Our laboratory is interested in the physiological role of the Na,K-ATPase, particularly the function of the different alpha isoforms of this enzyme. The present application is directed toward understanding role of the Na,K-ATPase and its cardiac glycoside binding site in regulation of blood pressure during pregnancy. In addition, we have developed mice where the alpha2 Na,K-ATPase isoform gene is specifically deleted in lung to evaluate the role of this isoform in alveolar fluid clearance. These animals survive and show an interesting phenotype during lung injury. With respect to our goal of understanding the role of the Na,K-ATPase cardiac glycoside binding site during pregnancy, we have recently demonstrated that this cardiac glycoside binding site, which is conserved during evolution, plays a role in the development of hypertension. We have genetically engineered animals where the alpha2 isoform of the Na,K-ATPase, which is normally sensitive to cardiac glycosides, is resistant to these compounds, specifically to ouabain, digoxin and digitoxin. Interestingly, while wild type animals develop hypertension in response to glucocorticotropic hormone stimulation, targeted animals do not. This indicates that the cardiac glycoside binding site of the Na,K- ATPase plays a physiological role and that a naturally occurring ligand must exist that interacts with this site. In fact, endogenous cardiac glycoside-like compounds have been identified in mammals and they are the most logical candidates for the natural ligand of the Na,K-ATPase. They are elevated in number of pathological conditions, such as hypertension, as well as non-pathological conditions where the regulation of blood pressure is important, such as pregnancy. Our preliminary data indicate that the cardiac glycoside binding site plays a role in the regulation of blood pressure during pregnancy. Specifically, the ouabain-resistant alpha2 isoform mice exhibit lower blood pressure than wild type control littermates during pregnancy. In the present proposal we will investigate this phenomenon and define the mechanism by which the ouabain binding site of Na,K-ATPase regulates maternal blood pressure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Evans, Frank
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University of Cincinnati
Schools of Medicine
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Radzyukevich, Tatiana L; Neumann, Jonathon C; Rindler, Tara N et al. (2013) Tissue-specific role of the Na,K-ATPase ?2 isozyme in skeletal muscle. J Biol Chem 288:1226-37
Rindler, Tara N; Lasko, Valerie M; Nieman, Michelle L et al. (2013) Knockout of the Na,K-ATPase ?2-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol 304:H1147-58
Lorenz, John N; Oshiro, Naomi; Loreaux, Elizabeth L et al. (2012) DOCA-salt hypertension does not require the ouabain-sensitive binding site of the ?2 Na,K-ATPase. Am J Hypertens 25:421-9
Despa, Sanda; Lingrel, Jerry B; Bers, Donald M (2012) Na(+)/K)+)-ATPase ?2-isoform preferentially modulates Ca2(+) transients and sarcoplasmic reticulum Ca2(+) release in cardiac myocytes. Cardiovasc Res 95:480-6
Schaefer, Tori L; Lingrel, Jerry B; Moseley, Amy E et al. (2011) Targeted mutations in the Na,K-ATPase ? 2 isoform confer ouabain resistance and result in abnormal behavior in mice. Synapse 65:520-31
Rindler, Tara N; Dostanic, Iva; Lasko, Valerie M et al. (2011) Knockout of the Na,K-ATPase ýýýýý-isoform in the cardiovascular system does not alter basal blood pressure but prevents ACTH-induced hypertension. Am J Physiol Heart Circ Physiol 301:H1396-404
Lorenz, John N; Lasko, Valerie M; Nieman, Michelle L et al. (2011) Renovascular hypertension using a modified two-kidney, one-clip approach in mice is not dependent on the *1 or *2 Na-K-ATPase ouabain-binding site. Am J Physiol Renal Physiol 301:F615-21
Wansapura, Arshani N; Lasko, Valerie M; Lingrel, Jerry B et al. (2011) Mice expressing ouabain-sensitive ?1-Na,K-ATPase have increased susceptibility to pressure overload-induced cardiac hypertrophy. Am J Physiol Heart Circ Physiol 300:H347-55
DeAndrade, Mark P; Yokoi, Fumiaki; van Groen, Thomas et al. (2011) Characterization of Atp1a3 mutant mice as a model of rapid-onset dystonia with parkinsonism. Behav Brain Res 216:659-65
Lingrel, Jerry B (2010) The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na,K-ATPase. Annu Rev Physiol 72:395-412

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