She eld S10 2JF1 The e ects of the b-adrenoceptor agonists isoprenaline and salbutamol on IgE-mediated histamine release from human lung mast cells (HLMC) were evaluated. Both agonists (10 710 ± 10 75 M) inhibited histamine 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). Moreover, the mean data indicated that salbutamol was a partial agonist when compared with isoprenaline. However, there was a large degree of interexperimental variability because, in 11 of 32 experiments, salbutamol was a full agonist and, in 21 of 32 experiments, a partial agonist relative to isoprenaline. These data suggest that di erent HLMC preparations possess variable receptor reserves.2 The e ect of the irreversible b-adrenoceptor antagonist, bromoacetylalprenolol menthane (BAAM), on the inhibition of IgE-mediated histamine release by both isoprenaline and prostaglandin E 2 (PGE 2 ) was assessed. Whereas BAAM (100 nM) antagonized the isoprenaline inhibition of histamine release from activated HLMC, BAAM had no e ect on the PGE 2 inhibition. Pretreatment of HLMC with the b 2 -selective competitive antagonist, ICI 118551 (100 nM), protected against the loss in responsiveness to isoprenaline following treatment with BAAM. 3 Concentrations of 1, 10 and 100 nM of BAAM caused dose-dependent rightward shifts in the doseresponse curve for the isoprenaline inhibition of histamine release. Furthermore, there was a dosedependent reduction in the maximal inhibitory response obtained with isoprenaline following treatments with increasing concentrations of BAAM. Although the rightward shifts in the isoprenaline doseresponse curves, with a given concentration of BAAM, were similar in all experiments, there was some variability in the depression of the maximal response in individual experiments. Thus, in 6 of 16 experiments, BAAM (1 nM) did not depress the maximal response to isoprenaline, whereas in 10 of 16 experiments there was a depression (7 to 49% reduction) in the maximal response. These data suggest that di erent HLMC preparations possess variable receptor reserves. 4 Isoprenaline was more potent as an inhibitor in those HLMC preparations in which there was a larger receptor reserve (i.e. preparations in which the maximal inhibitory response to isoprenaline was una ected by pretreatment with 1 nM BAAM). 5 The in¯uence of receptor reserve on the inhibition by salbutamol of histamine release from HLMC was evaluated. There was a good correlation (r=0.77) between receptor reserve and the maximal response (relative to isoprenaline) obtained with salbutamol. Thus, HLMC preparations with larger receptor reserves were more responsive to salbutamol. 6 Receptor reserve in¯uenced the desensitization of b-adrenoceptor-mediated responses in HLMC. Cells were incubated (24 h) with isoprenaline (1 mM), washed and then the ability of a second isoprenaline (10 710 ± 10 75 M) exposure to inhibit histamine release was assessed. The pretreatment caused a reduction in the isoprenaline inhi...

1 The b-adrenoceptor agonist, isoprenaline, inhibited the IgE-mediated release of histamine from human lung mast cells (HLMC) in a dose-dependent manner. Maximal inhibitory e ects were obtained with 0.1 mM isoprenaline. However, the inhibition of histamine release from HLMC by isoprenaline (0.1 mM) was highly variable ranging from 33 to 97% inhibition (mean, 59+3%, n=27). 2 Long-term (24 h) incubation of HLMC with isoprenaline led to a subsequent reduction in the ability of a second exposure of isoprenaline to inhibit IgE-mediated histamine release from HLMC. The impairment in the ability of isoprenaline (0.1 mM) to inhibit histamine release following desensitizing conditions (1 mM isoprenaline for 24 h) was highly variable amongst HLMC preparations ranging from essentially negligible levels of desensitization in some preparations to complete abrogation of the inhibitory response in others (mean, 65+6% desensitization, n=27). 3 The ability of HLMC to recover from desensitization was investigated. Following desensitizing conditions (1 mM isoprenaline for 24 h), HLMC were washed and incubated for 24 h in bu er and the e ectiveness of isoprenaline (0.1 mM) to inhibit IgE-mediated histamine release from HLMC was assessed. The extent of recovery was highly variable with some HLMC preparations failing to recover and others displaying a complete restoration of responsiveness to isoprenaline (mean, 40+6% recovery, n=23).4 The e ects of the glucocorticoid, dexamethasone, were also investigated. Long-term (24 ± 72 h) treatments with dexamethasone (0.1 mM) had no e ect on IgE-mediated histamine release from HLMC. Additionally, long-term (24 ± 72 h) treatments with dexamethasone (0.1 mM) had no e ect on the e ectiveness of isoprenaline to inhibit histamine release. However, long-term (24 ± 72 h) treatments with dexamethasone (0.1 mM) protected against the functional desensitization induced by incubation (24 h) of HLMC with isoprenaline (1 mM). The protective e ect was time-dependent and pretreatment of HLMC with dexamethasone for either 24, 48 or 72 h prevented desensitization by either 15+7, 19+5 or 51+10%, respectively (n=5 ± 7). 5 HLMC preparations which were relatively refractory to isoprenaline even after withdrawal (24 h) from desensitizing conditions responded more e ectively to isoprenaline (0.1 mM) if dexamethasone (0.1 mM) was also included during the recovery period (19+9% recovery after 24 h in bu er; 50+8% recovery after 24 h with dexamethasone, n=5). 6 These data indicate that the responses of di erent HLMC preparations to isoprenaline, the susceptibility of HLMC to desensitization and the ability of HLMC to recover from desensitizing conditions varies markedly. Dexamethasone, which itself has no direct e ects on IgE-mediated histamine release from HLMC, protected HLMC from the functional desensitization to b-adrenoceptor agonists. Because b 2 -adrenoceptor agonists and glucocorticoids are important in the therapeutic management of asthma and as the HLMC is probably important in certain types of asthma, these ...