The left ansa subclavia was stimulated at supramaximal intensity at a frequency of Hz in open-chest, anaesthetized dogs for periods of about 10 min. Arterial blood pressure, myocardial contractile force, and coronary sinus blood flow reached peak values after 1 or 2 min of stimulation, and then declined gradually throughout the remainder of stimulation. In hearts that averaged 159 +/- 10 (SEM) g, the norepinephrine (NE) overflow rose to a peak value of 470 +/- 128 ng/min at the end of 1 min of sympathetic stimulation in the control animals. By the 10th min of stimulation, the NE overflow had diminished to 97 +/- 24 ng/min. In animals pretreated with cocaine (5 mg/kg) or with phenoxybenzamine (5 mg/kg), the peak NE overflow rates were 288 +/- 62 and 980 +/- 148 mg/min, respectively, and the rate of NE overflow declined to levels of 104 +/- 39 and 128 +/- 30 ng/min, respectively by the 10th min of stimulation. Since there was a profound, progressive diminution in the rate of NE overflow during sustained cardiac sympathetic stimulation regardless of whether or not NE reuptake was suppressed, it is concluded that the reduction in NE overflow reflects a curtailment of neuronal release of NE rather than an acceleration of reuptake.