How does NaCl raise blood pressure? A new paradigm for the pathogenesis of salt-dependent hypertension

Dept. of Physiology, Univ. of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD, 21201, USA.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 11/2011; 302(5):H1031-49. DOI: 10.1152/ajpheart.00899.2011
Source: PubMed


Excess dietary salt is a major cause of hypertension. Nevertheless, the specific mechanisms by which salt increases arterial constriction and peripheral vascular resistance, and thereby raises blood pressure (BP), are poorly understood. Here we summarize recent evidence that defines specific molecular links between Na(+) and the elevated vascular resistance that directly produces high BP. In this new paradigm, high dietary salt raises cerebrospinal fluid [Na(+)]. This leads, via the Na(+)-sensing circumventricular organs of the brain, to increased sympathetic nerve activity (SNA), a major trigger of vasoconstriction. Plasma levels of endogenous ouabain (EO), the Na(+) pump ligand, also become elevated. Remarkably, high cerebrospinal fluid [Na(+)]-evoked, locally secreted (hypothalamic) EO participates in a pathway that mediates the sustained increase in SNA. This hypothalamic signaling chain includes aldosterone, epithelial Na(+) channels, EO, ouabain-sensitive α(2) Na(+) pumps, and angiotensin II (ANG II). The EO increases (e.g.) hypothalamic ANG-II type-1 receptor and NADPH oxidase and decreases neuronal nitric oxide synthase protein expression. The aldosterone-epithelial Na(+) channel-EO-α(2) Na(+) pump-ANG-II pathway modulates the activity of brain cardiovascular control centers that regulate the BP set point and induce sustained changes in SNA. In the periphery, the EO secreted by the adrenal cortex directly enhances vasoconstriction via an EO-α(2) Na(+) pump-Na(+)/Ca(2+) exchanger-Ca(2+) signaling pathway. Circulating EO also activates an EO-α(2) Na(+) pump-Src kinase signaling cascade. This increases the expression of the Na(+)/Ca(2+) exchanger-transient receptor potential cation channel Ca(2+) signaling pathway in arterial smooth muscle but decreases the expression of endothelial vasodilator mechanisms. Additionally, EO is a growth factor and may directly participate in the arterial structural remodeling and lumen narrowing that is frequently observed in established hypertension. These several central and peripheral mechanisms are coordinated, in part by EO, to effect and maintain the salt-induced elevation of BP.

37 Reads
  • Source
    • "The binding of ouabain to its receptor, Na+/K+-ATPase, inhibits ATPase activity and initiates several cellular signaling pathways [1]. Ouabain could play important roles in the maintenance of sodium and body fluid homeostasis and in the regulation of arterial pressure; consequently, ouabain may also affect the pathogenesis of hypertension [2]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ouabain is a cardiac glycoside produced in the adrenal glands and hypothalamus. It affects the function of all cells by binding to Na+/K+-ATPase. Several lines of evidence suggest that endogenous ouabain could be involved in the pathogenesis of essential (particularly, salt-sensitive) hypertension. However, information regarding the postulated hypertensive effect of the long-term administration of low-dose exogenous ouabain is inconsistent. This study was designed to help settle this controversy through the use of telemetric monitoring of arterial blood pressure and to elucidate the ouabain-induced alterations that could either promote or prevent hypertension. Ouabain (63 and 324 µg/kg/day) was administered subcutaneously to male Wistar rats. Radiotelemetry was used to monitor blood pressure, heart rate and measures of cardiovascular variability and baroreflex sensitivity. The continuous administration of ouabain for 3 months did not elevate arterial blood pressure. The low-frequency power of systolic pressure variability, urinary excretion of catecholamines, and cardiovascular response to restraint stress and a high-salt diet as well as the responsiveness to α1-adrenergic stimulation were all unaltered by ouabain administration, suggesting that the activity of the sympathetic nervous system was not increased. However, surrogate indices of cardiac vagal nerve activity based on heart rate variability were elevated. Molecular remodeling in mesenteric arteries that could support the development of hypertension (increased expression of the genes for the Na+/Ca2+ exchanger and Na+/K+-ATPase α2 isoform) was not evident. Instead, the plasma level of vasodilatory calcitonin gene-related peptide (CGRP) significantly rose from 55 (11, SD) in the control group to 89 (20, SD) pg/ml in the ouabain-treated rats (PTukey's = 18.10-5). These data show that long-term administration of exogenous ouabain does not necessarily cause hypertension in rodents. The augmented parasympathetic activity and elevated plasma level of CGRP could be linked to the missing hypertensive effect of ouabain administration.
    PLoS ONE 10/2014; 9(10):e108909. DOI:10.1371/journal.pone.0108909 · 3.23 Impact Factor
  • Source
    • "increased cytoplasmic Ca2+; and iv. elevated myogenic tone and vascular reactivity [29], [43]. This same ouabain-activated Ca2+ signaling pathway operates in human arterial myocytes [54], and is activated in Milan hypertensive rats, a model with high circulating EO [55],[56]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Central nervous system (CNS) administration of angiotensin II (Ang II) raises blood pressure (BP). The rise in BP reflects increased sympathetic outflow and a slower neuromodulatory pressor mechanism mediated by CNS mineralocorticoid receptors (MR). We investigated the hypothesis that the sustained phase of hypertension is associated also with elevated circulating levels of endogenous ouabain (EO), and chronic stimulation of arterial calcium transport proteins including the sodium-calcium exchanger (NCX1), the type 6 canonical transient receptor potential protein (TRPC6), and the sarcoplasmic reticulum calcium ATPase (SERCA2). Wistar rats received a chronic intra-cerebroventricular infusion of vehicle (C) or Ang II (A, 2.5 ng/min, for 14 days) alone or combined with the MR blocker, eplerenone (A+E, 5 µg/day), or the aldosterone synthase inhibitor, FAD286 (A+F, 25 µg/day). Conscious mean BP increased (P<0.05) in A (123±4 mm Hg) vs all other groups. Blood, pituitary and adrenal samples were taken for EO radioimmunoassay (RIA), and aortas for NCX1, TRPC6 and SERCA2 immunoblotting. Central infusion of Ang II raised plasma EO (0.58±0.08 vs C 0.34±0.07 nM (P<0.05), but not in A + E and A + F groups as confirmed by off-line liquid chromatography (LC)-RIA and LC-multistage mass spectrometry. Two novel isomers of EO were elevated by Ang II; the second less polar isomer increased >50-fold in the A+F group. Central Ang II increased arterial expression of NCX1, TRPC6 and SERCA2 (2.6, 1.75 and 3.7-fold, respectively; P<0.01)) but not when co-infused with E or F. Adrenal and pituitary EO were unchanged. We conclude that brain Ang II activates a CNS-humoral axis involving plasma EO. The elevated EO reprograms peripheral ion transport pathways known to control arterial Na+ and Ca2+ homeostasis; this increases contractility and augments sympathetic effects. The new axis likely contributes to the chronic pressor effect of brain Ang II.
    PLoS ONE 10/2014; 9(10):e108916. DOI:10.1371/journal.pone.0108916 · 3.23 Impact Factor
  • Source
    • "Angiotensin II-mediated vasoconstriction and aldosterone-mediated salt retention lead to increase in peripheral resistance and blood volume. Impaired sodium excretion leading to expansion of extracellular fluid volume and peripheral vasoconstriction is frequent in later stages of CKD [19]. Other important factors contributing to CKD hypertension are sympathetic hyperactivation, chronic hyperparathyroidism, endothelial dysfunction, reduced renalase activity, drug administration (cyclosporine, glucocorticoids, EPO) and sleep apnea [20–22]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypertension secondary to chronic kidney disease prevails in earlier childhood and obesity-related primary hypertension in adolescence. Both are associated with a high risk of renal and cardiovascular morbidity. In children with chronic kidney disease, uncontrolled hypertension may accelerate progression to end-stage renal disease before adulthood is reached and increase a child's risk of cardiac death a thousand-fold. Obesity-related hypertension is a slow and silent killer, and though early markers of renal damage are recognized during childhood, end-stage renal disease is a risk in later life. Renal damage will be a formidable multiplier of cardiovascular risk for adults in whom obesity and hypertension tracks from childhood. Management options to prevent renal damage will vary for these different target groups. This review provides a summary of the available renoprotective strategies in order to aid physicians involved in the care of this challenging group of children.
    Current Hypertension Reports 04/2014; 16(4):423. DOI:10.1007/s11906-014-0423-2 · 3.44 Impact Factor
Show more