The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

• Iva Dostanic-Larson

  Departments of Molecular Genetics, Biochemistry, and Microbiology and Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7; and Departments of Medicine and Biochemistry and Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5

• James W. Van Huysse

  Departments of Molecular Genetics, Biochemistry, and Microbiology and Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7; and Departments of Medicine and Biochemistry and Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5

• John N. Lorenz

  Departments of Molecular Genetics, Biochemistry, and Microbiology and Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7; and Departments of Medicine and Biochemistry and Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5

• Jerry B Lingrel

  Departments of Molecular Genetics, Biochemistry, and Microbiology and Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7; and Departments of Medicine and Biochemistry and Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5

抄録

The Na,K-ATPase contains a binding site for cardiac glycosides, such as ouabain, digoxin, and digitoxin, which is highly conserved among species ranging from Drosophila to humans. Although advantage has been taken of this site to treat congestive heart failure with drugs such as digoxin, it is unknown whether this site has a natural function in vivo . Here we show that this site plays an important role in the regulation of blood pressure, and it specifically mediates adrenocorticotropic hormone (ACTH)-induced hypertension in mice. We used genetically engineered mice in which the Na,K-ATPase α2 isoform, which is normally sensitive to cardiac glycosides, was made resistant to these compounds. Chronic administration of ACTH caused hypertension in WT mice but not in mice with an ouabain-resistant α2 isoform of Na,K-ATPase. This finding demonstrates that the cardiac glycoside binding site of the Na,K-ATPase plays an important role in blood pressure regulation, most likely by responding to a naturally occurring ligand. Because the α1 isoform is sensitive to cardiac glycosides in humans, we developed mice in which the naturally occurring ouabain-resistant α1 isoform was made ouabain-sensitive. Mice with the ouabain-sensitive “human-like” α1 isoform and an ouabain-resistant α2 isoform developed ACTH-induced hypertension to greater extent than WT animals. This result indicates that the cardiac glycoside binding site of the α1 isoform can also mediate ACTH-induced hypertension. Taken together these results demonstrate that the cardiac glycoside binding site of the α isoforms of the Na,K-ATPase have a physiological function and supports the hypothesis for a role of the endogenous cardiac glycosides.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 102 (44), 15845-15850, 2005-10-21

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1361699994755559936
• NII論文ID: 30016242451
• DOI: 10.1073/pnas.0507358102
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.0507358102
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