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Assessment of MK-467, a peripheral alpha 2-adrenergic receptor antagonist, with intravenous clonidine.

Abstract
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.
AuthorsJ B Warren, C T Dollery, D Sciberras, M R Goldberg
JournalClinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 50 Issue 1 Pg. 71-7 (Jul 1991) ISSN: 0009-9236 [Print] United States
PMID1677320 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Adrenergic alpha-Antagonists
  • Blood Glucose
  • Insulin
  • Quinolizines
  • vatinoxan
  • Clonidine
  • Norepinephrine
Topics
  • Administration, Oral
  • Adrenergic alpha-Antagonists (pharmacology)
  • Adult
  • Blood Glucose (drug effects)
  • Blood Pressure (drug effects)
  • Clonidine (antagonists & inhibitors, pharmacology)
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Humans
  • Insulin (blood)
  • Male
  • Norepinephrine (blood)
  • Quinolizines (pharmacology)
  • Random Allocation
  • Salivation (drug effects)

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