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Abstract
Nine different β-adrenoceptor antagonists (BAA), five with intrinsic sympathomimetic activity (ISA), were examined for their ability to inhibit isoproterenol-stimulated adenylate cyclase (AC) activity and specific125I-cyanopindolol (CYP) binding in crude membrane particles from human myocardium. The BAA's were: propranolol, pindolol, timolol, alprenolol, metoprolol, atenolol, prenalterol, ICI 141.292 'Visacor', and ICI 118.587 'Corwin'. Whether BAAs with strong ISA were able to stimulate AC activity by themselves were examined in separate experiments and compared to the AC stimulation by full agonists. All the BAAs caused a concentration dependent, and at high doses apparently complete, inhibition of both isoproterenol-stimulated AC activity and 125I-CYP binding. Both assays made possible a 'potency-ranking' of the different BAAs (pindolol Propranolol and timolol >ICI 142.292 and alprenolol > ICI 118.587, prenalterol and metoprolol > atenolol). Corrected IC50-values, derived from inhibition curves with both techniques, show that receptor binding and inhibition of receptor function follow each other closely. Prenalterol caused a very weak AC activation (5.4% of maximum), whereas the TSA-blockers', pindolol, ICI 141.292, and ICI 118.587 were unable to stimulate AC activity at concentrations which completely displaced 125I-CYP binding. In comparison, norepinephrine stimulated AC activity to the same level as isoproterenol (three to four times basal activity) and the pVselective agonist terbutaline caused some 50% of maximal AC stimulation. This raises the question whether ISA is due to AC activation. The effect upon AC activation and 125I-CYP binding of drugs with β2-selectivity shows that both β1- and β2-receptors are coupled to the AC.