title: Sodium-hydrogen exchange inhibition attenuates glycoside-induced hypertrophy in rat ventricular myocytes.
abstract: OBJECTIVE
  Cardiac glycosides induce cardiomyocyte hypertrophy via yet to be defined mechanisms. These hypertrophic effects are likely related to changes in intracellular signalling secondary to Na(+)-K(+) ATPase (NKA) inhibition which would produce elevations in intracellular sodium concentrations. Sodium-hydrogen exchanger isoform 1 (NHE-1) also contributes to intracellular sodium regulation. Accordingly, we determined the contribution of NHE-1 to cardiac glycoside-induced hypertrophy.
  
  
  RESULTS
  The majority of the experiments were performed on cultured neonatal rat ventricular myocytes exposed to either ouabain (100 microM) or digoxin (40 microM) for 24 h, although additional experiments were also done using adult left ventricular myocytes with 30 microM of either glycoside. Both glycosides increased cell surface area by 30% and atrial natriuretic peptide gene expression by two- to three-fold (P < 0.05 for both). These effects were associated with a significant reduction in the expression of two NKA isoforms, alpha(2) and alpha(3), whereas the alpha(1) isoform was unaffected. Conversely, both glycosides increased NHE-1 expression in cardiomyocytes by approximately two-fold and significantly increased intracellular sodium concentrations by more than 60% (P < 0.05). Both ouabain and digoxin were also found to significantly increase phosphorylation of mitogen-activated protein kinases. All these effect were prevented when identical experiments were carried out in the presence of the NHE-1 inhibitors EMD 87580 or AVE 4890. Identical results were obtained using adult myocytes, although this was associated with downregulation of all three NKA isoforms. Glycoside-induced increase in cell shortening or intracellular Ca(2+) transients was not significantly affected by NHE-1 inhibition.
  
  
  CONCLUSIONS
  When taken together, these studies show that NHE-1 inhibition attenuates the hypertrophic effect of cardiac glycosides without affecting inotropic parameters and suggest a possible approach to limiting glycoside-induced hypertrophic responses while preserving therapeutic, i.e. inotropic, actions.
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, N6A 5C1.
authors.forename: Xiaohong Tracey
authors.initials: XT
authors.lastname: Gan
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Gong
authors.forename: Jenny
authors.initials: J
authors.lastname: Xue
authors.forename: James V
authors.initials: JV
authors.lastname: Haist
authors.forename: Donglin
authors.initials: D
authors.lastname: Bai
authors.forename: Morris
authors.initials: M
authors.lastname: Karmazyn
mesh_terms: D000818:Animals; D002301:Cardiac Glycosides / Q000633:toxicity*; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy*; D004077:Digoxin / Q000633:toxicity; D006352:Heart Ventricles; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000201:enzymology*; D010042:Ouabain / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics
chemical_list: D002301:Cardiac Glycosides; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D010042:Ouabain; D004077:Digoxin; D012964:Sodium; D020928:Mitogen-Activated Protein Kinases; D000254:Sodium-Potassium-Exchanging ATPase