The characteristics of inhibition of histamine release from human lung fragments by sodium cromoglycate, salbutamol and chlorpromazine.

1 Three drugs have been tested for activity against antigen-induced histamine release from passively sensitized human lung fragments after increasing periods of pre-incubation before challenge.2 After 30 s pre-incubation, sodium cromoglycate inhibited histamine release in the concentration range 0.2-200 muM, producing a maximum inhibition of 33.0%. As the pretreatment period was extended, tolerance developed in a dose-related manner, resulting in a 48.3% and 82.8% loss of activity of the 200 muM dose after 60 min and 19 h pre-incubation, respectively. Tolerance was independent of extracellular calcium and was poorly reversible. Lung tissue desensitized to cromoglycate was cross-tolerant to the related drug, bufrolin, but not to salbutamol or chlorpromazine.3 In acute studies, salbutamol (0.03-3.0 muM) produced dose-related inhibition of histamine release, with a maximum inhibition of 72.2%. The effect was blocked stereoselectively by 1 muM propranolol, suggesting that it occurred through an interaction with lung beta-adrenoceptors. Increasing the pre-incubation time with salbutamol from 30 s to 19 h did not produce tolerance. Inhibition produced by incubation with salbutamol for 19 h was totally prevented when propranolol was added at the beginning of the pre-incubation period, indicating that it resulted from stimulation of beta-receptors and not from a non-specific or toxic effect. However, studies of reversibility of effect through washing or late addition of propranolol did indicate some change in the nature of salbutamol inhibition with time.4 Chlorpromazine was a weak inhibitor of immunological histamine release. A 100 muM concentration was ineffective after 30 s pre-incubation but its activity increased with time. Pre-incubation of lung fragments with this concentration for 1 h or longer, or with a 1 mM dose for a shorter period, provoked histamine release in the absence of antigen. Effects of chlorpromazine were not reversed by washing.5 The different characteristics shown by sodium cromoglycate, salbutamol and chlorpromazine indicate that these drugs inhibit histamine release by interfering with the secretory mechanisms in different ways.