Effect of Centrally Acting a-Adrenergic Agonists

Three studies were undertaken to reevaluate (1) whether there is a peripheral component in the reduction of sympathetic activity caused by centrally acting drugs; and (2) whether the antihypertensive effect of these drugs is due entirely to this reduction. Plasma growth hormone and norepinephrine concentrations were used as respective markers of central a-adrenoceptor stimulation and peripheral sympathetic activity. In six normal volunteers, intravenous infusion of 0.2 mg clonidine and 2 mg guanfacine was compared. The falls in systolic blood pressure and plasma norepinephrine concentration were slightly greater after clonidine (18 mm Hg and 0.22 ng/ml) than after guanfacine (12 mm Hg and 0.13 ng/ml) administration. These falls occurred earlier than the rise in growth hormone, which rose to a maximum of 23 and 20 IU/ml respectively at 45 minutes after dosing. In six patients with essential hypertension clonidine and a-methyldopa caused similar falls in blood pressure and plasma norepinephrine concentration although these changes occurred later with a-methyldopa. Plasma growth hormone levels remained undetectable in most patients. In Wistar rats the effect of central and peripheral «2-blockade on clonidine-induced changes was compared. Two groups of six rats received intravenous RX 781094, 0.3 mg/kg, or vehicle 10 minutes before receiving clonidine, 5 ;u.g/kg i.v. In the latter, control group, clonidine reduced mean blood pressure by 30.7 ± 1.9 mm Hg and heart rate by 46 ± 6.7 beats/min. Plasma norepinephrine fell from 0.22 ± 0.023 ng/ ml to 0.116 ± 0.013 ng/ml. After pretreatment with RX 781094, blood pressure did not change and heart rate fell by 18 ± 2.7 beats/min. Plasma norepinephrine rose from 0.253 ± 0.03 ng/ml to 0.445 ± 0.062 after RX 781094 and then fell to 0.36 ± 0.045 ng/ml after clonidine. Two further groups received either RX 781094,10 ng i.c.v., or vehicle 10 minutes prior to receiving clonidine, 5 ftglkg i.v. In the controls clonidine caused falls in blood pressure and heart rate comparable to results achieved in human volunteers. After RX 781094 administration, blood pressure and heart rate fell by 6.0 ± 2.0 mm Hg and by 31 ± 6.0 beats/min. In the controls clonidine reduced plasma norepinephrine from 0.29 ± 0.26 ng/ml to 0.19 ± 0.13 ng/ml; after RX 781094 pretreatment, clonidine reduced plasma norepinephrine from 0.31 ± 0.038 to 0.25 ± 0.04 ng/ml. These three studies indicate that the hypotensive effect of the drugs studied is due largely to their sympatholytic action, and that this action is mediated mainly at central a-adrenergic receptors. (Hypertension 6 (Suppl II):II-57-II-62, 1984)