Excess dietary salt intake is strongly correlated with cardiovascular disease and is regarded as a major contributing factor to the pathogenesis of hypertension. Recent evidence suggests that dietary salt intake acts centrally with other factors to elevate sympathetic nerve activity and arterial blood pressure. Despite recent studies to indicate these effects are mediated by elevations in plasma sodium concentration, the mechanisms by which dietary salt intake or hypernatermia act within the brain to increase sympathetic outflow in salt-sensitive hypertension is not known. Our long-term goal is to identify the neural pathways and cellular mechanism(s) that increase sympathetic nerve activity in salt- sensitive hypertension. The current objective of this application is to identify how changes in dietary salt intake and plasma sodium concentration are sensed by the central nervous system to activate sympathetic circuits to raise arterial blood pressure. The central hypothesis is that increases in plasma sodium concentration activate osmosensitive neurons in the organum vasculosum of the lamina terminalis (OVLT) through transient receptor vanilloid or benzamil-sensitive channels. Subsequent activation of downstream pathways through the hypothalamus and ventrolateral medulla increase sympathetic outflow and blood pressure. We also hypothesize the osmosensory transduction pathways are sensitized in salt-sensitive hypertension. Our rationale for this project is that identification of the cellular elements that mediate the intrinsic osmosensitivity of these neurons and how this translates to changes in arterial blood pressure will provide a framework for the development of novel therapeutic treatments. Supported by strong preliminary data, we will test this hypothesis through 3 specific aims: 1) Aim 1 will identify the cellular elements in OVLT neurons that detect changes in plasma osmolality and subsequently regulate sympathetic outflow and arterial blood pressure, 2) Aim 2 will determine whether the discharge responses, basal firing rates, and membrane properties of OVLT neurons is altered in salt- sensitive hypertension, and 3) Aim 3 will identify the cellular mechanisms within OVLT that increase sympathetic outflow and arterial blood pressure in salt-sensitive hypertension. The approach is innovative because these experiments, for the first time, will identify the cellular element in the central nervous system that detects changes in plasma sodium concentration to regulate sympathetic outflow and arterial blood pressure. The proposed research is significant as these findings will provide a platform for the development of novel therapeutic treatments to target neurons outside the blood brain barrier for the treatment of salt-sensitive hypertension and cardiovascular disease.
Excess dietary salt intake greatly increases the risk for adverse cardiovascular events and the development of hypertension. Recent evidence suggests that dietary salt works in the central nervous system with other factors to raise arterial blood pressure. This proposal will identify the cellular mechanism the enables the central nervous system to monitor the level of salt intake and alter cardiovascular function.
|Kinsman, Brian J; Nation, Haley N; Stocker, Sean D (2017) Hypothalamic Signaling in Body Fluid Homeostasis and Hypertension. Curr Hypertens Rep 19:50|
|Kinsman, Brian J; Simmonds, Sarah S; Browning, Kirsteen N et al. (2017) Organum Vasculosum of the Lamina Terminalis Detects NaCl to Elevate Sympathetic Nerve Activity and Blood Pressure. Hypertension 69:163-170|
|Stocker, Sean D; Kinsman, Brian J; Sved, Alan F (2017) Recent Advances in Neurogenic Hypertension: Dietary Salt, Obesity, and Inflammation. Hypertension :|
|Kinsman, Brian J; Browning, Kirsteen N; Stocker, Sean D (2017) NaCl and osmolarity produce different responses in organum vasculosum of the lamina terminalis neurons, sympathetic nerve activity and blood pressure. J Physiol 595:6187-6201|
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|Stocker, Sean D; Lang, Susan M; Simmonds, Sarah S et al. (2015) Cerebrospinal Fluid Hypernatremia Elevates Sympathetic Nerve Activity and Blood Pressure via the Rostral Ventrolateral Medulla. Hypertension 66:1184-90|
|Stocker, Sean D; Gordon, Kathryn W (2015) Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation. J Neurophysiol 113:1302-9|
|Kinsman, Brian; Cowles, James; Lay, Jennifer et al. (2014) Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor. Am J Physiol Regul Integr Comp Physiol 307:R1092-100|
|Steiner, Jennifer L; Bardgett, Megan E; Wolfgang, Lawrence et al. (2014) Glucocorticoids attenuate the central sympathoexcitatory actions of insulin. J Neurophysiol 112:2597-604|
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