Date of Award
Open Access Dissertation
Doctor of Philosophy in Biological Sciences (PhD)
Administrative Home Department
Department of Biological Sciences
Committee Member 1
Jason R. Carter
Committee Member 2
Tarun K. Dam
Committee Member 3
Hypertension (HTN) is a major risk factor for the development of cardiovascular disease, and it’s estimated that over 80 million adults in the United States have HTN. Essential HTN often demonstrates sensitivity to salt, and reductions in dietary salt attenuate high blood pressure in this population. Evidence indicates that the paraventricular nucleus (PVN) of the hypothalamus is a key driver of HTN due to excess salt intake. The cellular mechanisms whereby PVN neuronal activity is augmented in response to salt are largely unknown. Previous work from our lab has demonstrated that small conductance calcium activated potassium (SK) channel function is diminished in the PVN in HTN induced by a 2% high salt (HS) combined with chronic infusion of angiotensin II (AngII) (AngII-salt HTN). In study 1 we demonstrate SK channel dysfunction in AngII-salt HTN. Furthermore, SK channel dysfunction was present in rats fed a HS diet alone indicating that dietary salt likely plays a dominant role in reducing SK channel function. In study 2 we examined the contribution of the endoplasmic reticulum (ER), and intracellular organ largely responsible for intracellular Ca2+ homeostasis, in regulating sympathoexcitatory response in vivo, and neuronal excitability in vitro. We demonstrate that inhibiting ER function in the PVN augments sympathetic nerve activity and blood pressure in vivo, and neuronal excitability in vitro. We further demonstrate that HS diet augments excitability of PVN neurons through altered ER Ca2+ store function. Collectively, we demonstrate that HS diet diminishes SK channel function in the PVN and altered ER Ca2+ regulation may contribute to the augmented neuronal excitability in the PVN due to HS intake. Together, these mechanisms providing new and exciting targets for the treatment of salt-sensitive HTN.
Larson, Robert, "CENTRAL NEURAL MECHANISMS OF SALT-SENSITIVE HYPERTENSION", Open Access Dissertation, Michigan Technological University, 2016.