Repeated methacholine challenge produces tolerance in normal but not in asthmatic subjects

Repeated methacholine challenge in normal nonasthmatic subjects (who require higher doses of methacholine than do asthmatic subjects to produce a 20 percent decrease in FEV1) can produce progressively diminishing methacholine responsiveness (or tolerance) with serial challenges. To determine whether tolerance to methacholine occurs in asthmatic subjects as it does in nonasthmatic subjects, we studied eight young (mean age, 24 years) mild asthmatic patients (occasional but not regular use of bronchodilator medications, PC20 methacholine range 0.1 to 7.0 mg/ml) who underwent five sequential methacholine challenges at 1.5-h intervals. Serially increasing concentrations of methacholine were given until FEV1 fell by 20 percent. Results were compared with those in seven nonasthmatic control subjects who underwent an identical protocol. As seen in previous studies, the normal subjects demonstrated significant tolerance to methacholine when each of five challenges was compared to the first. By contrast, in the asthmatic group, the mean cumulative dose of methacholine producing a 20 percent fall in FEV1 in the fifth challenge was not significantly different from the dose required in the first challenge. These results indicate that marked tolerance to methacholine does not occur in mild asthmatic patients with multiple repeated challenges over 6 h. The lower cumulative dose of methacholine required by asthmatic patients may be insufficient to produce tolerance.