Date of Award

Fall 12-17-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cellular & Integrative Physiology

First Advisor

Irving H. Zucker

Abstract

Over activation of the sympathetic nervous system is prevalent in many forms of cardiovascular disease such as chronic heart failure (CHF) and hypertension. Although increased neuronal renin-angiotensin system activity in presympathetic neurons has been well implicated in mediating this sympatho-excitation, many of the neuronal effects of angiotensin II (Ang II) signaling remain poorly understood. One particular mechanism of Ang II-mediated increases in presympathetic neuronal activity is through reductions in voltage-gated K+ currents. Another pathway that has profound effects on neuronal K+ currents and that has been previously implicated in Ang II-signaling is brain-derived neurotrophic factor (BDNF) activity through its receptor tyrosine kinase B (TrkB). Therefore, we hypothesized that BDNF/TrkB signaling is an important mediator of the neuronal effects of Ang II in modulating voltage-gated K+ currents and autonomic dysfunction in cardiovascular disease states such as CHF and hypertension. We employed cell culture and whole-animal models to explore this hypothesis and utilized electrophysiological, molecular, and in vivo physiological techniques. Patch-clamp studies demonstrated that BDNF is involved in Ang II-induced reductions to K+ currents. Further in-vivo experiments found that overexpression of Kv4.3 into the rostral ventrolateral medulla attenuates the increase in sympathetic nerve activity of rats post-myocardial infarction. Baroreflex dysfunction is common in CHF, and desensitization of central neuronal areas such as the nucleus tractus solitarius (NTS) can mediate this dysfunction. We therefore hypothesized that changes in BDNF/TrkB signaling in the NTS mediated baroreflex dysfunction in CHF. Blocking TrkB with ANA-12 in the NTS blunted baroreflex sensitivity in sham rats but had little effect on the already blunted baroreflex sensitivity of CHF rats. TrkB expression was reduced in CHF rats, implicating reduced BDNF/TrkB signaling in the NTS as a mechanism for reduced baroreflex sensitivity during CHF. In a final set of experiments we explored the connection between Ang II and BDNF in vivo. Central administration of Ang II increased mean arterial pressure and induced sympatho-excitation, both of which were attenuated by coinfusion of ANA-12. Overall, these data implicate BDNF as an important factor in mediating the neuronal effects of Ang II on K+ currents, hemodynamics, baroreflex sensitivity, and sympathetic nerve activity.

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