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• W2113877993 abstract "LETTERS TO THE EDITORSodium pumps: ouabain, ion transport, and signaling in hypertensionMordecai P. Blaustein, John M. Hamlyn, and Thomas L. PalloneMordecai P. Blaustein, John M. Hamlyn, and Thomas L. PallonePublished Online:01 Jul 2007https://doi.org/10.1152/ajprenal.00092.2007MoreSectionsPDF (32 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat to the editor: A recent Editorial Focus in this journal (7) addresses the newly recognized role of the sodium pump as both an ion transport protein and a hormone receptor with its own signaling cascade. The relative importance of the cardiotonic steroids (CTS) as endogenous signaling hormones versus their ability to inhibit the sodium pump is of great interest. Indeed, the article noted that “although all digitalis-like compounds inhibit Na-K-ATPase-mediated transport, they differ considerably in terms of their hypertensive effects.” The author concludes that “these findings do not support the prevailing hypothesis that the pathophysiological effect of digitalis results from inhibition of… transport activity.” This implies that the hypertensive effect of CTS may be due to the action of these agents as regulators of signal transduction, entirely unrelated “to its (Na-K-ATPase's) role as an ion pump.” The discoveries related to Src kinase-mediated signal transduction by Na-K-ATPase add a new dimension to the view that the endogenous cardiotonic steroids comprise a novel hormone system. Nevertheless, the view that CTS induced hypertension is unrelated to inhibition of ion transport is inconsistent with published reports. Regrettably, the Editorial Focus does not cite key articles that support the conclusion that CTS hypertension is secondary to inhibition of sodium pumps.It is true that the tendency of certain CTS to induce hypertension does not correlate with their relative potency as Na-K-ATPase inhibitors (8, 9). The most obvious comparison is that ouabain induces hypertension while digoxin (1, 9) and a digitoxigenin derivative, PST-2238 (4), are antihypertensive. This need not imply that ouabain's effect on blood pressure is unrelated to inhibition of Na+ transport. Instead, these data are consistent with the interpretation that some CTS have mixed agonist/antagonist properties.Viability of the hypothesis that enhancement of cytoplasmic Ca2+ responses by ouabain is related to inhibition of Na-K-ATPase relies on the secondary effect of Na+ on Na/Ca exchange. There is now direct evidence that elevation of blood pressure is a consequence of reduced transport activity of the ouabain-sensitive Na-K-ATPase α2-isoform (2, 3, 10) and the resultant Ca2+ gain mediated by Na/Ca exchange (3, 5, 10). Moreover, reduced α2 expression leads to murine hypertension (10). The vascular myogenic effect of that model is prevented by the Na/Ca exchange inhibitor SEA0400 (10). A key role for Na/Ca exchange is revealed by the observation that SEA0400 lowers blood pressure in ouabain-induced hypertension and other forms of salt-dependent hypertension, but not salt-independent hypertension (5). These findings demonstrate that ouabain's hypertensive effect depends on its inhibition of the Na-K-ATPase and Ca2+ gain via Na/Ca exchange. Thus Src signaling, alone, appears to be insufficient to raise blood pressure in ouabain-induced hypertension although an accessory role is not excluded.Comparison of the effect of reduced expression of the α2 Na-K-ATPase (6) with that of low-dose ouabain on cell signaling may be a useful way to determine the roles of altered Na+ and Ca2+ in mediating the effects of ouabain on Src kinase signaling.REFERENCES1 Abarquez RF. Digitalis in the treatment of hypertension. A preliminary report. Acta Med Philipp 3: 161–170, 1967.PubMed | Google Scholar2 Dostanic I, Paul RJ, Lorenz JN, Theriault S, Van Huysse JW, Lingrel JB. The α2 isoform of Na,K-ATPase mediates ouabain-induced hypertension in mice and increased vascular contractility in vitro. Am J Physiol Heart Circ Physiol 288: H477–H485, 2005.Link | ISI | Google Scholar3 Dostanic-Larson I, Van Huysse JW, Lorenz JN, Lingrel JB. The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation. Proc Natl Acad Sci USA 102: 15845–15850, 2005.Crossref | PubMed | ISI | Google Scholar4 Ferrari P, Ferrandi M, Tripodi G, Torielli L, Padoani G, Minotti E, Melloni P, Bianchi G. PST 2238: a new antihypertensive compound that modulates Na,K-ATPase in genetic hypertension. J Pharmacol Exp Ther 288: 1074–1083, 1999.PubMed | ISI | Google Scholar5 Iwamoto T, Kita S, Zhang J, Blaustein MP, Arai Y, Yoshida S, Wakimoto K, Komuro I, Katsuragi T. Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle. Nature Med 10: 1193–1199, 2004.Crossref | PubMed | ISI | Google Scholar6 James PF, Grupp IL, Grupp G, Woo AL, Askew GR, Croyle ML, Welsh RA, Lingrel JB. Identification of a specific role for the Na,K-ATPase alpha 2 isoform as a regulator of calcium in the heart. Mol Cell 3: 555–563, 1999.Crossref | PubMed | ISI | Google Scholar7 Kaunitz JD. Membrane transport proteins: not just for transport anymore. Am J Physiol Renal Physiol 290: F995–F996, 2006.PubMed | ISI | Google Scholar8 Manunta P, Hamilton BP, Hamlyn JM. Structure-activity relationships for the hypertensinogenic activity of ouabain: role of the sugar and lactone ring. Hypertension 37: 472–477, 2001.Crossref | PubMed | ISI | Google Scholar9 Manunta P, Hamilton J, Rogowski AC, Hamilton BP, Hamlyn JM. Chronic hypertension induced by ouabain but not digoxin in the rat: antihypertensive effect of digoxin and digitoxin. Hypertens Res 23, Suppl: S77–S85, 2000.Crossref | PubMed | ISI | Google Scholar10 Zhang J, Lee MY, Cavalli M, Chen L, Berra-Romani R, Balke CW, Bianchi G, Ferrari P, Hamlyn JM, Iwamoto T, Lingrel JB, Matteson DR, Wier WG, Blaustein MP. Sodium pump α2 subunits control myogenic tone and blood pressure in mice. J Physiol 569: 243–256, 2005.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: M. P. Blaustein, Univ. of Maryland School of Medicine, 655 West Baltimore St., Baltimore, MD 21201-1559 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByAugmentation of Ouabain-Induced Increase in Heart Muscle Contractility by Akt Inhibitor MK-220622 July 2018 | Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 24, No. 1P-Type Pumps: Na+,K+-ATPaseFormation of New High Density Glycogen-Microtubule Structures Is Induced by Cardiac SteroidsJournal of Biological Chemistry, Vol. 287, No. 9Critical Roles of the Na+/K+-ATPase in Apoptosis and CNS DiseasesCa2+ influx mechanisms in caveolae vesicles of pulmonary smooth muscle plasma membrane under inhibition of α2β1 isozyme of Na+/K+-ATPase by ouabainLife Sciences, Vol. 84, No. 5-6Reply to Blaustein et al.Jonathan D. Kaunitz1 July 2007 | American Journal of Physiology-Renal Physiology, Vol. 293, No. 1 More from this issue > Volume 293Issue 1July 2007Pages F438-F438 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.00092.2007PubMed17616574History Published online 1 July 2007 Published in print 1 July 2007 Metrics" @default.
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