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 (I(to)) in diabetic cardiomyopathy support a metabolic mechanism for K(+) channel downregulation. In particular, I(to) 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 I(to) in diabetic rat myocytes act similarly in non- diabetic models of heart failure. 3. Depressed I(to) 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 I(to) 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 I(to) 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.