Up-regulation of K + channels in diabetic rat ventricular myocytes by insulin and glutathione

Zhi Xu, Kaushik P Patel, Marjorie F. Lou, George J Rozanski

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Objective: The cardiac pathogenesis of diabetes mellitus involves oxidative stress that elicits profound changes in myocardial glutathione, an endogenous regulator of cell function. This study examined the role of glutathione in regulating K + channel activity in isolated ventricular myocytes from diabetic rats and its relationship to insulin signaling. Methods and results: Colorimetric analysis of extracts of ventricular tissue from Sprague-Dawley rats showed that the basal level of reduced glutathione (GSH) was significantly less in rats with experimental diabetes compared with sham controls, consistent with oxidative stress conditions. This change in GSH status paralleled a significant decrease in the activity of γ-glutamylcysteine synthetase, a major pathway involved in GSH homeostasis. Voltage-clamp studies confirmed that, compared with control myocytes, K + channels carrying the transient outward current (I to ) are down-regulated in the diabetic state and that this electrophysiological change is reversed by in vitro treatment with insulin for 2-3 h. Incubation of diabetic rat myocytes with GSH also normalized I to density compared with untreated myocytes, but with a longer time course than insulin. To determine if up-regulation of I to by insulin was mediated by alterations in myocyte GSH, insulin-responsiveness of diabetic rat myocytes was tested in the presence of 1,3-bis-chloroethyl-nitrosourea, an inhibitor of glutathione reductase, or buthionine sulfoximine, a blocker of γ-glutamylcysteine synthetase. Neither blocker alone altered I to density in diabetic rat myocytes when compared with untreated cells, but each blocked the effect of insulin to up-regulate I to . Conclusions: These data suggest that oxidative stress-induced alteration in GSH redox state plays an important role in regulating I to channel function and that GSH homeostasis in ventricular myocytes is functionally coupled to insulin signaling.

Original languageEnglish (US)
Pages (from-to)80-88
Number of pages9
JournalCardiovascular research
Volume53
Issue number1
DOIs
StatePublished - Jan 10 2002

Fingerprint

Muscle Cells
Glutathione
Up-Regulation
Insulin
Glutamate-Cysteine Ligase
Oxidative Stress
Homeostasis
Buthionine Sulfoximine
Tissue Extracts
Glutathione Reductase
Oxidation-Reduction
Sprague Dawley Rats
Diabetes Mellitus

Keywords

  • Diabetes
  • Free radicals
  • K channel
  • Myocytes
  • Repolarization

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Up-regulation of K + channels in diabetic rat ventricular myocytes by insulin and glutathione . / Xu, Zhi; Patel, Kaushik P; Lou, Marjorie F.; Rozanski, George J.

In: Cardiovascular research, Vol. 53, No. 1, 10.01.2002, p. 80-88.

Research output: Contribution to journalArticle

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