Pulmonary responses of salbutamol tolerant guinea-pigs to aminophylline and ipratropium bromide.

Groups of guinea-pigs were pretreated with salbutamol (15 micrograms/kg s.c. 3 times/day for 7 days) and compared with controls (saline treated) by measurement of the effects of i.v. dosage with salbutamol (1-10 micrograms/kg), aminophylline (5-20 mg/kg) or ipratropium bromide (1-10 micrograms/kg) on total lung resistance in the anaesthetised state. The bronchodilator effects of these three drugs were measured as attenuation of the bronchoconstrictor response to a standard dose of histamine (3 micrograms/kg i.v.). The salbutamol-pretreated guinea-pigs gave significantly reduced responses to salbutamol (at 2, 5 and 10 micrograms/kg) and to aminophylline (at 10 and 20 mg/kg) whilst the responses to ipratropium bromide were similar to controls. A further group of control guinea-pigs was used to examine the effects of beta-adrenoceptor blockade (propranolol 4 mg/kg) on the responses to the bronchodilators. Propranolol blocked completely the responses to salbutamol (10 micrograms/kg) and to aminophylline (5, 10 and 20 micrograms/kg) without affecting the response to ipratropium bromide. The findings indicate that the pretreatment regime employed causes the development of tolerance to the bronchodilator effects of salbutamol and that this tolerance extends to aminophylline, but not to ipratropium bromide. The effects of propranolol and of tolerance to salbutamol suggest that the bronchodilator response to aminophylline is mediated in large part by activation of airway beta-adrenoceptors. The findings also suggest that ipratropium bromide may provide effective bronchodilation (in the presence of parasympathetic tone) in lungs which have become tolerant to beta-adrenoceptor agonists, though whether this may be extrapolated from the guinea pig to man remains to be demonstrated.