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• W1991054920 abstract "LETTERS TO THE EDITORReply to Blaustein et al.Jonathan D. KaunitzJonathan D. KaunitzPublished Online:01 Jul 2007https://doi.org/10.1152/ajprenal.00206.2007MoreSectionsPDF (34 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations reply: Blaustein et al. (2) have responded to the Editorial Focus (9) by stating that it “did not cite key articles that support the conclusion that CTS (cardiotonic steroids) hypertension is secondary to inhibition of sodium pumps.” To support their view, they cited several articles supporting the role of the Na-K-ATPase α2-isoform and the Na/Ca exchanger (NCX) in their role in CTS-related hypertension. I thank Blaustein and colleagues (2) for highlighting these recent studies supporting the role of Na-K-ATPase and NCX in hypertension pathogenesis.Since first proposed by Blaustein (1) and by Haddy and Overbeck (6) in the late 1970s, the role of endogenous CTS (ECTS) in the pathogenesis of volume-expanded hypertension has been intensively studied. Notable milestones have included the discovery of ECTS in humans and in experimental animals, and the recent data implicating Na-K-ATPase isoforms and the NCX using transgenic mice (4, 14). Nevertheless, many aspects of the hypothesis are supported by equivocal data. A fundamental conundrum, stressed by Hansen (7), is that ECTS are measured at concentrations at 1 nM or below, whereas for many of the cited studies, including those cited below, ouabain concentrations of 10–100 nM or higher are used in vascular smooth muscle in vitro (3, 8, 14), casting doubt on the applicability of the in vitro data to the clinical syndrome. It is not known, for example, whether the hypertensinogenic effect of ouabain is central, peripheral, or mixed (3). The same criticism could be leveled at the proposed mechanism wherein ouabain triggers a signal cascade, as the concentration used in one study at least was 100 μM, ∼5 logs greater than the ECTS concentration (11). Nevertheless, animals studies suggest that ouabain administered at doses that produce concentrations similar to those present endogenously can produce hypertension.Orlov et al. (13) calculated the Km for ouabain for inhibition of Na-K-ATPase-mediated 86Rb inhibition as 10–100 nM for human and 10–100 μM for isolated rat vascular smooth muscle cells, far higher concentrations than are present endogenously. Since 1 nM ouabain increases cell calcium (15), the data support the hypothesis that ECTS may indeed increase vascular tone via an Na-K-ATPase- and NCX-mediated mechanism, but independently of inhibition of Na-K-ATPase ion transport activity. This hypothesis is also supported by work of Manunta and colleagues (12), also cited herein, who showed that inhibition of Na-K-ATPase catalytic activity and the hypertensinogenic effect of cardiac glycosides correlate poorly.The nature of the putative ion gradient-independent coupling between Na-K-ATPase and NCX function has not been directly addressed to any extent, which led to my initial speculation that some form of protein-protein interaction, as has been proposed for other epithelial transport proteins (5, 10) is present. Whatever the precise mechanism, the hypothesis advanced in the 1970s that an endogenous humoral agent can produce hypertension through an Na-K-ATPase-mediated mechanism has been largely borne out by subsequent studies. Further insight into its pathogenesis will doubtless uncover useful therapeutic targets.REFERENCES1 Blaustein MP. Sodium ions, calcium ions, blood pressure regulation, and hypertension: a reassessment and a hypothesis. Am J Physiol Cell Physiol 232: C165–C173, 1977.Link | ISI | Google Scholar2 Blaustein MP, Hamlyn JM, Pallone TL. Am J Physiol Renal Physiol; doi:10.1152/ajprenal.00092.2007.Google Scholar3 Dostanic I, Paul RJ, Lorenz JN, Theriault S, Van Huysse JW, Lingrel JB. The alpha2-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 Scholar4 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 Scholar5 Favia M, Fanelli T, Bagorda A, Di SF, Reshkin SJ, Suh PG, Guerra L, Casavola V. NHE3 inhibits PKA-dependent functional expression of CFTR by NHERF2 PDZ interactions. Biochem Biophys Res Commun 347: 452–459, 2006.Crossref | PubMed | ISI | Google Scholar6 Haddy FJ, Overbeck HW. The role of humoral agents in volume expanded hypertension. Life Sci 19: 935–947, 1976.Crossref | PubMed | ISI | Google Scholar7 Hansen O. No evidence for a role in signal-transduction of Na+/K+-ATPase interaction with putative endogenous ouabain. Eur J Biochem 270: 1916–1919, 2003.Crossref | PubMed | Google Scholar8 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. Nat Med 10: 1193–1199, 2004.Crossref | PubMed | ISI | Google Scholar9 Kaunitz JD. Membrane transport proteins: not just for transport anymore. Am J Physiol Renal Physiol 290: F995–F996, 2006.PubMed | ISI | Google Scholar10 Lamprecht G, Heil A, Baisch S, Lin-Wu E, Yun CC, Kalbacher H, Gregor M, Seidler U. The down regulated in adenoma (dra) gene product binds to the second PDZ domain of the NHE3 kinase A regulatory protein (E3KARP), potentially linking intestinal Cl−/HCO3− exchange to Na+/H+ exchange. Biochemistry 41: 12336–12342, 2002.Crossref | PubMed | ISI | Google Scholar11 Liu J, Tian J, Haas M, Shapiro JI, Askari A, Xie Z. Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. J Biol Chem 275: 27838–27844, 2000.Crossref | PubMed | ISI | Google Scholar12 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 Scholar13 Orlov SN, Taurin S, Hamet P. The alpha1-Na/K pump does not mediate the involvement of ouabain in the development of hypertension in rats. Blood Press 11: 56–62, 2002.Crossref | PubMed | ISI | Google Scholar14 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 alpha2 subunits control myogenic tone and blood pressure in mice. J Physiol 569: 243–256, 2005.Crossref | PubMed | ISI | Google Scholar15 Zhu Z, Tepel M, Neusser M, Zidek W. Low concentrations of ouabain increase cytosolic free calcium concentration in rat vascular smooth muscle cells. Clin Sci (Lond) 90: 9–12, 1996.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. D. Kaunitz, Bldg. 114, Suite 217, West Los Angeles VA Medical Centre, 11301 Wilshire Blvd., Los Angeles, CA 90073 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 293Issue 1July 2007Pages F439-F439 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.00206.2007History Published online 1 July 2007 Published in print 1 July 2007 Metrics" @default.
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