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Molecular mechanism of β‐adrenergic receptor blockers with intrinsic sympathomimetic activity
Author(s) -
Jasper Jeffrey R.,
Michel Martin C.,
Insel Paul A.
Publication year - 1988
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2.13.2901994
Subject(s) - pindolol , forskolin , intrinsic activity , cyclase , chemistry , adenylate kinase , stimulation , propranolol , medicine , endocrinology , receptor , celiprolol , beta (programming language) , adrenergic receptor , iodocyanopindolol , pharmacology , agonist , biology , biochemistry , heart rate , computer science , blood pressure , programming language
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 K I values observed for inhibition of isoproterenol‐stimulated cAMP accumulation or of βAR ([ 125 I]iodocyanopindolol) binding for each of the β blockers with ISA were comparable in magnitude to their respective EC 50 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.—J asper , J. R.; M ichel , M. C.; I nsel , M. C. Molecular mechanism of β‐adrenergic receptor blockers with intrinsic sympathomimetic activity. FASEB J. 2: 2891‐2894; 1988.