In normal subjects, beta-adrenergic stimulation lowers the serum potassium, whereas alpha-stimulation raises it. Epinephrine, a mixed alpha and beta agonist, acutely lowers the blood potassium in normal subjects, but not in patients with end-stage renal disease. This study was designed to determine whether the resistance to the hypokalemic effect of epinephrine in dialysis patients is due to a blunted beta-adrenergic response, or to an augmented alpha-adrenergic response. The infusion of epinephrine at low doses (0.01 μg/kg/min) produced a significant increase in serum potassium in hemodialysis patients (+0.21 ± 0.07 mmol/liter, P < 0.05), as compared to a nonsignificant decrease (-0.06 ± 0.04 mmol/liter) in normal subjects. Epinephrine at high physiologic doses (0.04 μg/kg/min) failed to significantly change the serum potassium in the dialysis patients (-0.10 ± 0.14 mmol/liter), but substantially lowered serum potassium in the controls (-0.64 ± 0.10 mmol/liter, P < 0.001). There was no significant correlation (r = 0.03) between the baseline serum potassium concentration and the magnitude of change during epinephrine infusion. Epinephrine infusion (0.04 μg/kg/min) during beta-blockade with propranolol produced a greater rise in serum potassium in the dialysis patients as compared to the controls (+0.69 ± 0.11 vs. +0.32 ± 0.11 mmol/liter, P < 0.05). Epinephrine infusion (0.01 μg/kg/min) during alpha-blockade with phentolamine resulted in similar changes in serum potassium in dialysis patients and in normal control (-0.10 ± 0.12 vs. -0.10 ± 0.06 mmol/liter). Moreover, phentolamine reversed the increase in serum potassium observed in dialysis patients during the infusion of epinephrine following beta-blockade. These results suggest that hemodialysis patients have an impaired extrarenal clearance of potassium in response to epinephrine, that is attributable to an enhanced hyperkalemic response to alpha-adrenergic stimulation.