Direct labelling of beta 2-adrenoceptors. Comparison of binding potency of 3H-ICI 118,551 and blocking potency of ICI 118,551

Naunyn Schmiedebergs Arch Pharmacol. 1985 Oct;331(1):40-51. doi: 10.1007/BF00498850.

Abstract

A radioligand that selectively labels beta 2-adrenoceptors, 3H-ICI 118,551 (3H-ICI), is introduced. Experiments were performed on guinea-pig tissues. The binding characteristics of 3H-ICI on lung membrane particles are compared with the blocking characteristics of ICI 118,551 against the tracheo-relaxant effects of (-)-noradrenaline, (-)-adrenaline and (+/-)-fenoterol. Binding to both beta 1- and beta 2-adrenoceptors were also performed with 3H-(-)-bupranolol on lung and ventricular myocardium. The binding inhibition characteristics of unlabelled ICI 118,551 on ventricle were compared with its characteristics as antagonist of the positive chronotropic effects of (-)-noradrenaline, (-)-adrenaline and (+/-)-fenoterol in spontaneously beating right atria. 1. ICI 118,551 blocked more the relaxant effects of (+/-)-fenoterol and (-)-adrenaline than those of (-)-noradrenaline on trachea. The positive chronotropic effects of (+/-)-fenoterol on sinoatrial node were blocked more than those of both (-)-adrenaline and (-)-noradrenaline. A non-linear regression analysis of blocking data with ICI 118,551 according to the model of Lemoine and Kaumann (1983) revelas that both beta 1- and beta 2-adrenoceptors contribute to the tracheo-relaxant and positive chronotropic effects of agonists. The estimated equilibrium dissociation constants pKB (-log KB = pKB; mol/l) were 7.1 and 9.6 for beta 1- and beta 2-adrenoceptors, respectively. Tracheal beta 2-adrenoceptors contribute 99%, 97% and 7%, sinoatrial beta 2-adrenoceptors contribute 76%, 3% and 0% to the fractional stimuli induced by (+/-)-fenoterol, (-)-adrenaline and (-)-noradrenaline, respectively. 2. 3H-ICI associated to beta 2-adrenoceptors of lung membranes with a kon of 0.521 X nmol-1 X min-1 and dissociated with a koff of 0.19 min-1. 3H-ICI bound to lung beta 2-adrenoceptors with an equilibrium dissociation constant pKL* of 9.2. Unlabelled ICI 118,551, (-)-bupranolol, (+)-bupranolol, (-)-adrenaline, (-)-noradrenaline and (+/-)-fenoterol competed with 3H-ICI for lung beta 2-adrenoceptors with pKL-values of 9.0, 9.4, 8.1, 5.9, 4.9 and 6.4, respectively. 3. 3H-(-)-bupranolol associated to beta-adrenoceptors of lung membranes with a kon 1.21 X nmol-1 X min-1 and dissociated with a koff of 0.26 min-1. 3H-(-)-bupranolol bound to lung beta 2-adrenoceptors and to heart beta 1-adrenoceptors with a pKL of 9.6 and a pKL of 8.8, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / metabolism*
  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Bisoprolol
  • Bupranolol / metabolism
  • Bupranolol / pharmacology
  • Female
  • Fumarates / pharmacology
  • Glutamates / pharmacology
  • Glutamic Acid
  • Guinea Pigs
  • In Vitro Techniques
  • Kinetics
  • Lung / metabolism
  • Male
  • Membranes / metabolism
  • Myocardium / metabolism
  • Propanolamines / metabolism*
  • Propanolamines / pharmacology
  • Pyruvates / pharmacology
  • Pyruvic Acid
  • Receptors, Adrenergic, beta / metabolism*
  • Sinoatrial Node / metabolism
  • Trachea / metabolism

Substances

  • Adrenergic beta-Antagonists
  • Fumarates
  • Glutamates
  • Propanolamines
  • Pyruvates
  • Receptors, Adrenergic, beta
  • Glutamic Acid
  • ICI 118551
  • Pyruvic Acid
  • Bupranolol
  • fumaric acid
  • Bisoprolol