1. Airway responses to inhaled salbutamol were measured in two groups of six normal non-atopic subjects. In each group there was a dose-dependent increase in specific airways conductance after salbutamol inhaled in cumulative doses from 25 to 600 μg. 2. In the first group these studies were repeated weekly during and after the subjects had taken regular inhaled salbutamol for 4 weeks, in doses increasing to 500 μg four times daily by week 4. Then, while subjects were continuing to receive regular salbutamol, the studies were repeated after 48 h of inhaled sodium cromoglycate (20 mg four times daily) and again after 48 h of beclomethasone dipropionate (200 μg four times daily). 3. In the second group the studies were repeated after 10 days of regular inhaled salbutamol (500 μg four times daily). 4. There was no change in airway response to inhaled salbutamol after 4 weeks or 10 days regular salbutamol therapy, or after 48 h of sodium cromoglycate or beclomethasone dipropionate therapy. 5. This study did not show the development of resistance to β-agonists in the airways of normal subjects. These findings are discussed in the context of other studies which have shown the development of resistance, and we suggest that there may be a spectrum of susceptibility to the development of impaired airway responsiveness following regular treatment with β-adrenergic drugs.

1. Airway, metabolic and cyclic nucleotide responses to intravenous salbutamol were measured in five patients with mild asthma who had taken no medication in the week before the study. The studies were repeated after the patient had taken regular inhaled salbutamol for 4 weeks, in doses increasing to 2000 μg daily in week 4. 2. The pretreatment airway, metabolic and cyclic nucleotide responses to salbutamol were similar to those previously reported in normal subjects. These patients therefore did not show evidence of partial β-adrenoceptor blockade. 3. After 4 weeks' salbutamol therapy the airway response to intravenous salbutamol was unchanged. 4. The glucose, pyruvate and adenosine 3′:5′-cyclic monophosphate (cyclic AMP) responses to intravenous salbutamol were depressed after regular salbutamol administration. The dose-response curve for non-esterified fatty acids and insulin, though displaced downwards, did not indicate an impaired response to salbutamol since the shape was unchanged. There was no significant change in the lactate, glycerol and total ketone response. 5. This study confirms that tissues differ in the ease with which they develop resistance to β-adrenoceptor agonists. Asthmatic airways appear to be relatively protected from developing resistance when compared with other tissues in asthmatic patients and when compared with the airways of normal subjects.

1. The airway and metabolic responses to an intravenous β 2 -agonist salbutamol have been investigated in normal subjects before and after chronic administration of inhaled salbutamol, 1600 μg daily for 2 weeks. 2. Before chronic inhalation of salbutamol there was a dose-dependent increase in specific airway conductance after intravenous salbutamol in cumulative doses from 25 to 300 μg. 3. Measurement of concentrations of blood glucose, lactate, pyruvate, glycerol, ketone bodies, non-esterified fatty acids, insulin, plasma cyclic AMP and cyclic GMP were made after each increment of salbutamol and all showed an increase apart from cyclic GMP. 4. After chronic inhalation of salbutamol there was a decrease in the airway, metabolic and insulin response to intravenous salbutamol. The cyclic AMP response showed little change. 5. This study confirms the development of adrenergic resistance in the airways of normal subjects after large doses of inhaled salbutamol and shows that this is associated with widespread metabolic adrenergic resistance.