title: Metabolic control of sodium transport in streptozotocin-induced diabetic rat hearts.
abstract: Diabetic and control cardiomyocytes encapsulated in agarose beads and superfused with modified medium 199 were studied with 23Na- and 31P-NMR. Baseline intracellular Na+ was higher in diabetic (0.076 +/- 0.01 micromoles/mg protein) than in control (0.04 +/- 0.01 micromoles/mg protein) (p < 0.05). Baseline betaATP and phosphocreatine (PCr) (peak area divided by the peak area of the standard, methylene diphosphonate) were lower in diabetic than in control, e.g., betaATP control, 0.70 +/- 0.07; betaATP diabetic, 0. 49 +/- 0.04 (p < 0.027); PCr control, 1.20 +/- 0.13; PCr diabetic, 0. 83 +/- 0.11 (p < 0.03). This suggests that diabetic cardiomyocytes have depressed bioenergetic function, which may contribute to abnormal Na,K-ATPase function, and thus, an increase in intracellular Na+. In the experiments presented herein, three interventions (2-deoxyglucose, dinitrophenol, or ouabain infusions) were used to determine whether, and the extent to which, energy deficits or abnormalities in Na,K-ATPase function contribute to the increase in intracellular Na+. In diabetic cardiomyocytes, 2-deoxyglucose and ouabain had minimal effect on intracellular Na+, suggesting baseline depression of, or resetting of both glycolytic and Na,K-ATPase function, whereas in control both agents caused significant increases in intracellular Na+after 63 min exposure: 2-deoxyglucose control, 32.9 +/- 8.1%; 2-deoxyglucose diabetic, -4.6 +/- 6% (p < 0.05); ouabain control, 50.5 +/- 8.8%; ouabain diabetic, 21.2 +/- 9.2% (p < 0.05). In both animal models, dinitrophenol was associated with large increases in intracellular Na+: control, 119.0 +/- 26.9%; diabetic, 138.2 +/- 12.6%. Except for the dinitrophenol intervention, where betaATP and PCr decreased to levels below 31P-NMR detection, the energetic metabolites were not lowered to levels that would compromise sarcolemmal function (Na,K-ATPase) in either control or diabetic cardiomyocytes. In conclusion, in diabetic cardiomyocytes, even though abnormal glycolytic and Na, K-ATPase function was associated with increases in intracellular Na+, these increases were not directly related to global energy deficit.
authors.affiliation: Biochemistry/Biophysics Department, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Doliba
authors.forename: A M
authors.initials: AM
authors.lastname: Babsky
authors.forename: S L
authors.initials: SL
authors.lastname: Wehrli
authors.forename: T M
authors.initials: TM
authors.lastname: Ivanics
authors.forename: M F
authors.initials: MF
authors.lastname: Friedman
authors.forename: M D
authors.initials: MD
authors.lastname: Osbakken
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001692:Biological Transport; D016022:Case-Control Studies; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D010477:Perfusion; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013311:Streptozocin; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000963:Antimetabolites; D004791:Enzyme Inhibitors; D014475:Uncoupling Agents; D010042:Ouabain; D013311:Streptozocin; D003847:Deoxyglucose; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D019297:2,4-Dinitrophenol