Javier Stern (Advisor)
Doctor of Philosophy (PhD)
Under normal conditions, blood pressure is tightly regulated through autonomic tonic and reflex mechanisms. However, when the set-point for blood pressure is chronically elevated, hypertension occurs. Hypertension if untreated can lead to further complications including heart failure, stroke and kidney failure. Elevated sympathetic outflow is known to contribute to the development and/or maintenance of hypertension, and while the hypothalamic paraventricular nucleus (PVN), a preautonomic center, has been implicated in the elevation of sympathetic activity during hypertension, the precise pathophysiological mechanisms underlying sympathoexcitation remain unclear. Subthreshold ion channels, including the A-type K +(I A) and the T-type Ca 2+(I T), are important mechanisms regulating the ability of neurons to generate firing activity, and changes in I Aactivity have been reported during hypertension. Thus, the first aim of the study focused on characterizing the basic biophysical and functional properties of I Ain presympathetic PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM). Our studies demonstrated the presence of a functionally relevant I Ain PVN-RVLM neurons, which actively modulated the action potential waveform and firing activity. The second aim of the study was to determine whether alterations in the biophysical properties of I Acontributed to enhanced neuronal excitability of PVN-RVLM neurons during hypertension. Our studies indicated that diminished I Aavailability constituted a contributing mechanism underlying hyperexcitability in these neurons during hypertension. Previous studies have indicated an opposing balance between the subthreshold ion channels, I Aand I T. Thus, the final aim of the study assessed the biophysical competition between I Aand I T, and functionally addressed the influence of such balance on the activity of PVN-RVLM neurons under normal and hypertensive conditions. Our studies indicated that the balance between I Aand I Twas shifted during hypertension in favor of I Tactivity, resulting in increased I T-dependent low threshold spikes, elevated intracellular calcium levels, and enhanced basal spontaneous firing activity during this condition. Taken together, this study confirms the importance of intrinsic factors, in particular the balance between opposing subthreshold conductances, in regulating the central control of cardiovascular output under normal and pathological conditions.
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