TOLERANCE TO SYMPATHOMIMETIC BRONCHODILATORS IN GUINEA‐PIG ISOLATED LUNGS FOLLOWING CHRONIC ADMINISTRATION in vivo

Abstract

1 Pretreatment of the guinea-pig subcutaneously three times daily with either 5 μg/kg isoprenaline or adrenaline reduced the response of the isolated perfused histamine-constricted lung when challenged with either the same or a different sympathomimetic bronchodilator. The longer the animals were pretreated and the higher the dose of bronchodilator the greater was the degree of tolerance developed. 2 Tolerance was developed to aminophylline in the same preparation when the guinea-pig had been pretreated with aminophylline or isoprenaline. Cross-tolerance also developed to adrenaline when the guinea-pig had been pretreated with aminophylline. 3 Tolerance was still persistent in guinea-pigs one and two weeks after pretreatment three times daily with either isoprenaline or adrenaline (5 μg/kg s.c.) for seven days in the same preparation. Only after three weeks was the tolerance diminished. 4 These results suggest that asthmatic patients who use bronchodilators excessively may become refractory to the bronchodilator effect of these drugs. They also support the hypothesis that induced cross-resistance to endogenous sympathetic stimulation could lead to a deterioration of the asthmatic state in patients using the sympathomimetic bronchodilators and that this may explain the increase in asthma mortality rate. 5 A mechanism of tolerance to sympathomimetic bronchodilators is postulated.