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 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.
Department of Clinical Pharmacology, RPMS, Hammersmith Hospital, London, England.
J B
JB
Warren
C T
CT
Dollery
D
D
Sciberras
M R
MR
Goldberg
D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D009638:Norepinephrine / Q000097:blood; D011807:Quinolizines / Q000494:pharmacology*; D011897:Random Allocation; D012472:Salivation / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; D007328:Insulin; D011807:Quinolizines; C055732:vatinoxan; D003000:Clonidine; D009638:Norepinephrine