Relative potencies of various beta-adrenoceptor antagonists (BAA) at the level of the human myocardial beta-adrenoceptor-adenylate cyclase (AC) complex. Is intrinsic sympathomimetic activity (ISA) due to AC activation?

Nine different beta-adrenoceptor antagonists (BAA), five with intrinsic sympathomimetic activity (ISA), were examined for their ability to inhibit isoproterenol-stimulated adenylate cyclase (AC) activity and specific 125I-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 greater than or equal to propranolol and timolol greater than ICI 142.292 and alprenolol greater than ICI 118.587, prenalterol and metoprolol greater than 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 'ISA-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 beta 2-selective 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 beta-selectivity shows that both beta 1- and beta 2-receptors are coupled to the AC.