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Molecular Mechanisms Linking Salt to Hypertension

Physiological role of the ₁- and ₂-isoforms of the Na⁺-K⁺-ATPase and biological significance of their cardiac glycoside binding site

¹Departments of Molecular Genetics, Biochemistry and Microbiology, and ²Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio; ³University of Ottawa Heart Institute, Hypertension Unit, Ottawa; and ⁴Departments of Medicine and Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada

An interesting feature of Na⁺-K⁺-ATPase is that it contains four isoforms of the catalytic -subunit, each with a tissue-specific distribution. Our laboratory has used gene targeting to define the functional role of the ₁- and ₂-isoforms. While knockout mice demonstrated the importance of the ₁- and ₂-isoforms for survival, the knockin mice, in which each isoform can be individually inhibited by ouabain and its function determined, demonstrated that both isoforms are regulators of cardiac muscle contractility. Another intriguing aspect of the Na⁺-K⁺-ATPase is that it contains a binding site for cardiac glycosides, such as digoxin. Conservation of this site suggests that it may have an in vivo role and that a natural ligand must exist to interact with this site. In fact, cardiac glycoside-like compounds have been observed in mammals. Our recent study demonstrates that the cardiac glycoside binding site of the Na⁺-K⁺-ATPase plays a role in the regulation of blood pressure and that it mediates both ouabain-induced and ACTH-induced hypertension in mice. Whereas chronic administration of ouabain or ACTH caused hypertension in wild-type mice, it had no effect on blood pressure in mice with a ouabain-resistant ₂-isoform of Na⁺-K⁺-ATPase. Interestingly, animals with the ouabain-sensitive ₁-isoform and a ouabain-resistant ₂-isoform develop ACTH-induced hypertension to a greater extent than wild-type animals. Taken together, these results demonstrate that the cardiac glycoside binding of the Na⁺-K⁺-ATPase has a physiological role and suggests a function for a naturally occurring ligand that is stimulated by administration of ACTH.

ouabain; adrenocorticotropic hormone; blood pressure regulation; cardiotonic steroids

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