β-Adrenergic Catecholamine Regulation of Lymphocyte Sensitivity: Heterologous Desensitization to Prostaglandin E2by Isoproterenol*

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Abstract
Human lymphocytes isolated from peripheral blood increased c[cyclic]AMP production up to 2.5-fold in a dose-dependent manner in the presence of the .beta.-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 .mu.M, but neither 8-bromo-cAMP nor 8-bromo-cGMP had the desensitizing effects of isoproterenol. Evidence of similar heterologous desensitization to PGE2 by isoproterenol was sought in vivo by infusing subjects with the .beta.-adrenergic catecholamine. Lymphocytes isolated during the course of infusion showed a loss of sensitivity to both isoproterenol and PGE2 over a 60-min period. Lymphocytes from asthmatic patients receiving chronic .beta.-adrenergic catecholamine therapy (80 mg metaproterenol/day) also showed reduced sensitivity to both isoproterenol and PGE2 compared to cells from normal subjects. .beta.-adrenergic catecholamines apparently have heterologous desensitizing effects in human tissues, at least with respect to PGE2. Heterologous desensitization is a property of acute regulation of .beta.-adrenergic catecholamine and PGE2 target cell function and occurs in vivo as well as in vitro. Some therapeutic effects of .beta.-adrenergic catecholamine administration may be attributed to desensitization to more than 1 agonist.
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