Chronic terbutaline treatment desensitizes beta-adrenergic inhibition of lymphocyte activation in healthy volunteers.
1. A substantial body of evidence has accumulated that beta-adrenoceptor mediated increases in human lymphocyte cyclic AMP can inhibit activation of resting lymphocytes. The aim of this study was to determine whether this effect might desensitize during chronic beta-adrenoceptor agonist treatment. We assessed the effects of 2 weeks treatment with the beta 2-adrenoceptor agonist terbutaline (3 x 5 mg day-1 p.o.) on isoprenaline-induced inhibition of concanavalin A-evoked lymphocyte activation in nine healthy male volunteers. Lymphocyte activation was determined by [3H]-thymidine incorporation (as a measure of proliferation), and inositol phosphate formation was assessed in [3H]-myo-inositol prelabelled lymphocytes in the presence of 10 mM LiCl. 2. Terbutaline treatment caused a significant reduction in isoprenaline (1 nM-10 microM)-induced increases in lymphocyte cyclic AMP content; the maximal increase was 14 +/- 3 pmol/10(6) cells before and 7 +/- 2 pmol/10(6) cells (n = 9, P < 0.05) after terbutaline treatment. 3. The mitogen concanavalin A (Con A, 1-32 micrograms ml-1)-induced increase in inositol phosphate formation was significantly enhanced after terbutaline treatment (max. increase before treatment: 255 +/- 25% above basal; after treatment 453 +/- 16% above basal; n = 9, P < 0.001), while isoprenaline (1 nM-10 microM)-induced inhibition of Con A (16 micrograms ml-1)-evoked increases in inositol phosphate formation was significantly reduced after the terbutaline treatment (max. inhibition before treatment: 22 +/- 4%; after treatment 9 +/- 1%, n = 9, P < 0.01). 4. Con A (1.25-10 micrograms ml-1)-induced increases in [3H]-thymidine incorporation into the lymphocytes (as a measure of proliferation) was not affected by the terbutaline treatment. On the other hand, isoprenaline (1 nM-1 microM)-induced inhibition of Con A (5 micrograms ml-1)-evoked lymphocyte proliferation (max. inhibition: 33 +/- 7%, n = 9) was almost completely abolished after the terbutaline treatment. 5. We conclude that chronic treatment with terbutaline desensitizes lymphocyte beta 2-adrenoceptors and, therefore, the inhibitory effect of cyclic AMP on lymphocyte activation.
Werner
C
C
Institute of Pharmacology and Toxicology, Martin-Luther-University of Halle-Wittenberg, Saale, Germany.
Poller
U
U
Brodde
O E
OE
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D013726:Terbutaline / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D007295:Inositol Phosphates; D018343:Receptors, Adrenergic, beta-2; D003208:Concanavalin A; D000242:Cyclic AMP; D007545:Isoproterenol; D013726:Terbutaline