Summary
Propranolol, pindolol, practolol and metoprolol were investigated for β-adrenoceptor blocking activities in the guinea-pig right atrium and tracheal strip preparation, both in the absence and presence of 2.8% bovine serum albumin. Similarly, the influence of 2.8% albumin on the antagonism of ouabain-induced arrhythmias in the guinea-pig right atrium was studied. Local anesthetic activities were measured on the isolated, partially desheathed, frog sciatic nerve.
Incubation with albumin decreased the in vitro atrial β-adrenoceptor blocking potency of propranolol against (-)-isoprenaline-induced positive chronotropism by a factor of 12 whereas the activity on tracheal receptors was 4.5 times lower. The activities of pindolol, practolol and metoprolol both on atrial and tracheal β-receptors were not significantly influenced by the presence of albumin. The results demonstrate the important role of albumin binding in causing differences in the in vivo and in vitro cardiac β-adrenoceptor blocking potency ratios of propranolol compared to the other β-receptor antagonists studied.
The large difference between β-adrenoceptor blocking and minimal antiarrhythmic concentrations, the approximately 1000 times lower antiarrhythmic activity of practolol compared to propranolol and the very significant correlation between the antiarrhythmic and local anesthetic activities demonstrate that the antagonism of ouabain-induced arrhythmias in the isolated right atrium of the guinea pig is solely due to the ‘membrane-stabilizing’ properties of the β-receptor antagonists. The moderate decrease of the antiarrhythmic potency of propranolol by 2.8% albumin was concluded to have no relevance for the in vivo situation.
Binding to 2.8% albumin was investigated using the ultracentrifugation technique. For propranolol a linear relationship was found between log concentration and percent binding which amounted to 88.2% at 10−6 M. In contrast, protein binding of pindolol, practolol and metoprolol was low and concentration independent.
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Zaagsma, J., Meems, L. & Boorsma, M. β-Adrenoceptor studies. Naunyn-Schmiedeberg's Arch. Pharmacol. 298, 29–36 (1977). https://doi.org/10.1007/BF00510983
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DOI: https://doi.org/10.1007/BF00510983