The effect of norepinephrine on exogenous vasopressin antidiuresis was investigated in water-loaded subjects. After an initial 2 to 3 hr period of water loading (phase 1), 10-100 mU of vasopressin per hr were infused at a constant rate for 1 hr (phase 2) followed by infusion of 10-100 mU of vasopressin per hr plus 600 mug of l-norepinephrine per hr for 1 hr (phase 3). Endogenous creatinine clearance, osmolal clearance, and free water clearance (in milliliters/minute) and sodium and chloride excretion (in milliequivalents/minute) were measured. In 10 subjects given 10-20 mU of vasopressin per hr during phases 2 and 3, free water clearance decreased significantly from phase 1 to phase 2 (9.3 to 0.15, P = 0.001) and increased during phase 3 norepinephrine infusion to 4.7 ml/min (P = 0.001). A comparable decrease in phase 2 free water clearance was observed in four subjects given 50 or 100 mU of vasopressin per hr during phases 2 and 3 (P < 0.01); however, the phase 3 norepinephrine infusion in these subjects was not associated with an increase in free water clearance. Creatinine clearance, osmolal clearance, and sodium and chloride excretion were unchanged throughout the studies in both groups of subjects.A two phase study in seven subjects confirmed that 10, 20, or 75 mU of vasopressin per hr susstained antidiuresis during phase 2 for at least 2 hr and that free water clearance values were essentially constant in the individual subject after the first 30 min of infusion. The magnitude of the (phase 3) norepinephrine-induced increase in free water clearance (4.5 +/- 0.64 ml/min) during infusion of 10-20 mU of vasopressin per hr, the failure of norepinephrine to increase free water clearance during infusion of 50-100 mU of vasopressin per hr, and the relatively constant endogenous creatinine and osmolal clearance rates would suggest that the norepinephrine inhibition of vasopressin antidiuresis was not the result of alterations in renal blood flow. A post-phase 3 infusion of vasopressin in four subjects resulted in a marked decrease in free water clearance, indicating that the norepinephrine inhibition of vasopressin antidiuresis was not accountable on the basis of decreased medullary hypertonicity. These data support the hypothesis that catecholamine blocks the cellular mechanism of vasopressin antidiuresis in vivo. The observation that norepinephrine did not inhibit the antidiuresis produced by the infusion of 50 or 100 mU of vasopressin per hr suggests that this inhibition might be competitive. A possible role of catecholamine in the mechanism of cold diuresis is suggested.