OF WORK Many factors involved in the pathogenesis of NaCl sensitive hypertension remain to be clarified, including mechanisms of dysregulation of the Na/K pump (NKP). Previous studies in our laboratory have shown that two endogenous ligands of Na/K ATPase (NKA), ouabain-like factor (OLC) and marinobufagenin (MBG) exhibit vasoconstrictor activity, and are responsive to saline loading and plasma volume expansion (VE). At the same time, OLC and MBG differ with respect to effective stimuli to increase and their time courses, and their targets ( -3 and -1 isoforms of the sodium pump). During the current year we have completed two projects studying digitalis-like factors (DLF) in rats, during acute VE, and during a combination of high salt intake and isolation stress. In VE, OLC increased in the pituitary, while MBG rose in plasma. In the second, chronic experiment, in rats exposed to isolation stress, the excretion of OLC but not MBG was stimulated. Conversely, plasma MBG, but not OLC was responsive to a high NaCl diet. Both procedures alone did not affect the blood pressure (BP). At the same time, the combination of high NaCl diet with isolation stress resulted in an initial response of OLC followed by a progressive increase in MBG excretion, which paralleled an increase in BP. The studies of combined action of DLFs were continued in Dahl hypertension, which resembles salt hypertension in humans in many aspects. The first experiment showed that acute salt loading of both Dahl salt-sensitive (DS) and salt-resistant (DR) rats elicited similar DLF responses in both strains: an acute rise in OLC excretion followed by a slower rise in MBG, which paralleled the BP increase. However, chronic exposure of DS and DR to 4% and 8% NaCl diet revealed differences in the DLF responses: in DS, an initial transient rise of OLC was followed by a delayed but sustained rise in MBG, which paralleled a dramatic hypertensive response. No such DLF responses were observed in DR. In another study, in human mesenteric arteries, we have shown that distribution of NKA isoforms was different from that in rat vessels, both -1 and -3 subunit were present in sarcolemma and in nerve endings membranes. At nanomolar concentrations, MBG and OLC interacted with nerve endings NKA causing an apparent stimulation of NKP by norepinephrine, which overshadowed the inhibition of sarcolemmal NKP.Clinical studies have demonstrated increased plasma levels of MBG in volume-expanded states, such as essential hypertension, renal failure, and preeclampsia. Data on further characterization of plasma bufodienolide DLF are consistent with our previous results obtained with the urinary inhibitor.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000609-06
Application #
6097847
Study Section
Special Emphasis Panel (LCS)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Fedorova, Larisa V; Raju, Vanamala; El-Okdi, Nasser et al. (2009) The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition. Am J Physiol Renal Physiol 296:F922-34
Fedorova, Olga V; Simbirtsev, Andrey S; Kolodkin, Nikolai I et al. (2008) Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension. J Hypertens 26:2414-25
Kennedy, David J; Elkareh, Jihad; Shidyak, Amjad et al. (2008) Partial nephrectomy as a model for uremic cardiomyopathy in the mouse. Am J Physiol Renal Physiol 294:F450-4
Bagrov, Alexei Y; Shapiro, Joseph I (2008) Endogenous digitalis: pathophysiologic roles and therapeutic applications. Nat Clin Pract Nephrol 4:378-92
Kashkin, Vladimir A; Zvartau, Edwin E; Fedorova, Olga V et al. (2008) Endogenous bufadienolide mediates pressor response to ethanol withdrawal in rats. Eur Neuropsychopharmacol 18:74-7
Anderson, David E; Fedorova, Olga V; Morrell, Christopher H et al. (2008) Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives. Am J Physiol Regul Integr Comp Physiol 294:R1248-54
Fedorova, Olga V; Zhuravin, Igor A; Agalakova, Natalia I et al. (2007) Intrahippocampal microinjection of an exquisitely low dose of ouabain mimics NaCl loading and stimulates a bufadienolide Na/K-ATPase inhibitor. J Hypertens 25:1834-44
Elkareh, Jihad; Kennedy, David J; Yashaswi, Belvadi et al. (2007) Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy. Hypertension 49:215-24
Bagrov, Yakov Y; Manusova, Natalia B; Frolova, Elena V et al. (2007) Endogenous sodium pump inhibitors, diabetes mellitus and preeclampsia Preliminary observations and a hypothesis. Pathophysiology 14:147-51
Kennedy, David J; Vetteth, Sandeep; Periyasamy, Sankaridrug M et al. (2006) Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy. Hypertension 47:488-95

Showing the most recent 10 out of 35 publications