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β-Adrenergic Catecholamine Regulation of Lymphocyte Sensitivity: Heterologous Desensitization to Prostaglandin E₂ by Isoproterenol^*

Biochemical Pharmacology Laboratory and the Department of Medicine, UCLA-San Fernando Valley Program, Veterans Administration Medical Center Sepulveda, California 91343

Address requests for reprints to: Dr. J. Frederick Krall, Biochemical Pharmacology Laboratory, UCLA-San Fernando Valley Program, Veterans Administration Medical Center, Sepulveda, California 91343.

Human lymphocytes isolated from peripheral blood increased cAMP production up to 2.5-fold in a dosedependent manner in the presence of the β-adrenergic catecholamine agonist isoproterenol and up to 5-fold in the presence of prostaglandin E² (PGE₂). Cells maximally stimulated by PGE₂ failed to show further increases in cAMP production when isoproterenol was also added, suggesting that the same cells were sensitive to both agonists. When incubated with isoproterenol for up to 30 min and then washed free of the agonist before restimulation with fresh isoproterenol or PGE₂, cells showed a time-dependent loss of sensitivity to both agonists. Isoproterenol- dependent desensitization to PGE2 was both less extensive and more slowly developing than desensitization to isoproterenol, and proceeded in the presence of indomethacin and in indomethacin-pretreated cells. Both desensitization to PGE₂ and cAMP production demonstrated similar isoproterenol dose dependency with a half-maximal concentration of 0.1 µM, but neither 8-bromo-cAMP nor 8-bromo-cGMP had the desensitizing desensitizing effects of isoproterenol.

Evidence of similar heterologous desensitization to PGE₂ by isoproterenol was sought in vivo by infusing subjects with the β-adrenergic catecholamine. Lymphocytes isolated during the course of infusion showed a loss of sensitivity to both isoproterenol and PGE₂ over a 60-min period. In addition, lymphocytes from asthmatic patients receiving chronic β-adrenergic catecholamine therapy (80 mg metaproterenol/day) also showed reduced sensitivity to both isoproterenol and PGE₂ compared to cells from normal subjects.

We conclude that β-adrenergic catecholamines have heterologous desensitizing effects in human tissues, at least with respect to PGE₂. Heterologous desensitization is a property of acute regulation of β-adrenergic catecholamine and PGE₂ target cell function and occurs in vivo as well as in vitro. As a consequence, some therapeutic effects of β-adrenergic catecholamine administration may be attributed to desensitization to more than one agonist.

^* This work was supported by Research and Development Funds from the V.A. Presented, in part, at the 61st Annual Meeting of The Endocrine Society, Anaheim, CA, June 1979.

Received November 28, 1979.

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