Dose-dependent suppression of norepinephrine appearance rate in plasma by clonidine in man

Clonidine is an alpha 2-receptor agonist which lowers both blood pressure and plasma norepinephrine (NE) levels in man. To determine whether the clonidine-induced fall in plasma NE is due to decreased NE appearance into plasma or increased NE clearance from plasma, NE infusions [( 3H]NE; 15 microCi/m2 bolus and 0.35 microCi/m2 X min infusion) were performed in 10 normal subjects, aged 25-56 yr. Arterialized plasma samples were obtained for measurements of steady state [3H]NE specific activity and plasma NE to allow calculation of plasma NE appearance rate and NE clearance before and 120-140 min after 1.5 and 5.0 micrograms/kg oral clonidine. Using an identical protocol, responses were compared in 4 subjects after placebo administration. Clonidine produced a dose-related reduction in mean arterial blood pressure, but no significant change in heart rate. The basal supine plasma NE concentration of 204 +/- 21 pg/ml (mean +/- SEM) fell by 27% (P less than 0.02) after low dose clonidine and by 51% (P less than 0.001) after high dose clonidine. There was no change in plasma epinephrine levels. The basal plasma NE appearance rate of 0.25 +/- 0.03 microgram/m2 X min was reduced by 32% (P less than 0.01) after low dose clonidine and by 52% (P less than 0.001) after high dose clonidine. The basal plasma NE clearance of 1.2 +/- 0.08 liters/m2 X min was unchanged after clonidine treatment. There was no change in mean plasma NE levels, plasma NE appearance rate, or mean arterial pressure after placebo administration. These findings demonstrate that the clonidine-induced fall in plasma NE levels is due to a dose-dependent suppression of plasma NE appearance rate and provide evidence for alpha 2-adrenergic inhibition of sympathetic nervous system activity in normotensive subjects.