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Vol. 291, Issue 3, 1164-1171, December 1999

Binding, Partial Agonism, and Potentiation of alpha 1-Adrenergic Receptor Function by Benzodiazepines: A Potential Site of Allosteric Modulation1

David J. J. Waugh, Robert J. Gaivin, Derek S. Damron, Paul A. Murray and Dianne M. Perez

Departments of Molecular Cardiology (D.J.J.W., R.J.G., D.M.P.) and Anesthesiology Research (D.S.D., P.A.M.), The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

Benzodiazepines, a class of drugs commonly used to induce anesthesia and sedation, can attenuate intracellular calcium oscillations evoked by alpha 1-adrenergic receptor (alpha 1-AR) stimulation in pulmonary artery smooth muscle cells. We postulated a direct action of benzodiazepines in modulating alpha 1-AR function at the receptor level. Benzodiazepines bound to each of the cloned alpha 1-AR subtypes (alpha 1a-, alpha 1b-, or alpha 1d-AR) on COS-1 cell membranes transiently transfected to express a single population of alpha 1-AR subtype. The ability of benzodiazepines to alter alpha 1-AR signal transduction was investigated by measuring total inositol phosphate generation in rat-1 fibroblast cells, stably transfected to express a single alpha 1-AR subtype. By themselves, benzodiazepines displayed partial agonism. At alpha 1b-ARs and alpha 1d-ARs, the maximal inositol phosphate response to phenylephrine was potentiated almost 2-fold by either midazolam or lorazepam (100 µM). At alpha 1a-ARs, diazepam, lorazepam, and midazolam all increased the maximal response of the partial agonist clonidine at these receptors, whereas the response to the full agonist phenylephrine was unaltered or inhibited. The potentiating actions of midazolam and its partial agonism at alpha 1-ARs was blocked by the addition of 1 µM prazosin, an alpha 1-AR antagonist, and not by a gamma -aminobutyric acidA-receptor antagonist. These studies show that benzodiazepines modulate the function of alpha 1-ARs in vitro, and this is the first report of a potential allosteric site on alpha 1-ARs that may be therapeutically useful for drug design.

0022-3565/99/2913-1164$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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