title: Endogenous cardiotonic steroids in kidney failure: a review and an hypothesis.
abstract: In response to progressive nephron loss, volume and humoral signals in the circulation have increasing relevance. These signals, including plasma sodium, angiotensin II, and those related to volume status, activate a slow neuromodulatory pathway within the central nervous system (CNS). The slow CNS pathway includes specific receptors for angiotensin II, mineralocorticoids, and endogenous ouabain (EO). Stimulation of the pathway leads to elevated sympathetic nervous system activity (SNA) and increased circulating EO. The sustained elevation of circulating EO (or ouabain) stimulates central and peripheral mechanisms that amplify the impact of SNA on vascular tone. These include changes in synaptic plasticity in the brain and sympathetic ganglia that increase preganglionic tone and amplify ganglionic transmission, amplification of the impact of SNA on arterial tone in the vascular wall, and the reprogramming of calcium signaling proteins in arterial myocytes. These increase SNA, raise basal and evoked arterial tone, and elevate blood pressure (BP). In the setting of CKD, we suggest that sustained activation/elevation of the slow CNS pathway, plasma EO, and the cardiotonic steroid marinobufagenin, comprises a feed-forward system that raises BP and accelerates kidney and cardiac damage. Block of the slow CNS pathway and/or circulating EO and marinobufagenin may reduce BP and slow the progression to ESRD.
authors.affiliation: Department of Physiology, University of Maryland Baltimore, Baltimore, MD; and Nephrology, Dialysis and Hypertension Division, Scientific Institute San Raffaele, Università "Vita-Salute" San Raffaele, Milan, Italy. Electronic address: jhamlyn@umaryland.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Hamlyn
authors.affiliation: Department of Physiology, University of Maryland Baltimore, Baltimore, MD; and Nephrology, Dialysis and Hypertension Division, Scientific Institute San Raffaele, Università "Vita-Salute" San Raffaele, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
mesh_terms: D002018:Bufanolides / Q000378:metabolism*; D002301:Cardiac Glycosides / Q000378:metabolism*; D018450:Disease Progression; D005728:Ganglia, Sympathetic / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D009473:Neuronal Plasticity; D010042:Ouabain / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism
chemical_list: D002018:Bufanolides; D002301:Cardiac Glycosides; C093896:marinobufagenin; D010042:Ouabain
keywords: Brain; Dialysis; Hypertension; Marinobufagenin; Ouabain