Methacholine versus histamine: paradoxical response of spirometry and ventilation distribution

We investigated the differential effect of histamine and methacholine on sp irometry and ventilation distribution (where indexes S-cond and S-acin repr esent conductive and acinar ventilation heterogeneity; Verbanck S, Schuerma ns D, Van Muylem A, Noppen M, Paiva M, and Vincken W. J Appl Physiol 83: 18 07-1816, 1997). Thirty normal subjects were challenged with cumulative dose s of 6.52 mu mol histamine and, on a separate day, with either 6.67 mu mol methacholine (equal-dose group; n = 15) or 13.3 mu mol methacholine (double -dose group; n = 15). Largest average forced expiratory volume in 1 s (FEV1 ) decreases or S-cond increases obtained in either group were -9% and +286% , respectively; S-acin remained unaffected at all times. In the equal-dose group, a smaller FEV1 decline (P = 0.002) after methacholine was paralleled by a smaller S-cond increase (P = 0.041) than with histamine. However, in the double-dose group, methacholine maintained a smaller FEV1 decline (P = 0.009) while inducing a larger S-cond increase (P = 0.006) than did histami ne. The differential action of histamine and methacholine is confined to th e conductive airways, where histamine likely causes the greatest overall ai rway narrowing and methacholine induces the largest parallel heterogeneity in airway narrowing, probably at the level of the large and small conductiv e airways, respectively. The observed ventilation heterogeneities predict a risk for dissociation between ventilation-perfusion mismatch and spirometr y, particularly after methacholine challenge.