The clearance of norepinephrine from plasma and the spillover rate of norepinephrine into plasma were determined in conscious unrestrained spontaneously hypertensive rats by measuring the concentrations of 3H-norepinephrine and norepinephrine in arterial plasma after 90 min of i.v. infusion with 3H-norepinephrine. In 50 conscious spontaneously hypertensive rats treated with saline (control animals), the following basal values were obtained: plasma norepinephrine concentration = 149 +/- 5 pg/ml; plasma epinephrine concentration = 61 +/- 4 pg/ml; norepinephrine clearance = 188 +/- 4 ml min-1 kg-1; and norepinephrine spillover rate = 27.5 +/- 0.8 ng min-1 kg-1. A significant portion of infused 3H-norepinephrine appeared to be cleared from the plasma by the uptake1 process, since desipramine decreased norepinephrine clearance by 32%. The vasodilating agents hydralazine and minoxidil produced dose-related increases in norepinephrine spillover rate and plasma norepinephrine concentration, but the percent increases in norepinephrine spillover rate exceeded the percent increases in plasma norepinephrine concentration because of concomitant increases in norepinephrine clearance, particularly after treatment with minoxidil. The increase in norepinephrine clearance caused by hydralazine and minoxidil probably resulted from the increase in cardiac output and resultant increase in hepatic and/or pulmonary blood flow. Adrenal secretion of norepinephrine did not appear to contribute to the elevation in norepinephrine spillover rate elicited by hydralazine and minoxidil. Chlorisondamine suppressed norepinephrine spillover rate by 77%, in association with a 70% decline in plasma epinephrine concentration, whereas bretylium lowered norepinephrine spillover rate by only 41%, with no change in plasma epinephrine concentration. The decrements in norepinephrine clearance caused by chlorisondamine (-23%) and bretylium (-15%) were more or less proportional to the magnitude of the vasodepression caused by these drugs. Both norepinephrine spillover rate and clearance fell in a dose-related fashion after treatment with clonidine. After treatment with the sympathoinhibitory agents chlorisondamine, bretylium and clonidine, the percent decreases in norepinephrine spillover rate always exceeded the percent decreases in plasma norepinephrine concentration. Based on these observations, we conclude that norepinephrine spillover rate provides a more accurate measurement of the activity of the peripheral sympathetic nervous system than does plasma norepinephrine concentration in conscious spontaneously hypertensive rats.