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LETTERS TO THE EDITOR
1Greater Los Angles Veterans Affairs Healthcare System, 2Department of Medicine, 3School of Medicine, University of California, and 3Brentwood Biomedical Research Institute, Los Angeles, California
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 
2-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.
FOOTNOTES
Address 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: jake{at}ucla.edu)
REFERENCES
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