The lymphocyte beta-adrenoceptor in normal subjects and patients with bronchial asthma: the effect of different forms of treatment on receptor function.

187

Ten niessee 37232 AB S T R A C T High levels of beta receptor agonist have previously been showin to dowvn-regulate beta receptor density on circulating leukocytes in man; however, the factors controlling receptor density under physiological conditionis have not previously beein de-fined. To determine whether beta receptor density is normally down-reguilated by circulating, physiological levels of catecholamlines we have examined the relationship between receptor density and catecholamine levels. Urinary epinephrine and norepinephrine were significantly reciprocally correlated to lymphocyte receptor density. A similar relationship existed between beta receptor density and supine plasma epinephrine, norepinephrine, upright epinephrine, and norepinephrine levels. Change in sodium intake from 10 to 400 meq/d cauised a 52% increase in lymphocyte and a 48% increase in polymorphonuclear beta receptor density. The changes in receptor density were accompanied by an increase in the sensitivity to isoproterenol measured as a fall in the dose of isoproterenol required to raise the heart rate by 25 beats per minute. Beta receptor density on both lymphocyte and polymorphonuclear cells was significantly correlated to the cardiac sensitivity to isoproterenol.

Section: Resultsmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Regulation of Human Leukocyte Beta Receptors by Endogenous Catecholamines

Fraser¹,

Nadeau²,

Robertson³

et al. 1981

187

“…Because it is difficult to study samples of lung in human subjects, several investigators have used either peripheral blood leukocytes or lymphocytes to show that asthmatics have decreased stimulation of cyclic AMP by beta adrenergic agonists (7,8). Two problems must be considered in assessing these studies: (a) beta adrenergic responses and receptors in T and B lymphocytes may be quite different (9,10), and thus changes in adrenergic response in asthmatics might reflect altered distribution of cells in lymphocyte subpopulations; and (b) prior administration of beta adrenergic agonists reportedly diminishes subsequent beta adrenergic stimulation of leukocyte cyclic AMP (11)(12)(13). Thus, changes in responsiveness of asthmatics might arise from therapy as well as from the disease itself.…”

Section: Introductionmentioning

confidence: 99%

Beta Adrenergic Receptors of Polymorphonuclear Particulates in Bronchial Asthma

Galant¹,

Duriseti²,

Underwood³

et al. 1980

105

A B S T R A C T We have tested the beta adrenergic receptor theory of bronchial asthma by determining the number and affinity of binding sites of the beta adrenergic radioligand [3H]dihydroalprenolol (DHA) and the activity ofadenylate cyclase in broken cell preparations of polymorphonuclear leukocytes (PMN). We studied 31 control subjects (group 1), 30 asthmatics receiving no systemic adrenergic medication (group 2), and 17 asthmatics receiving adrenergic agonists systemically (group 3). Control subjects and asthmatics taking no adrenergic drugs bound similar amounts of DHA at 0.5 nM and 30 nM DHA and had about 900 binding sites per PMN. In contrast, asthmatics receiving adrenergic agonists had a >70% decrease in their number of DHA binding sites per PMN (254+±57). In a subset of our three groups of subjects (eight from group 1, six from group 2, and five from group 3) we measured DHA binding at several DHA concentrations and found similar values (0.4-0.7 nM) for the dissociation constant of DHA among these subjects.In further studies we examined the interaction of the agonist (-)-isoproterenol with beta adrenergic receptors in 8 normal subjects and 10 asthmatics not receiving adrenergic medication. We tested the ability of isoproterenol to compete for DHA binding sites and to stimulate adenylate cyclase in sonicates prepared from PMN and examined under identical conditions. The dissociation constants for the competition of isoproterenol for DHA binding sites in normal and asthmatic subjects were virtually identical (-1.0,M). In addi-

“…Human lymphocytes containing a homogeneous population of 02-adrenoceptors cou-pled to the adenylate cyclase are suitable tissues to study alterations of fl-adrenoceptor function in man (3; for references see 4). An agonist-induced decrease in fl-adrenoceptor number in lymphocytes from healthy as well as asthmatic subjects has been observed after prolonged treatment with fl-adrenergic agonists (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The resulting tachyphylaxis may markedly limit the therapeutic efficacy of fl-adrenergic bronchodilator therapy in asthma (16)(17)(18)(19).…”

mentioning

confidence: 99%

Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen.

Brodde¹,

Brinkmann²,

Schemuth³

et al. 1985

146

We investigated, in 36 healthy volunteers, the effects of prednisone and ketotifen on recovery of lymphocyte j2-adrenoceptor density (determined by (-)-'"iodocyanopindolol binding) and responsiveness (assessed by lymphocyte cyclic AMP IcAMPI responses to 10 AtM (-)-isoprenaline) after desensitization by the p2-agonist terbutaline. Terbutaline (3 X 5 mg/d) decreased lymphocyte #2-adrenoceptor density by -40-50%; concomitantly, lymphocyte cAMP responses to 10 ,gM (-)-isoprenaline were significantly reduced. After withdrawal of terbutaline 2-adrenoceptor, density and responsiveness gradually increased, reaching predrug levels after 4 d.Prednisone (1 X 100 mg orally) accelerated ,f2-adrenoceptor recovery; only 8-10 h after administration of the steroid ,62-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached values not significantly different from pretreatment levels. Similar effects were obtained with ketotifen (2 mg; thereafter 2 X 1 mg/d for 4 d): 24 h after application of the drug (32-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached pretreatment levels. Furthermore, ketotifen simultaneously applied with terbutaline completely prevented terbutaline-induced decrease in lymphocyte i2-adrenoceptor density and responsiveness. Prednisone (1 X 100 mg orally) or ketotifen (2 mg; thereafter 2 X 1 mg/d for 2 d) had no significant influence on lymphocyte #2-adrenoceptor density in healthy volunteers not pretreated with terbutaline, but shifted the ratio high-to-low affinity state of the lymphocyte j#2-adrenoceptor toward high affinity state.We conclude that glucocorticoids as well as ketotifen can accelerate recovery of density and responsiveness of lymphocyte B2-adrenoceptors desensitized by long-term treatment with 2-agonists. Such an effect may have clinical implications for preventing tachyphylaxis of asthmatic patients against therapy with 02-agonists.