The purpose of this study was to investigate whether sympathetic stimulation modulated the rise in extracellular K+concentration ([K+]0) evoked by acute myocardial ischemia. In 35 α-chloralose-anesthetized dogs, we measured changes in [K+]Oduring acute myocardial ischemia in the presence and absence of sympathetic stimulation or norepinephrine infusion. A series of four 5 -minute occlusions of the distal left anterior descending coronary artery (LAD) was completed in 18 dogs. Thirty minutes of reperfusion separated each LAD occlusion. Four to five K+-sensitive electrodes were inserted into the left ventricular midmyocardium that was perfused by the distal LAD. Lead II of the electrocardiogram, arterial pressure, and [K+]0were recorded, and the right atrium was paced at a constant cycle length. The first, second, and fourth LAD occlusions were done in the absence of sympathetic stimulation or norepinephrine infusion. The changes in [K+]Oevoked by the first LAD occlusion differed (p<0.05) from those elicited by the second and fourth occlusions. However, the changes in [K+]0during the second and fourth LAD occlusions were similar (p>0.2) and served as controls for the responses obtained during the third occlusion. Two minutes before the third LAD occlusion, sympathetic stimulation (4 Hz) or norepinephrine infusion (0.25–0.5 μg/kg per minute i.v.) was begun and was continued until 2 minutes after reperfusion. We found that sympathetic stimulation and norepinephrine infusion increased (p<0.05) myocardial blood flow in both normal and ischemic tissue. The mean response recorded by 23 K+-sensitive electrodes in 11 dogs showed that sympathetic stimulation increased (p<0.001) the [K+]0at 1,2,3,4, and 5 minutes after the onset of LAD occlusion compared with the second and fourth occlusions. In contrast, the mean response recorded by 20 K+-sensitive electrodes in seven dogs showed that norepinephrine infusion reduced (p<0.02) the [K+]0at 4 and 5 minutes after the onset of LAD occlusion. These data show that sympathetic stimulation increased the [K+]0evoked by acute myocardial ischemia, an effect that was not mimicked by the intravenous administration of norepinephrine.