Mechanism of Methacholine Dose-Response Plateaus in Normal Subjects

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Abstract
Normal subjects develop plateaus on dose-response curves produced from inhalation challenge tests with bronchoconstricting agonists. These plateaus occur after only mild degrees of airway narrowing despite the fact that, if unloaded, maximally activated airway smooth muscle (ASM) should be able to cause airway closure. Plateaus may develop because, despite maximal activation, the muscle load pro- vided by lung parenchymal recoil and tidal swings in airway transmural pressure are sufficient to pre- vent further ASM shortening. Alternatively, progressive ASM activation may occur throughout the plateau, but progressive hyperinflation and/or parenchymal stiffening could increase parenchymal load and attenuate further airway narrowing. In the first case, maximal ASM activation causes the plateau and in the second case the plateau is caused by progressive activation balanced by progres- sive loading. To test which of these mechanisms is responsible for the plateau, we measured pulmo- nary resistance (R L ) and the maximal, minimal, and mean pulmonary elastic recoil pressure (P ELmax , P ELmin , and P ELmean ) during tidal breathing throughout methacholine challenge in 10 normal subjects. P ELmean served as our measure of ASM afterload. Subjects swallowed an esophageal balloon and in- haled doubling concentrations of methacholine (1 to 256 mg/ml). R L was measured after each dose, as was P EL . All subjects developed a plateau on the dose-response curve defined by , 25% change in R L over three successive doses. During the R L plateau, there was no significant further increase in P ELmean , i.e., P ELmean also plateaued. These data are consistent with the hypothesis that maximal activa- tion of ASM is balanced by an equal afterload at the maximal dose-response plateau. Airway hyperre- sponsiveness could result from a failure of afterload to attenuate muscle shortening after maximal ac- tivation. Moore BJ, King GG, D'yachkova Y, Ahmad HR, Paré PD. Mechanism of methacholine dose-response plateaus in normal subjects. AM J RESPIR CRIT CARE MED 1998;158:666-669.