Kinetics of accumulation, efflux and the pharmacological effects of tritiated dihydroazapetine on the rabbit aorta

J Pharmacol Exp Ther. 1977 Aug;202(2):278-86.

Abstract

Azepatine, a potent alpha adrenergic antagonist, was catalytically reduced with tritium and hydrogen gas to form dihydroazapetine. The pA2 azapetine was 7.9 whereas that of dihydroazapetine was 6.6, corresponding to a 20-fold decrease in potency. 3H-dihydroazapetine is accumulated into three kinetically distinct compartment in the denervated rabbit aorta. Likewise, efflux of the labeled antagonist occurs from three compartments. The rat constant for onset of alpha adrenoreceptor blockade is 3.15 min-1 which is nearly identical to the rate constant for entry of 3H-dihydroazapetine into a rapidly filling compartment (3.86 min-1) possibly representing the extracellular space. These data are consistent with the hypothesis that onset of alpha adrenoreceptor blockade by dihydroazapetine is diffusion limited.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic alpha-Antagonists / chemical synthesis
  • Adrenergic alpha-Antagonists / metabolism*
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / metabolism
  • Dibenzazepines / chemical synthesis
  • Dibenzazepines / metabolism*
  • Dibenzazepines / pharmacology
  • In Vitro Techniques
  • Kinetics
  • Male
  • Muscle Contraction / drug effects*
  • Muscle Denervation
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism*
  • Rabbits
  • Time Factors
  • Tritium

Substances

  • Adrenergic alpha-Antagonists
  • Dibenzazepines
  • Tritium
  • dihydroazapetine