Cardiac-sympathetic dysfunction in hypertension

Bardsley, E

Abstract:: The work presented in this thesis examined the cellular and molecular phenotypes associated with sympathetic over-activity in the initiation and progression of hypertension in the prehypertensive spontaneously hypertensive rat (preSHR) and spontaneously hypertensive rat (SHR), with validation of key molecular pathways in human stellate ganglia.

Chapter One provided an overview of the short and long-term regulation of arterial blood pressure. This chapter focussed specifically...
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APA Style

Bardsley, E. (2018). Cardiac-sympathetic dysfunction in hypertension [PhD thesis]. University of Oxford.

MLA Style

Bardsley, E. Cardiac-Sympathetic Dysfunction in Hypertension. University of Oxford, 2018.

Chicago Style

Bardsley, E. 2018. “Cardiac-Sympathetic Dysfunction in Hypertension.” PhD thesis, University of Oxford.
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Authors

+ Bardsley, E More by this author

Division:: MSD
Department:: Doctoral Training Centre - MSD
Role:: Author

Contributors

+ Paterson, D

Role:: Supervisor

+ Wellcome Trust OXION Programme More from this funder

Grant:: 105409/Z/14/Z

DOI:: 10.5287/ora-z591qoqjq
Type of award:: DPhil
Level of award:: Doctoral
Awarding institution:: University of Oxford

Keywords:: Sympathetic nervous system

Calcium imaging

RNA sequencing

FRET

Stellate ganglia

Neurogenic Hypertension
Subjects:: Sympathetic nervous system

Cardiovascular disease

Stellate ganglia

Physiology

Hypertension
UUID:: uuid:12a7f308-ea82-4c3a-8b6b-a2c20c2ce4ec
Deposit date:: 2019-03-10

Related item:: Dysregulation of neuronal Ca2+ channel linked to heightened sympathetic phenotype in prohypertensive states
Description:: Hypertension is associated with impaired nitric oxide (NO)-cyclic nucleotide (CN)-coupled intracellular calcium (Ca(2+)) homeostasis that enhances cardiac sympathetic neurotransmission. Because neuronal membrane Ca(2+) currents are reduced by NO-activated S-nitrosylation, we tested whether CNs affect membrane channel conductance directly in neurons isolated from the stellate ganglia of spontaneously hypertensive rats (SHRs) and their normotensive controls. Using voltage-clamp and cAMP-protein kinase A (PKA) FRET sensors, we hypothesized that impaired CN regulation provides a direct link to abnormal signaling of neuronal calcium channels in the SHR and that targeting cGMP can restore the channel phenotype. We found significantly larger whole-cell Ca(2+) currents from diseased neurons that were largely mediated by the N-type Ca(2+) channel (Cav2.2). Elevating cGMP restored the SHR Ca(2+) current to levels seen in normal neurons that were not affected by cGMP. cGMP also decreased cAMP levels and PKA activity in diseased neurons. In contrast, cAMP-PKA activity was increased in normal neurons, suggesting differential switching in phosphodiesterase (PDE) activity. PDE2A inhibition enhanced the Ca(2+) current in normal neurons to a conductance similar to that seen in SHR neurons, whereas the inhibitor slightly decreased the current in diseased neurons. Pharmacological evidence supported a switching from cGMP acting via PDE3 in control neurons to PDE2A in SHR neurons in the modulation of the Ca(2+) current. Our data suggest that a disturbance in the regulation of PDE-coupled CNs linked to N-type Ca(2+) channels is an early hallmark of the prohypertensive phenotype associated with intracellular Ca(2+) impairment underpinning sympathetic dysautonomia.
Related item:: RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity
Description:: Cardiovascular disease is the most prevalent age-related illness worldwide, causing approximately 15 million deaths every year. Hypertension is central in determining cardiovascular risk and is a strong predictive indicator of morbidity and mortality; however, there remains an unmet clinical need for disease-modifying and prophylactic interventions. Enhanced sympathetic activity is a well-established contributor to the pathophysiology of hypertension, however the cellular and molecular changes that increase sympathetic neurotransmission are not known. The aim of this study was to identify key changes in the transcriptome in normotensive and spontaneously hypertensive rats. We validated 15 of our top-scoring genes using qRT-PCR, and network and enrichment analyses suggest that glutamatergic signalling plays a key role in modulating Ca2+ balance within these ganglia. Additionally, phosphodiesterase activity was found to be altered in stellates obtained from the hypertensive rat, suggesting that impaired cyclic nucleotide signalling may contribute to disturbed Ca2+ homeostasis and sympathetic hyperactivity in hypertension. We have also confirmed the presence of these transcripts in human donor stellate samples, suggesting that key genes coupled to neurotransmission are conserved. The data described here may provide novel targets for future interventions aimed at treating sympathetic hyperactivity associated with cardiovascular disease and other dysautonomias.
Related item:: Transcriptional profiling of stellate ganglia from normotensive and spontaneously hypertensive rat strains
Description:: The course of hypertension remains poorly understood, although impairment of the sympathetic nervous systems is thought to play a role in its aetiology. In this study, RNA-sequencing (RNAseq) was used to identify transcriptomal differences in the sympathetic stellate ganglia between 16-week-old normotensive Wistar rats and spontaneously hypertensive rats (SHR). Sequencing quality was assessed by FastQC and quasi-mapping rate by Salmon. Differential expression results were confirmed by real time reverse transcriptase Quantitative Polymerase Chain Reaction (qRT-PCR). RNAseq analysis was found to be predictive and representative of transcriptomal changes when compared to qRT-PCR by correlation analysis. Whether these changes underpin physiological sympathetic phenotypes associated with hypertension remains to be established, however this dataset identifies lead transcripts as a priori targets for further investigation.
Related item:: Impaired cAMP-cGMP cross-talk during cardiac sympathetic dysautonomia
Related item:: Neurotransmitter switching coupled to β-adrenergic signaling in sympathetic neurons in prehypertensive states.
Description:: Single or combinatorial administration of β-blockers is a mainstay treatment strategy for conditions caused by sympathetic overactivity. Conventional wisdom suggests that the main beneficial effect of β-blockers includes resensitization and restoration of β1-adrenergic signaling pathways in the myocardium, improvements in cardiomyocyte contractility, and reversal of ventricular sensitization. However, emerging evidence indicates that another beneficial effect of β-blockers in disease may reside in sympathetic neurons. We investigated whether β-adrenoceptors are present on postganglionic sympathetic neurons and facilitate neurotransmission in a feed-forward manner. Using a combination of immunocytochemistry, RNA sequencing, Förster resonance energy transfer, and intracellular Ca2+ imaging, we demonstrate the presence of β-adrenoceptors on presynaptic sympathetic neurons in both human and rat stellate ganglia. In diseased neurons from the prehypertensive rat, there was enhanced β-adrenoceptor–mediated signaling predominantly via β2-adrenoceptor activation. Moreover, in human and rat neurons, we identified the presence of the epinephrine-synthesizing enzyme PNMT (phenylethanolamine-N-methyltransferase). Using high-pressure liquid chromatography with electrochemical detection, we measured greater epinephrine content and evoked release from the prehypertensive rat cardiac-stellate ganglia. We conclude that neurotransmitter switching resulting in enhanced epinephrine release, may provide presynaptic positive feedback on β-adrenoceptors to promote further release, that leads to greater postsynaptic excitability in disease, before increases in arterial blood pressure. Targeting neuronal β-adrenoceptor downstream signaling could provide therapeutic opportunity to minimize end-organ damage caused by sympathetic overactivity.
Related item:: Neurocardiac regulation: From Cardiac Mechanisms to Novel Therapeutic Approaches
Description:: Cardiac sympathetic overactivity is a well-established contributor to the progression of neurogenic hypertension and heart failure, yet the underlying pathophysiology remains unclear. Recent studies have highlighted the importance of acutely regulated cyclic nucleotides and their effectors in the control of intracellular calcium and exocytosis. Emerging evidence now suggests that a significant component of sympathetic overactivity and enhanced transmission may arise from impaired cyclic nucleotide signalling, resulting from compromised phosphodiesterase activity, as well as alterations in receptor-coupled G-protein activation. In this review, we address some of the key cellular and molecular pathways that contribute to sympathetic overactivity in hypertension and discuss their potential for therapeutic targeting.

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Cardiac-sympathetic dysfunction in hypertension

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