Am. J. Respir. Crit. Care Med., Volume 158, Number 2, August 1998, 666-669

Mechanism of Methacholine Dose-Response Plateaus in Normal Subjects

B. J. MOORE, G. G. KING, Y. D'YACHKOVA, H. R. AHMAD, and PETER D. PARÉ

University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, British Columbia, Canada

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 provided by lung parenchymal recoil and tidal swings in airway transmural pressure are sufficient to prevent 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 progressive loading. To test which of these mechanisms is responsible for the plateau, we measured pulmonary resistance (RL) and the maximal, minimal, and mean pulmonary elastic recoil pressure (PEL_max, PEL_min, and PEL_mean) during tidal breathing throughout methacholine challenge in 10 normal subjects. PEL_mean served as our measure of ASM afterload. Subjects swallowed an esophageal balloon and inhaled doubling concentrations of methacholine (1 to 256 mg/ml). RL was measured after each dose, as was PEL. All subjects developed a plateau on the dose-response curve defined by < 25% change in RL over three successive doses. During the RL plateau, there was no significant further increase in PEL_mean, i.e., PEL_mean also plateaued. These data are consistent with the hypothesis that maximal activation of ASM is balanced by an equal afterload at the maximal dose-response plateau. Airway hyperresponsiveness could result from a failure of afterload to attenuate muscle shortening after maximal activation.

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