Methacholine versus histamine: paradoxical response of spirometry and ventilation distribution

Abstract

We investigated the differential effect of histamine and methacholine on spirometry and ventilation distribution (where indexes S cond and S acin represent conductive and acinar ventilation heterogeneity; Verbanck S, Schuermans D, Van Muylem A, Noppen M, Paiva M, and Vincken W. J Appl Physiol 83: 1807–1816, 1997). Thirty normal subjects were challenged with cumulative doses of 6.52 μmol histamine and, on a separate day, with either 6.67 μmol methacholine (equal-dose group; n = 15) or 13.3 μmol 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 histamine. The differential action of histamine and methacholine is confined to the conductive airways, where histamine likely causes the greatest overall airway narrowing and methacholine induces the largest parallel heterogeneity in airway narrowing, probably at the level of the large and small conductive airways, respectively. The observed ventilation heterogeneities predict a risk for dissociation between ventilation-perfusion mismatch and spirometry, particularly after methacholine challenge.