Age-associated increase in salt sensitivity is accompanied by a shift in the atrial natriuretic peptide modulation of the effect of marinobufagenin on renal and vascular sodium pump

Background: Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG. Methods: In younger (3-month-old) and older (12-month-old) Sprague–Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and &agr;-ANP at baseline and following acute NaCl loading (20%, 2.5 ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by &agr;-ANP in vitro. Results: As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10 mmHg, P < 0.01) and greater inhibition of NKA in aorta (39 vs. 7%, P < 0.01), 30% less natriuresis, and less inhibition of renal NKA (25 vs. 42%, P < 0.05) in the presence of comparable responses of &agr;-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and &agr;-ANP failed to modulate MBG-induced NKA inhibition. Conclusion: Age-associated downregulation of cGMP/PKG-dependent signaling impairs the ability of ANP to modulate the effects of MBG on the sodium pump, which contributes to salt sensitivity.

[1]  S. Haller,et al.  Monoclonal antibody against marinobufagenin reverses cardiac fibrosis in rats with chronic renal failure. , 2012, American journal of hypertension.

[2]  Erika Salvi,et al.  Genes Involved in Vasoconstriction and Vasodilation System Affect Salt-Sensitive Hypertension , 2011, PloS one.

[3]  E. Silva,et al.  Renal aging in WKY rats: Changes in Na+,K+-ATPase function and oxidative stress , 2010, Experimental Gerontology.

[4]  J. Shapiro,et al.  Endogenous cardiotonic steroids and salt-sensitive hypertension. , 2010, Biochimica et biophysica acta.

[5]  K. Yamagishi,et al.  Relationship of urinary cGMP excretion with aging and menopausal status in a general population. , 2009, Journal of atherosclerosis and thrombosis.

[6]  O. Fedorova,et al.  Endogenous cardiotonic steroids and differential patterns of sodium pump inhibition in NaCl-loaded salt-sensitive and normotensive rats. , 2009, American journal of hypertension.

[7]  J. Shapiro,et al.  Endogenous Cardiotonic Steroids: Physiology, Pharmacology, and Novel Therapeutic Targets , 2009, Pharmacological Reviews.

[8]  E. Lakatta,et al.  Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension , 2008, Journal of hypertension.

[9]  C. Scavone,et al.  Age-related changes in cerebellar phosphatase-1 reduce Na,K-ATPase activity , 2008, Neurobiology of Aging.

[10]  David E. Anderson,et al.  Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[11]  E. Frohlich,et al.  The aging hypertensive heart: a brief update , 2008, Nature Clinical Practice Cardiovascular Medicine.

[12]  A. Richards,et al.  Natriuretic Peptides: Update on Peptide Release, Bioactivity, and Clinical Use , 2007, Hypertension.

[13]  E. Lakatta,et al.  ANP Differentially Modulates Marinobufagenin-Induced Sodium Pump Inhibition in Kidney and Aorta , 2006, Hypertension.

[14]  N. Maeda,et al.  The role of natriuretic peptides in cardioprotection. , 2006, Cardiovascular research.

[15]  E. Lakatta,et al.  Brain ouabain stimulates peripheral marinobufagenin via angiotensin II signalling in NaCl-loaded Dahl-S rats , 2005, Journal of hypertension.

[16]  C. Scavone,et al.  Age-related changes in cyclic GMP and PKG-stimulated cerebellar Na,K-ATPase activity , 2005, Neurobiology of Aging.

[17]  E. Lakatta,et al.  Myocardial PKC &bgr;2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension , 2003, Hypertension.

[18]  E. Lakatta,et al.  Marinobufagenin, an endogenous ligand of alpha-1 sodium pump, is a marker of congestive heart failure severity , 2002, Journal of hypertension.

[19]  E. Lakatta,et al.  Endogenous Ligand of &agr;1 Sodium Pump, Marinobufagenin, Is a Novel Mediator of Sodium Chloride–Dependent Hypertension , 2002, Circulation.

[20]  J. Bełtowski,et al.  Regulation of renal tubular sodium transport by cardiac natriuretic peptides: two decades of research. , 2002, Medical science monitor : international medical journal of experimental and clinical research.

[21]  T. Lue,et al.  Age-related decrease of protein kinase G activation in vascular smooth muscle cells. , 2001, Biochemical and biophysical research communications.

[22]  P. Greengard,et al.  INCREASED BLOOD PRESSURE AND LOSS OF ANP-INDUCED NATRIURESIS IN MICE LACKING DARPP-32 GENE , 2001, Clinical and experimental hypertension.

[23]  E. Lakatta,et al.  Endogenous Na,K Pump Ligands Are Differentially Regulated During Acute NaCl Loading of Dahl Rats , 2000, Circulation.

[24]  C. Bailly Effect of luminal atrial natriuretic peptide on chloride reabsorption in mouse cortical thick ascending limb: inhibition by endothelin. , 2000, Journal of the American Society of Nephrology : JASN.

[25]  Orton,et al.  EFFECTS ON BLOOD PRESSURE OF REDUCED DIETARY SODIUM AND THE DIETARY APPROACHES TO STOP HYPERTENSION ( DASH ) DIET , 2000 .

[26]  H. Fotis,et al.  Phosphorylation of the alpha-subunits of the Na+/K+-ATPase from mammalian kidneys and Xenopus oocytes by cGMP-dependent protein kinase results in stimulation of ATPase activity. , 1999, European journal of biochemistry.

[27]  G. Blanco,et al.  Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function. , 1998, American journal of physiology. Renal physiology.

[28]  K. Sweadner,et al.  Phosphorylation of Na,K-ATPase by Protein Kinase C at Ser18 Occurs in Intact Cells but Does Not Result in Direct Inhibition of ATP Hydrolysis* , 1997, The Journal of Biological Chemistry.

[29]  M. Omata,et al.  Elevation of ouabainlike compound levels with hypertonic sodium chloride load in rat plasma and tissues. , 1997, Hypertension.

[30]  A. Cowley,et al.  Genetic and nongenetic determinants of salt sensitivity and blood pressure. , 1997, The American journal of clinical nutrition.

[31]  T. Ogihara,et al.  [Bartter syndrome]. , 2020, Nihon rinsho. Japanese journal of clinical medicine.

[32]  P. Greengard,et al.  Activation/deactivation of renal Na+,K+‐ATPase: a final common pathway for regulation of natriuresis , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  C. Frampton,et al.  Renal, endocrine, and hemodynamic interactions of atrial and brain natriuretic peptides in normal men. , 1994, The American journal of physiology.

[34]  E. Barrett-Connor,et al.  Increasing sensitivity of blood pressure to dietary sodium and potassium with increasing age. A population study using casual urine specimens. , 1990, American journal of hypertension.

[35]  J. F. Hennessy Vascular tissue (Na,K)ATPase activity and aging in the F344 rat , 1988, Mechanisms of Ageing and Development.