats with a ligated femoral artery than in rats with freely perfused femoral arteries. The pressor response during static hindlimb muscle stretch was compared before and after the hindlimb arterial injection of 0.5 µg of bradykinin. The injection of bradykinin itself increased blood pressure to a greater extent in “ligated” rats (n=10) than in “freely perfused” rats (n=10). The increase in blood pressure during hindlimb muscle stretch, however, was not different before compared to after bradykinin injection in either freely perfused (control: 14±2, post-bradykinin: 15±2 mmHg, p=0.62) or ligated (control: 15±3, post-bradykinin: 14±2 mmHg, p=0.80) rats. Likewise, the increase in RSNA during stretch was not different before compared to after bradykinin injection in either group of rats. We conclude that bradykinin did not acutely sensitize the pressor response during hindlimb skeletal muscle stretch in either freely perfused or ligated decerebrate rats.

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The physiological significance of noradrenergic sympathohabenular ingrowth following medial septal lesions was investigated. Following septal lesions, sympathetic fibers originating in the superior cervical ganglia are known to sprout into the medial habenular nuclei, and into the hippocampal formation. Previous work involving sympathohippocampal ingrowth showed that firing rates in septal animals with no ingrowth showed that firing rates in septal animals with no ingrowth were higher than rates of septal animals with ingrowth and controls. Those results suggested that sympathetic ingrowth in the hippocampus had some functional capability in a modulatory manner. The primary aim of the present study was to determine if the peripheral sympathetic ingrowth into the medial habenular nuclei following a septal lesion is functionally significant. The results showed that firing rates of neurons of the medial habenulae in animals receiving septal lesions were significantly higher than rates of control animals and septal lesioned + ganglionectomized animals.

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.