Nocturnal asthma. Beta 2-adrenoceptors on peripheral mononuclear leukocytes, cAMP- and cortisol-plasma concentrations

To evaluate pathophysiologic mechanisms of the predominantly nocturnal complaints in atopic bronchial asthma, the expression and function of beta 2-adrenoceptors on peripheral mononuclear leukocytes (pMNL), the cAMP--as well as the cortisol--plasma concentrations were studied in eight healthy men and ten so far untreated male asthmatic patients at 4-h intervals for 24 h. No difference was seen in the beta 2-adrenoceptor density (Bmax) on pMNL between healthy and asthmatic men (24-h means +/- SE: 908 +/- 59 sites per cell and 821 +/- 54 sites per cell, respectively). The equilibrium dissociation constant (Kd), however, was significantly higher in the asthmatic patients (24-h mean +/- SE: 8.8 +/- 1.2 pmol/L vs 3.0 +/- 0.2 pmol/L in healthy men, p less than 0.0001), which is equivalent to a lower affinity of the beta 2-adrenoceptors for the radioligand 125iodocyanopindolol. Bmax showed a statistically significant circadian variation, but Kd did not. The circadian variation in Bmax was reflected in the basal intracellular cyclic adenosine-monophosphate (cAMP) content of the cells investigated. High Kd values (equivalent to low receptor affinities) tended to be associated with small increases of the intracellular cAMP content after in vitro stimulation by 10(-7) mol/L isoprenaline (isoproterenol) (24-h mean +/- SE: 1.4 +/- 0.2 pmol/10(6) cells; r = -0.529, p = 0.05 at r = -0.549, n = 10). Plasma cAMP concentrations were found to be significantly lower in the asthmatic patients (24-h means +/- SE: 22.9 +/- 1.3 nmol/L vs 29.1 +/- 1.1 nmol/L, p less than 0.0001). Plasma cortisol concentrations were significantly higher in the asthmatic patients (24-h means +/- SE: 0.500 +/- 0.084 mumol/L vs 0.319 +/- 0.063 mumol/L). The results support the hypothesis that a lesion of the beta-adrenergic system contributes to the pathophysiology of atopic bronchial asthma. In the patients investigated in this study, such a lesion could be demonstrated in the affinity rather than in the number of beta 2-adrenoceptors expressed on peripheral cells of the immune system (pMNL). According to present-day knowledge of adrenergic effects on pMNL, such an affinity decrease of beta 2-adrenoceptors could account for overshooting immune responses. In association with other factors influencing respiratory function, it could be responsible for the predominantly nocturnal complaints in atopic bronchial asthma. Plasma cortisol concentrations did not appear to be related to the principal cause of "nocturnal asthma;" they rather reflected an endogenous defense mechanism to the disease

Circannual variation in the expression of beta 2-adrenoceptors on human peripheral mononuclear leukocytes (MNLs)

Peripheral mononuclear leukocytes (MNLs) are widely used as a tissue model in studies of beta-adrenoceptor disturbances in hypertension and asthmatic diseases. The beta 2-adrenoceptor density (Bmax), however, depends not only on the gender of the person under study and on the time of day the blood specimens are obtained. Evidence is now reported for a circannual variation in the expression of beta 2-adrenoceptor sites on peripheral MNLs. In male volunteers the 24-h mean was found to be highest in the men studied in April/May (1135 +/- 10 sites/cell) and decreased to 891 +/- 16 sites/cell in August and to 712 +r90 sites/cell in December (means +/- SE, P less than 0.01 April/May compared to December). Concomitantly the circadian amplitude increased from 17.3% +/- 6.4% of 24-h mean in April/May to 28.2% +/- 1.4% of 24-h mean in August and to 34.2% +/- 4.2% of 24-h mean in December (means +/- SE, P less than 0.05, April/May compared to December). The circadian acrophase remained constant (190 degrees +/- 30 degrees equivalent to 12 h 40 min +/- 2 h 00 min, means +/- SE)