The aim of the present study was to define the cellular mechanisms underlying changes in K+ channel function in the failing heart after myocardial infarction. Rats with left coronary artery ligation were prepared and allowed to recover for 16 wk before study. Animals with chronic infarction exhibited marked cardiac hypertrophy and signs of heart failure, as indicated by a nearly twofold increase in heart weight- and lung weight-to-body weight ratios, respectively, compared with time-matched controls. Cardiac hypertrophy was also evident by a 49% increase in whole cell capacitance of isolated left ventricular myocytes (P < 0.05). Voltage-clamp experiments revealed that the maximum density of the Ca(2+)-independent, transient outward current (I.t.o.), measured at +60 mV, was 42% less in myocytes from infarcted hearts than in myocytes from control hearts (P < 0.05), whereas the inward rectifier current (IK1) density was not different between groups. The reduced Ito density in the infarcted group was reversed, however, in 4-5 h by treatment with exogenous dichloroacetate or pyruvate, both activators of pyruvate dehydrogenase. Moreover, control myocytes incubated for 6 h in the presence of an inhibitor of pyruvate dehydrogenase, 3-bromopyruvate, exhibited a concentration-dependent decrease in Ito density compared with untreated cells. The present data demonstrate that Ito density is reversibly decreased in surviving myocytes from infarcted hearts and suggest that mechanisms related to glucose metabolism via pyruvate dehydrogenase may be involved. These postinfarction changes in myocyte Ito channel function may relate to impaired contractility and arrhythmogenesis, which are characteristic of the intact, failing heart.