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Molecular mechanism of β‐adrenergic receptor blockers with intrinsic sympathomimetic activity

β‐Adrenergic receptor (βAR) blocking agents with intrinsic sympathomimetic activity (ISA) can induce modest increases in βAR‐stimulated activity, such as rate and force of contraction in cardiac tissue. The molecular basis for this activity has been elusive. Previous studies have suggested that these compounds do not stimulate cyclic AMP (cAMP) formation even though activation of adenylate cyclase is the generally accepted mechanism for βAR promotion of target cell response. In the current studies, we show that several βAR antagonists with ISA (dichloroisoproterenol, pindolol, and celiprolol) stimulate cAMP accumulation five‐, two‐, and threefold, respectively, in S49 lymphoma cells, but only if cells are simultaneously incubated with the diter‐pene forskolin. The KI values observed for inhibition of isoproterenol‐stimulated cAMP accumulation or of βAR ([125I]iodocyanopindolol) binding for each of the β blockers with ISA were comparable in magnitude to their respective EC50 values for forskolin‐potentiated cAMP accumulation. The forskolin‐potentiated responses of these compounds were abolished by the βAR‐antagonist propranolol. These results indicate that the ISA of β‐blocking drugs most likely results from a modest βAR‐mediated stimulation of adenylate cyclase activity. The results further suggest that treatment of target cells with forskolin provides a means to define partial agonism at receptors that are linked to stimulation of adenylate cyclase.—Jasper, J. R.; Michel, M. C.; Insel, M. C. Molecular mechanism of β‐adrenergic receptor blockers with intrinsic sympathomimetic activity. FASEB J. 2: 2891‐2894; 1988.