Sodium pumps, ouabain and aldosterone in the brain: A neuromodulatory pathway underlying salt-sensitive hypertension and heart failure. (March 2020)

• Record Type: Journal Article
• Authors: Leenen, Frans H.H.; Wang, Hong-Wei; Hamlyn, John M.
• Is Part Of: Cell calcium. Volume 86(2020)
• Publication Date: 2020-03
• Subjects: ABC ATP binding cassette -- ACE angiotensin converting enzyme -- aCSF artificial cerebrospinal fluid -- ACTH adrencorticotrophin hormone -- Ang II angiotensin II -- AT1R angiotensin II type 1 receptor -- BBB blood brain barrier -- BP blood pressure -- CNS central nervous system -- CSF cerebrospinal fluid -- c-SRC a non-receptor cellular tyrosine protein kinase -- CTS cardiotonic steroids -- DAF digoxin antibody fragments that bind EO and ouabain with high picomolar affinity -- ENaC epithelial sodium channel – benzamil sensitive -- EO endogenous ouabain -- EO-IR endogenous ouabain immunoreactive -- E2-P a stable active site phosphorylated conformation of the alpha subunit of the Na, K pump -- FSH follicle stimulating hormone -- GH growth hormone -- HPLC high performance liquid chromatography -- HSD3B1 hydroxysteroid-3β-dehydrogenase type 1 -- icv intracerebroventricular -- IR immunoreactive -- LH luteinizing hormone -- LTP long term potentiation -- LV left ventricle -- LVEDP left ventricular end diastolic pressure -- LVPSP left ventricular peak systolic pressure -- MBG marinobufagenin -- MI myocardial infarction -- MR mineralocorticoid receptor -- MS mass spectrometry -- MSH melanin stimulating hormone -- NADPH nicotine adenine dinucleotide phosphate reduced form -- Na, K pump sodium and potassium activated adenosine triphosphatase -- NCX sodium calcium exchanger -- NMR nuclear magnetic resonance -- nNOS neuronal nitric oxide synthase -- OATP1B3 organic anion transporting polypeptide 1B3 -- OVLT organum vasculosum of the lamina terminalis -- PRL prolactin -- PVN paraventricular nucleus -- sc subcutaneous -- SERCA arcoplasmic reticulum Ca-ATPase -- SFO subfornical organ -- SON supraoptic nucleus -- SREBP-2 sterol regulatory element binding protein-2 -- RIA radioimmunoassay -- RVLM rostral ventral lateral medulla -- TRPC6 transient receptor potential operated cation channel subfamily C, member 6 -- TSH thyroid stimulating hormone; Brain -- Calcium -- Hypertension -- Ouabain -- Sodium potassium pump; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2019.102151
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: Excess salt and/or angiotensin II stimulate a neuroendocrine pathway in the brain and raise blood pressure. The pathway involves three hormone-receptor pairs that work in a sequential manner. The pairs are: aldosterone and mineralocorticoid receptors, endogenous ouabain/α2 sodium pumps, and angiotensin II and its type 1 receptors. Activation of the pathway amplifies angiotensin II-evoked signaling in the paraventricular nucleus and increases sympathetic activity. In summary, pathway hormones regulate ion transport mechanisms in the brain that underlie hypertension and adverse outcomes in heart failure. Abstract: Accumulating evidence obtained over the last three decades has revealed a neuroendocrine system in the brain that mediates long term increases in blood pressure. The system involves distinct ion transport pathways including the alpha-2 isoform of the Na, K pump and epithelial sodium channels, as well as critical hormone elements such as angiotensin II, aldosterone, mineralocorticoid receptors and endogenous ouabain. Activation of this system either by circulating or central sodium ions and/or angiotensin II leads to a cascading sequence of events that begins in the hypothalamus and involves the participation of several brain nuclei including the subfornical organ, supraoptic and paraventricular nuclei and the rostral ventral medulla. Key events include heightened aldosterone synthesis and mineralocorticoid receptor activation, upregulation of epithelial sodium channels, augmented synthesis and secretion of endogenous ouabain from hypothalamic magnocellular neurons, and sustained increases in sympathetic outflow. The latter step depends upon increased production of angiotensin II and the primary amplification of angiotensin II type I receptor signaling from the paraventricular nucleus to the rostral ventral lateral medulla. The transmission of sympathetic traffic is secondarily amplified in the periphery by increased short- and long-term potentiation in sympathetic ganglia and by sustained actions of endogenous ouabain in the vascular wall that augment expression of sodium calcium exchange, increase cytosolic Ca 2+ and heighten myogenic tone and contractility. Upregulation of this multi-amplifier system participates in forms of hypertension where salt, angiotensin and/or aldosterone are elevated and contributes to adverse outcomes in heart failure.