ASSESSMENT OF MK-467, A PERIPHERAL ALPHA-2-ADRENERGIC RECEPTOR ANTAGONIST, WITH INTRAVENOUS CLONIDINE

The activity of MK-467, a new peripherally acting alpha-2-antagonist, was assessed in volunteers by a randomized, double-blind, crossover design. One hour after administration of either 15 mg or 30 mg MK-467 or placebo, 200-mu-g clonidine was given intravenously and observations were made for a further 8 hours. Clonidine reduced plasma norepinephrine levels to 79% +/- 7% of that of control 1 hour after infusion, an effect that was antagonized by low-dose MK-467 (p < 0.05). Mean systolic blood pressure increased by 4 mm Hg in the first hour after the 30 mg dose of MK-467 (p < 0.01), although there was no significant difference between the 3 study days in the maximal clonidine-induced decrease in systolic pressure, diastolic pressure, or heart rate. Clonidine induced a peak increase in mean blood glucose of 13%, which was antagonized by both doses of MK-467 (p < 0.05). Plasma insulin was suppressed by clonidine from 72 +/- 14 to 47 +/- 7 IU . L-1, an effect antagonised by both doses of MK-467 (p < 0.05 in each case). MK-467 had no effect on clonidine-induced increased drowsiness, xerostomia, or increase in growth hormone secretion, which is consistent with it being a peripherally acting specific alpha-2-antagonist. The small effect of MK-467 on clonidine-induced changes in plasma glucose and insulin suggests that peripheral alpha-2-adrenergic receptors play only a minor role in normal glucose homeostasis.