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Title: An in silico exploration of sympathetic drive in hypertension : from the preganglionic to the vessel
Author: Briant , Linford J. B.
ISNI:       0000 0004 5915 213X
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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The sympathetic nervous system controls blood pressure and blood flow in part by discretely regulating the diameter of arterial vessels throughout the body. The sympathetic activity exhibits many rhythms, one of which is due to central coupling to the respiratory pattern generator in the brainstem. Hypertension, or high blood pressure, is a chronic medical condition associated with pathologically increased sympathetic nerve activity (SNA) . It has been shown that in the spontaneously hypertensive (SH) strain of rat, this increased activity is characterised by an amplified respiratory-sympathetic coupling that is present at the time of onset of hypertension and this has been proposed to be a causal factor, perhaps generated by changes within the brainstem. Sympathetic preganglionic neurones (SPNs) are located in the spinal cord, and form the final central site for integration of information leading to the generation of sympathetic output. This output is determined by their intrinsic membrane properties, network connections and by synaptic inputs from spinal and supraspinal locations. Interestingly, some previous studies have inferred that SH rats exhibit spinal sympathetic hyperexcitability. In this thesis, whole-cell recording data from SPNs was analysed to obtain parameter estimates to ground modelling studies (recordings from rat workingheart brainstem preparations made by Dr Alexey O. Stalbovskiy). This formed the initial basis for an examination of the membrane properties of SPNs in normotensive control rats ('~TKY), which produced a classification of SPNs on the basis of their reflex responses. This was extended to look at a comparison of the properties of SPNs between hypertensive vs normotensive controls. The data revealed that SPNs in the SH rat exhibit increased output (with an increase in their respiratory modulated bursting) and excitability. Given that SPNs are known for their strong rectifying properties, with an unusually long transient outward rectification, or A-current (IA) ' these experimental data raised the question of whether a diminution of IA could account for the changes in SPN excitability and output in the SH rat. To test this hypothesis, a conductance-based model SPN was constructed in NEURON. A detailed parameter fitting was conducted to ensure the IA kinetics fitted the experimental data reported from previous in vitro recordings. Reduction of the maximal conductance density of IA by 15-30%, changed the excitability and output of the model from the WKY to a SH profile, with increased firing frequency, amplified respiratory modulation and smaller after-hyperpolarisations. This change in output is predominantly a consequence of altered synaptic integration. This prediction was tested in situ by administering 4-AP (an IA blocker) intrathecally. This increased SN A, elevated perfusion pressure and amplified the magnitude of Traube-Hering arterial pressure waves. These findings indicate that IA acts as a powerful filter on incoming synaptic drive to SPNs and that its diminution in the SH rat contributes to the increased sympathetic output underlying hypertension.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available