Salt-sensitive hypertension, a key component of essential hypertension, affects approximately 50% of hypertensive patients and dramatically increases the risk of adverse cardiovascular events. Excess dietary sodium intake is an established cause of hypertension, but there remains no clear understanding of the central molecular pathways acting to facilitate sodium homeostasis and normotension in salt-resistant phenotypes, or potential derangements in these antihypertensive systems in salt-sensitive hypertension. Therefore, there exists a critical need to elucidate the neural mechanisms that account for the phenotypic difference between salt-resistance and salt-sensitivity. The current studies hypothesize that hypothalamic paraventricular nucleus (PVN) Gαi2 proteins mediate the central responses activated to counter the development of salt-sensitive hypertension.
Salt-resistant (Sprague-Dawley, Dahl salt-resistant, Brown Norway) and salt-sensitive (Dahl salt-sensitive, 8-congenic Dahl salt-sensitive) rat phenotypes were utilized to investigate the role of central Gαi2 proteins in the physiological regulation of blood pressure in response to acute and chronic challenges to sodium homeostasis.
Salt-resistant animals remain normotensive following chronic high salt intake and exhibit an endogenous site-specific increase in PVN Gαi2 proteins. Exogenous oligodeoxynucleotide-mediated downregulation of Gαi2 proteins throughout the brain evokes rapid renal nerve-dependent hypertension, sodium retention, and sympathoexcitation in animals typically salt-resistant. In salt-sensitive animals, Gαi2 protein downregulation exacerbated salt-sensitive hypertension via a renal nerve-dependent mechanism. Central Gαi2 protein downregulation also resulted in prolonged elevated blood pressure mediated by an attenuated activation of parvocellular PVN neurons. The PVN is the critical brain site at which the antihypertensive compensatory action of Gαi2 protein mediated signal transduction influences blood pressure regulation.
PVN Gαi2 protein-mediated signal transduction represents a conserved central molecular pathway mediating sympathoinhibitory renal nerve-dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. This also differentially influences PVN parvocellular neuronal activation, sympathetic outflow, and arterial pressure in response to sodium challenges, independently of actions on magnocellular neurons and vasopressin release. Impairment of this signaling mechanism contributes to the development of salt-sensitive hypertension. Collectively, this work highlights the complex interaction between the CNS and kidney, and the role of the sympathetic nervous system, in the short and long-term regulation of blood pressure.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/16732 |
| Date | 15 June 2016 |
| Creators | Carmichael, Casey Yumi |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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