Enhancing glucose oxidation In Vitro restores depressed transient outward K+ current (Ito) in ventricular myocytes from diabetic rats

Zhi Xu, Kaushik P. Patel, George J. Rozanski

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Abstract

The aim of this study was to examine the effects of increasing glucose oxidation on cardiac K+ channel function in experimental diabetes mellitus induced by streptozotocin. Ito and inward rectifier (Ikl) K+ currents were recorded by the whole cell voltage-clamp technique in ventricular myocytes isolated from the hearts of 2- to 4-wk diabetic and age-matched control rats. Under basal recording conditions, Ito density and kinetics of inactivation (τ2) at +60 mV were ∼30% and ∼50% less in diabetics (n=23) than in control (n=22, P < 0.01), whereas Ikl was not altered. We separately tested two structurally different compounds that increase glucose oxidation: insulin and dichloroacetate (DCA). These agents had no effect on Ikl in either group of cells. However, each completely normalized Ito channel activity in myocytes from diabetic rats. Mean Ito density and τ2 al +60 mV after 4 h treatment arc summarized as follows: INSULIN DCA Untreated 0.01μM 0.1μM C+0.1μM Untreated 0.15mM 1.5mM C+1.5mM (n=12) (n=7) (n=16) (n=8) (n=12) (n=6) (n=9) (n=8) I1 (pA/pK)18.5±1.4 23.2±4.7 26.3±2.1* 26.4±4.1* 18.5±1.4 22.3±3.9 26.1±2.1* 27.6±4.7* τ2 (ms) 111±15 153±59 213±50* 228±35* 110±16 214±56 236±54* 238±35* * p<0.05 vs. untreated diabetics. C = control myocytes. n = number of myocytes. The time course of normalization of Ito density in diabetic myocytes was also examined at hourly intervals After exposure to insulin or DCA, mean Ito density started to increase at 1-2 h, and was totally normalized after 2-3 h. Moreover, 3-bromopyruvate, an inhibitor of glucose oxidation, significantly reduced maximum Ito density in normal myocytes after 6-8 h exposure (25.6±3.3 pA/pF for untreated vs. 16.3±1.5 pA/pF at 1μM, and 12.1±2.0 pA/pF at 10 μM, n=12, p<0.05). These findings suggest that depressed glucose metabolism in the diabetic heart may be a key factor underlying the suppression of Ito channel activity, which may contribute to the contractile derangements and propensity for arrhythmias associated with diabetic cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)A495
JournalFASEB Journal
Volume11
Issue number3
StatePublished - Dec 1 1997

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ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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