This project will investigate neural mechanisms of elevated sympathetic nerve activity (SNA), which is now widely recognized to play a key role in many forms of human hypertension (HTN). We will use our angiotensin II-dependent salt-sensitive model of HTN (AngII-salt HTN) to explore a number of innovations in this project, the first of which is conceptual. We hypothesize that the neurogenic phase of AngII-salt HTN is supported by exaggerated discharge of vasomotor neurons in the rostral ventrolateral medulla (RVLM) in response to excitatory input from the central respiratory network. Thus exaggerated respiratory-vasomotor neuron coupling is postulated to support elevated SNA and ABP in AngII-salt HTN. Specifically, we propose that post-inspiratory burst amplitude in splanchnic SNA (SSNA) is particularly important. This concept is consistent with the fact that SSNA is strongly respiratory modulated and with published data showing that interruption of SSNA by celiac ganglionectomy prevents the neurogenic phase of AngII-salt HTN. A second major innovation is the concept that exaggerated respiratory-SSNA coupling is mediated by  activation of AngII AT1 receptors and  prostaglandin E2 (PGE2) EP3 receptors in the RVLM. We propose that AT1 receptor activation results from inputs to RVLM from the hypothalamic PVN. Preliminary data in the application support this view. We further propose that EP3 receptor activation in rats with AngII-salt HTN likely results from local production of PGE2 in the RVLM. Support for PGE2 in the RVLM playing a functional role in AngII-salt HTN comes from our microinjection studies in which PGE2 in the RVLM increases SSNA and ABP in hypertensive rats, but not in normotensive controls. Collectively, these data led us to formulate the following specific aims: (1) To test the hypothesis that PVN inputs and AT1R activation in the RVLM are important in the development and maintenance of AngII-salt HTN. (2) To test the hypothesis that PGE2 and activation of EP3R in the RVLM also contribute significantly to the HTN. (3) To test the hypothesis that activation of local AT1R and EP3R each contribute to exaggerated respiratory-rhythmic burst discharge of RVLM vasomotor neurons.
In Aim 3 studies, we will also incorporate state of the art gene profiling methods to identify participating gene networks in the RVLM and to identify phenotypic markers of these neurons so that detailed cellular electrophysiology and imaging studies can be performed in the future to isolate favorable targets for anti-hypertensive treatment.
Hypertension (HTN) is a major risk factor for death due to cardiovascular disease, which accounted for 36% of US deaths in 2004 according to NIH NHLBI statistics. By the year 2020, the World Health Organization predicts that HTN will be the greatest single cause of death and disability worldwide. Because most (65-70%) hypertension is not effectively treated, there is an urgent need to understand the biological mechanisms of this disease so that more effective treatments can be developed.
|Bardgett, Megan E; Chen, Qing-Hui; Guo, Qing et al. (2014) Coping with dehydration: sympathetic activation and regulation of glutamatergic transmission in the hypothalamic PVN. Am J Physiol Regul Integr Comp Physiol 306:R804-13|
|Holbein, Walter W; Bardgett, Megan E; Toney, Glenn M (2014) Blood pressure is maintained during dehydration by hypothalamic paraventricular nucleus-driven tonic sympathetic nerve activity. J Physiol 592:3783-99|
|Bardgett, Megan E; Holbein, Walter W; Herrera-Rosales, Myrna et al. (2014) Ang II-salt hypertension depends on neuronal activity in the hypothalamic paraventricular nucleus but not on local actions of tumor necrosis factor-*. Hypertension 63:527-34|
|Bardgett, Megan E; Sharpe, Amanda L; Toney, Glenn M (2014) Activation of corticotropin-releasing factor receptors in the rostral ventrolateral medulla is required for glucose-induced sympathoexcitation. Am J Physiol Endocrinol Metab 307:E944-53|
|Holbein, Walter W; Toney, Glenn M (2013) Sympathetic network drive during water deprivation does not increase respiratory or cardiac rhythmic sympathetic nerve activity. J Appl Physiol (1985) 114:1689-96|
|Sharpe, Amanda L; Andrade, Mary Ann; Herrera-Rosales, Myrna et al. (2013) Rats selectively bred for differences in aerobic capacity have similar hypertensive responses to chronic intermittent hypoxia. Am J Physiol Heart Circ Physiol 305:H403-9|
|Carpenter, William E; Lam, Derek; Toney, Glenn M et al. (2013) Zinc, copper, and blood pressure: Human population studies. Med Sci Monit 19:1-8|
|Toney, Glenn M; Vallon, Volker; Stockand, James D (2012) Intrinsic control of sodium excretion in the distal nephron by inhibitory purinergic regulation of the epithelial Na(+) channel. Curr Opin Nephrol Hypertens 21:52-60|