title: Direct labelling of beta 2-adrenoceptors. Comparison of binding potency of 3H-ICI 118,551 and blocking potency of ICI 118,551.
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)
authors.forename: H
authors.initials: H
authors.lastname: Lemoine
authors.forename: B
authors.initials: B
authors.lastname: Ehle
authors.forename: A J
authors.initials: AJ
authors.lastname: Kaumann
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017298:Bisoprolol; D002046:Bupranolol / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005650:Fumarates / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011412:Propanolamines / Q000378:metabolism* / Q000494:pharmacology; D011773:Pyruvates / Q000494:pharmacology; D019289:Pyruvic Acid; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012849:Sinoatrial Node / Q000378:metabolism; D014132:Trachea / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D005650:Fumarates; D005971:Glutamates; D011412:Propanolamines; D011773:Pyruvates; D011943:Receptors, Adrenergic, beta; D018698:Glutamic Acid; C026777:ICI 118551; D019289:Pyruvic Acid; D002046:Bupranolol; C032005:fumaric acid; D017298:Bisoprolol