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Interaction of the antiarrhythmic agents SR 33589 and amiodarone with the β‐adrenoceptor and adenylate cyclase in rat heart
Author(s) -
Chatelain P.,
Meysmans L.,
Mattéazzi J.R.,
Beaufort Ph.,
Clinet M.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb16397.x
Subject(s) - medicine , forskolin , endocrinology , cyclase , amiodarone , chemistry , adenylate kinase , iodocyanopindolol , dissociation constant , pindolol , isoprenaline , glucagon , receptor , biology , intrinsic activity , propranolol , stimulation , agonist , hormone , atrial fibrillation
1 The effects of SR 33589 and amiodarone on the cardiac β‐adrenoceptor were studied in vitro and after chronic treatment by means of [ 125 I]‐(−)−iodocyanopindolol ([ 125 I]‐(−)−CYP) binding and measurement of adenylate cyclase activity. 2 Binding of [ 125 I]‐(−)−CYP was inhibited in a dose‐dependent manner by SR 33589 (IC 50 = 1.8 ± 0.4 μM, n H = 0.93 ± 0.06) and amiodarone (IC 50 = 8.7 ± 2.0 μM, n H = 0.92 ± 0.03). Saturation binding experiments indicated a non‐competitive interaction such that SR 33589 (1 and 3 μm) and amiodarone (5 and 10 μm) reduced the B max of [ 125 I]‐(−)−CYP binding without any effect on the K D . Kinetic studies showed that the rate of association of [ 125 I]‐(−)−CYP was unchanged while the rate of dissociation was increased both in the presence of SR 33589 (10 μm) and amiodarone (30 μM). 3 Under the same conditions, the receptor stimulated adenylate cyclase activity was inhibited in a dose‐dependent, but non‐competitive manner, by SR 33589 (isoprenaline‐, glucagon‐ and secretin‐stimulated enzyme inhibited 50% at 6.8 ± 0.6 μM, 31 ± 10 μm and 12 ± 3 μM, respectively) while the basal, GTP‐ and Gpp(NH)p‐stimulated enzyme was inhibited by 5–10% and the NaF and forskolin‐stimulated enzyme by 50% at 500 μM. Amiodarone exhibited a similar pattern of inhibition. 4 After chronic oral treatment (50, 100, 150 mg kg −1 per day, 14 days), both SR 33589 and amiodarone produced a dose‐dependent decrease in B max without any effect on K D as determined from [ 125 I]‐(−)−CYP saturation experiments and a decrease of the isoprenaline‐ and glucagon‐stimulated adenylate cyclase activity without any effect on basal enzyme activity or activity when stimulated by agents acting directly on regulatory catalytic units. 5 Unlike amiodarone, SR 33589 does not contain iodine substituents. Plasma levels of T 3 , T 4 and rT 3 were unchanged after SR 33589 treatment except a decrease in T 4 level at the highest dose whilst the T 4 T 3 ratio and the level of rT 3 were dose‐dependently increased by amiodarone treatment. 6 In vitro , SR 33589 and amiodarone were characterized as non‐competitive β‐adrenoceptor antagonists. Chronic treatment led to a down‐regulation of the β‐adrenoceptor; the down‐regulation cannot be attributed to an indirect effect mediated by the thyroid hormones. To reconcile these opposing observations, we propose that SR 33589 and amiodarone interact with the β‐adrenoceptor at a site close to the intracellular loops which are involved in the coupling with G s and contain the phosphorylable sites.