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Role of the Ouabain-Binding Site of Na,K-ATPase in Saline Loading and DOCA-Salt Hypertension

Loreaux, Elizabeth L.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1213990314

Abstract Details

2008, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry, and Microbiology.
Na,K-ATPase is ubiquitously expressed and is essential for maintaining electrochemical and osmotic gradients. The α subunit of Na,K-ATPase is the receptor for cardiotonic steroids which act through the ouabain-binding site and have been shown to be important in cardiovascular regulation. Interestingly, the presence of endogenous Na,K-ATPase ligands have been implicated in the natriuretic response to such perturbations as hypertension and salt loading, and it is therefore important to characterize the role of the ouabain-binding sites in this context. In most species, all α isoforms are sensitive to ouabain inhibition, an exception being the ubiquitously expressed α1 isoform of mice and rats, which is relatively ouabain-resistant. We used gene-targeted mice with reversed ouabain-sensitivity or -resistance of the α1 and/or α2 isoforms to investigate the contribution of this binding site to the natriuretic response to saline loading and to the development of DOCA-salt induced hypertension.We found that the natriuretic response to acute salt loading was altered in mice expressing the sensitive α1 isoform. The data show that, regardless of the sensitivity of the α2 isoform, conferring ouabain-sensitivity to the α1 isoform augmented the natriuretic response to acute salt load relative to controls. Additionally, when endogenous Na,K-ATPase inhibitors were sequestered with an anti-digoxin antibody fragment, Na+ excretion rates in the α1-sensitive isoform mice did not increase above levels seen in animals expressing the resistant α1 isoform. Since renal tubular epithelial cells express only the α1 isoform, these data provide convincing evidence that the ouabain-binding site of the Na,K-ATPase α1 isoform can participate in the natriuretic response to salt load through responding to endogenous Na,K-ATPase ligands. In the second study, we sought to determine whether the development of DOCA-salt hypertension is altered in mice expressing the ouabain-resistant α2 (α2R/R) isoform, which was previously shown to have a blunted response to ACTH-induced hypertension. Wild type mice and those expressing the α2R/R isoform were uninephrectomized and instrumented with telemetry implants for the continuous measurement of blood pressure. After recovery, DOCA pellets were implanted and animals were given saline to drink. Mean arterial pressure increased comparably in both groups. In separate groups of DOCA-salt treated mice instrumented with indwelling arterial catheters, treatment with an anti-digoxin antibody had no effect on blood pressure regardless of genotype. We also evaluated DOCA-salt hypertension in mice expressing a ouabain-sensitive α1 isoform and found that blood pressure increased similarly to the other two genotypes. These data suggest that the elevated pressure in DOCA-salt treated mice is not dependent on the interaction of endogenous Na,K-ATPase inhibitors with the α1 or α2 isoforms of Na,K-ATPase.
Jerry Lingrel, PhD (Committee Chair)
John Lorenz, PhD (Committee Member)
Gary Shull, PhD (Committee Member)
William Miller, PhD (Committee Member)
Rodney Dekoter, PhD (Committee Member)
107 p.
Biomedical Research
Na,K-ATPase; ouabain-binding site; natriuresis; DOCA-salt hypertension

Recommended Citations

Citations

  • Loreaux, E. L. (2008). Role of the Ouabain-Binding Site of Na,K-ATPase in Saline Loading and DOCA-Salt Hypertension [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1213990314

    APA Style (7th edition)

  • Loreaux, Elizabeth. Role of the Ouabain-Binding Site of Na,K-ATPase in Saline Loading and DOCA-Salt Hypertension. 2008. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1213990314.

    MLA Style (8th edition)

  • Loreaux, Elizabeth. "Role of the Ouabain-Binding Site of Na,K-ATPase in Saline Loading and DOCA-Salt Hypertension." Doctoral dissertation, University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1213990314

    Chicago Manual of Style (17th edition)

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