Neurogenic and Sympathoexcitatory Actions of NaCl in Hypertension

Abstract

Excess dietary salt intake is a major contributing factor to the pathogenesis of salt-sensitive hypertension. Strong evidence suggests that salt-sensitive hypertension is attributed to renal dysfunction, vascular abnormalities, and activation of the sympathetic nervous system. Indeed, sympathetic nerve transections or interruption of neurotransmission in various brain centers lowers arterial blood pressure (ABP) in many salt-sensitive models. The purpose of this article is to discuss recent evidence that supports a role of plasma or cerebrospinal fluid hypernatremia as a key mediator of sympathoexcitation and elevated ABP. Both experimental and clinical studies using time-controlled sampling have documented that a diet high in salt increases plasma and cerebrospinal fluid sodium concentration. To the extent it has been tested, acute and chronic elevations in sodium concentration activates the sympathetic nervous system in animals and humans. A further understanding of how the central nervous system detects changes in plasma or cerebrospinal fluid sodium concentration may lead to new therapeutic treatment strategies in salt-sensitive hypertension.

Gαi 2 -Protein–Mediated Signal Transduction

“…Despite no detectable change in either plasma sodium or osmolality in the current studies, we speculate minute changes in plasma sodium/osmolality following sodium ingestion sensed by osmoreceptor/sodium-sensitive receptors located in the hypothalamic PVN, the circumventricular organs 4,5 or the renal afferent nerve terminals, 17 trigger the observed alterations in protein expression. Human studies have reported the presence of a single nucleotide polymorphism (SNP) in the human GNAI2 gene is associated with increased hypertension risk by the Millennium Genome Project for Hypertension in Japan 35 and in Caucasian Italians.…”

“…4,7 The observed genetically conserved endogenous increase in PVN Gαi 2 protein expression in multiple salt-resistant phenotypes, and a failure of this response in the DSS rat, is of high physiological significance because of the pivotal role that the PVN plays in the neural network that influences sympathetic outflow and blood pressure regulation. 18 Our studies 1) implicate sympathetic innervation of the kidney as a critical component in the pathogenesis of salt-sensitive hypertension and, 2) suggest the underlying pathogenesis of salt-sensitive hypertension involves integration of both the central nervous system and the kidneys with communication being regulated by the renal sympathetic nerves via a CNS Gαi 2 protein-gated signal transduction pathway.…”

“…3 Despite the adverse impact of salt-sensitivity, the mchanism(s) by which dietary salt evokes increased blood pressure remain to be fully elucidated. 4 It has been hypothesized that, among many proposed mechanisms, impaired sympathetic nervous system activity plays a critical role in the development of salt-sensitive hypertension, 5–7 a theory supported by increased activation of the sympathetic nervous system in both animal models of salt-sensitive hypertension 8,9 and salt-sensitive humans. 10 In the setting of high salt intake the regulation of central sympathetic outflow to the kidneys, via the renal sympathetic nerves, is of critical importance due to the direct impact of the renal nerves on renal sodium reabsorption, blood volume, total peripheral resistance and long-term blood pressure.…”

“…4,5,7,16 In response to increased sodium intake sodium-sensitive receptors, present in the circumventricular organs and hypothalamic paraventricular nucleus (PVN), 4,5 activate multiple brain G-protein–coupled receptor (GPCR) systems (e.g., the α 2 -adrenoceptor) to inhibit renal sympathetic nerve activity to facilitate natriuresis, thus maintaining fluid and electrolyte homeostasis and normotension. 13,17,18 Despite our understanding of the role of multiple GPCR’s in the regulation of renal sympathoinhibition and subsequent natriuresis there remains a paucity of knowledge regarding potential common down-stream signal transduction pathways that are activated by GPCR’s to evoke these regulatory responses in-vivo .…”

Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor

“…Collectively, these findings suggest that TRPV1 and/or TRPV4 channels are not the primary mechanism by which the central nervous system responds to cellular dehydration during hypernatremia or hyperosmolality to increase thirst. hypernatremia; water intake; organum vasculosum of the lamina terminalis; subfornical organ; cellular dehydration THE CENTRAL NERVOUS SYSTEM plays a pivotal role in body fluid homeostasis through its ability to sense changes in osmotic pressure and subsequently alter fluid intake, secretion of antidiuretic hormone, natriuresis, and sympathetic nerve activity (5,19,30,42,45,50). Physiologically, changes in extracellular osmotic pressure are typically the result of changes in the extracellular concentration of Na ϩ and/or Cl Ϫ to produce cellular dehydration.…”