INFLUENCE OF RECEPTOR RESERVE ON BETA-ADRENOCEPTOR-MEDIATED RESPONSESIN HUMAN LUNG MAST-CELLS

1 The effects of the beta-adrenoceptor agonists isoprenaline and salbu tamol on IgE-mediated histamine release from human lung mast cells (HL MC) were evaluated. Both agonists (10(-10)-10(-5) M) inhibited histami ne release in a dose-dependent manner and isoprenaline (pD(2), 8.3+/-0 .1, mean+/-s.e.mean) was more potent than salbutamol (7.3+/-0.1). More over, the mean data indicated that salbutamol was a partial agonist wh en compared with isoprenaline. However, there was a large degree of in terexperimental variability because, in II of 32 experiments, salbutam ol was a full agonist and, in 21 of 32 experiments, a partial agonist relative to isoprenaline. These data suggest that different HLMC prepa rations possess variable receptor reserves. 2 The effect of the irreve rsible beta-adrenoceptor antagonist, bromoacetylalprenoloI menthane (B AAM), on the inhibition of IgE-mediated histamine release by both isop renaline and prostaglandin E-2 (PGE(2)) was assessed. Whereas BAAM (10 0 nM) antagonized the isoprenaline inhibition of histamine release fro m activated HLMC, BAAM had no effect on the PGE(2) inhibition. Pretrea tment of HLMC with the beta(2)-selective competitive antagonist, ICI 1 18551 (100 nM), protected against the loss in responsiveness to isopre naline following treatment with BAAM. 3 Concentrations of 1, 10 and 10 0 nM of BAAM caused dose-dependent rightward shifts in the dose-respon se curve for the isoprenaline inhibition of histamine release. Further more, there was a dose-dependent reduction in the maximal inhibitory r esponse obtained with isoprenaline following treatments with increasin g concentrations of BAAM. Although the rightward shifts in the isopren aline dose-response curves, with a given concentration of BAAM, were s imilar in all experiments, there was some variability in the depressio n of the maximal response in individual experiments. Thus, in 6 of 16 experiments, BAAM (1 nM) did not depress the maximal response to isopr enaline, whereas in 10 of 16 experiments there was a depression (7 to 49% reduction) in the maximal response. These data suggest that differ ent HLMC preparations possess variable receptor reserves. 4 Isoprenali ne was more potent as an inhibitor in those HLMC preparations in which there was a larger receptor reserve (i.e. preparations in which the m aximal inhibitory response to isoprenaline was unaffected by pretreatm ent with 1 nM BAAM). 5 The influence of receptor reserve on the inhibi tion by salbutamol of histamine release from HLMC was evaluated. There was a good correlation (r=0.77) between receptor reserve and the maxi mal response (relative to isoprenaline) obtained with salbutamol. Thus , HLMC preparations with larger receptor reserves were more responsive to salbutamol. 6 Receptor reserve influenced the desensitization of b eta-adrenoceptor-mediated responses in HLMC. Cells were incubated (24 h) with isoprenaline (1 mu M), washed and then the ability of a second isoprenaline (10(-10)-10(-5) M) exposure to inhibit histamine release was assessed. The pretreatment caused a reduction in the isoprenaline inhibition of histamine release although the extent of desensitizatio n was highly variable, ranging from essentially negligible levels in s ome preparations to substantial reductions (93% desensitization) in th e ability of isoprenaline to inhibit histamine release. There was a re asonable correlation (r=0.59) between receptor reserve and desensitiza tion. Preparations that possessed a larger receptor reserve were more resistant to desensitization. 7 Collectively, these data suggest that a receptor reserve exists for the beta-adrenoceptor-mediated inhibitio n of histamine release from HLMC but that the size of this reserve var ies between HLMC preparations. Moreover, the size of this receptor res erve may influence the sensitivity of HLMC to beta-adrenoceptor agonis ts and the susceptibility of individual HLMC preparations to desensiti zation.