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 micrograms
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 less than 0.05). Mean systolic blood pressure increased by 4 mm Hg in the first hour after the 30 mg dose of
MK-467 (p less than 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 less than 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 less than 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.