Investigation of occurrence of tolerance to bronchodilator drugs in chronically pretreated guinea-pigs.

1 The actions of sympathomimetic amines on isolated preparations of atria, trachea and ileum were studied in vitro in guinea-pigs, which had been pretreated for 5 or 12 days, by subcutaneous injection, with adrenaline (5 mug/kg), salbutamol (0.5 mug/kg), salbutamol (0.5 mug/kg), methoxamine (250 mug/kg) or saline (0.9% w/V NaCl solution). 2 In the trachea, a decrease in sensitivity (tolerance) to the relaxant effect of adrenaline was induced by pretreatment, for 12 but not for 5 days, with adrenaline. In these animals, cross-tolerance to isoprenaline or salbutamol was not observed. Tolerance to the relaxant actions of adrenaline isoprenaline or salbutamol was not observed after pretreatment with salbutamol. 3 In the trachea, pretreatment with methoxamine or adrenaline for 12 days did not change the sensitivity to the alpha-adrenoceptor-mediated contractor action of methoxamine. 4 In the atria from those guinea-pigs pretreated with adrenaline or salbutamol, there was no reduced sensitivity to the beta-adrenoceptor agonist actions of adrenaline, isoprenaline or salbutamol. In animals pretreated with methoxamine or adrenaline, there was no observable tolerance or cross tolerance to methoxamine with respect to its alpha-adrenoceptor-mediated positive inotropic action in the atria and no unequivocal evidence of a reduced sensitivity to that action of adrenaline. 5 It was confirmed that the twitch-like contractions of the longitudinal muscle of the electrically stimulated ileum were inhibited by sympatomimetic amines acting on alpha- and beta-adrenoceptors. There was no reduced sensitivity to the inhibitory actions of noradrenaline or isoprenaline on the twitch of ileum isolated from animals pretreated with adrenaline, salbutamol or methoxamine for 5 or 12 days. 6 From our results on these three preparations from the same animals, it is concluded that generalizations regarding changes in sensitivity to sympathomimetic amines following their prolonged administration should not be made in any one species.