A metabolic mechanism for cardiac K+ channel remodelling

George J. Rozanski, Zhi Xu

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

1. Electrical remodelling of the ventricle is a common pathogenic feature of cardiovascular disease states that lead to heart failure. Experimental data suggest this change in electrophysiological phenotype is largely due to downregulation of K+ channels involved in repolarization of the action potential. 2. Voltage-clamp studies of the transient outward current (Ito) in diabetic cardiomyopathy support a metabolic mechanism for K+ channel downregulation. In particular, Ito density is significantly increased in diabetic rat isolated ventricular myocytes treated in vitro with insulin or agents that activate pyruvate dehydrogenase. Recent data suggest this mechanism is not limited to diabetic conditions, because metabolic stimuli that upregulate Ito in diabetic rat myocytes act similarly in nondiabetic models of heart failure. 3. Depressed Ito channel activity is also reversed by experimental conditions that increase myocyte levels of reduced glutathione, indicating that oxidative stress is involved in electrical remodelling. Moreover, upregulation of Ito density by activators of glucose utilization is blocked by inhibitors of glutathione metabolism, supporting the premise that there is a functional link between glucose utilization and the glutathione system. 4. Electrophysiological studies of diabetic and non-diabetic disease conditions affecting the heart suggest Ito channels are regulated by a redox-sensitive mechanism, where glucose utilization plays an essential role in maintaining a normally reduced state of the myocyte. This hypothesis has implications for clinical approaches aimed at reversing pathogenic electrical remodelling in a variety of cardiovascular disease states.

Original languageEnglish (US)
Pages (from-to)132-137
Number of pages6
JournalClinical and Experimental Pharmacology and Physiology
Volume29
Issue number1-2
DOIs
StatePublished - 2002

Keywords

  • Glucose metabolism
  • Glutathione
  • Heart
  • Insulin
  • Potassium channels
  • Pyruvate dehydrogenase
  • Redox

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

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