Enhancement of airway reactivity to histamine by isoprenaline and related beta-adrenoceptor agonists in the guinea-pig

Abstract

1. The effect of isoprenaline, adrenaline and salbutamol on airway reactivity to histamine was observed in anaesthetized, ventilated guinea-pigs. Airway reactivity was determined before and 20 min and 90 min after a 30-min i.v. infusion of each agonist by constructing cumulative dose-response curves from breath-by-breath measurements of the effect of different rates of i.v. infusion of histamine on lung resistance (RL) and dynamic compliance (Cdyn). 2. (+/-)-Isoprenaline infused i.v. for 30 min at a rate of 0.4 mumol h-1 kg-1 caused bronchodilatation and a fall in blood pressure. Recovery to starting values of RL and Cdyn occurred within 20 min of stopping the infusion. 3. Reactivity to histamine was greatly enhanced when measured 20 min and 90 min after stopping the infusion of (+/- )-isoprenaline. This was not an effect of the prior infusion of histamine or of the dissolving solution. 4. Infusion of (-)-isoprenaline for 30 min at a rate of 0.2 mumol h-1 kg-1 also enhanced reactivity to histamine. However, enhancement of reactivity to histamine was not demonstrable after infusion of (+)-isoprenaline at equal or higher dose rates. 5. Infusions of bronchodilator concentrations of adrenaline and salbutamol also enhanced airway reactivity to histamine, but the bronchodilator effect of salbutamol lasted longer than that of isoprenaline or adrenaline and the development of hyperreactivity was delayed. 6. After acute bilateral vagotomy, infusion of (+/- )-isoprenaline enhanced airway reactivity but only at the highest dose of histamine. 7. (+/-)-Isoprenaline did not enhance contractile responses to histamine in isolated preparations of first branch bronchi. 8. We conclude that the bronchodilator effect of activating beta-adrenoceptors in the airways of guinea pigs is followed by a more persistent state of hyperreactivity to histamine.