The cardiac inward rectifier K+ current, IK1, plays an important role in stabilising resting membrane potential and shaping the action potential, thus controlling cellular excitability. IK1 has been implicated in the genesis of arrhythmias in heart failure (Pogwidz et al., 2001). In the present study we have investigated IK1 function and expression in ventricular myocytes of a sheep model of heart failure. Animals were anaesthetised with isoflurane (1-3% in oxygen) and perioperative analgesia provided (meloxicam 0.5mg/kg).Two pacemaker leads were implanted into the right ventricle of adult sheep. Following recovery, pacing was initiated at 210bpm for 4 weeks. Heart failure was assessed by echocardiography and in all cases ventricular chamber dilatation and decreased contractility were observed. Cells were isolated from the mid-myocardial region of the left ventricle by enzymatic digestion. IK1 was measured by voltage clamp at 37°C. Considering all data together, rapid-pacing had no effect on peak IK1 (-9.73 ± 0.67 pA/pF in control vs -8.62 ± 0.86 pA/pF in heart failure at -130mV, n = 18 and 30, respectively). However, in some animals IK1 amplitude was dramatically reduced (circa 69%). In a separate series of experiments, action potential duration was measured. In those cells where IK1 was markedly reduced, APD was greatly increased. This suggests a threshold above which the reduction in IK1 correlates with an increase in action potential duration (APD). In addition, fractional inactivation of IK1 was increased in heart failure suggesting molecular remodelling (0.21 ± 0.02 vs 0.39 ± 0.05, P<0.05, t-test, n = 18 and 30, respectively). In the sheep, IK1 is comprised of Kir2.1 and 2.3 subunits. Western blotting detected a decrease in expression of Kir2.3 protein (2.3 ± 0.19 vs 1.36 ± 0.06, P<0.05, t-test, n = 18 and 30, respectively). The relationship between IK1 and APD in this rapid-pacing model suggests that IK1 remodelling is a causative factor for the prolongation of the APD. Consequently, this may contribute to the increased propensity for arrhythmias in heart failure.