The relationship between acetylcholine- and histamine-induced constriction of large airways in normal subjects and subjects with asthma: A possible role for postreceptor mechanisms

Abstract

Whether in man histamine (H) and acetylcholine (ACH) airway responses are interrelated is controversial. With the use of quantitative nebulization and specific airway conductance ( G aw V L , we recorded noninvasive pharmacologic tests of H- and ACH-induced bronchoconstriction in 11 normal subjects (N) and nine subjects with asthma (AST) with and without pretreatment of 0.75 mg (A 0.75) and 1.50 mg (A 1.50) of inhaled atropine. Provocation dose 40 (PD 40) for H or ACH were different in N (0.8 × 10 −2 mol/L and 2.9 × 10 −2 mol/L, respectively) and AST (5.0 × 10 −3 mol/L and 7.8 × 10 −3 mol/L) but linearly related. The ratio PD 40-ACH PD 40-H was comparable in N and AST and similar to the ratio ACH sensitivity/H sensitivity found in vitro for large airways. The slopes of log dose-response curves (SLDRC) to H and SLDRC to ACH were of similar magnitude both in N and AST and linearly related; however, for either agonist, bronchial sensitivity (PD 40) and reactivity (SLDRC) failed to correlate. After A 0.75, the dose ratios (DR) of H and ACH were large, with substantial intersubject variability, and similar in N (4.32 and 9.54, respectively) and AST (5.97 and 5.64). Although numerically comparable, DR of H and DR of ACH were unrelated. After A 1.50, DR of H remained unchanged (4.53 in N and 5.44 in AST), but DR of ACH further increased (17.37 in N and 8.13 in AST). Pretreatment with A 0.75 respected the linear relationship of PD 40-H versus PD 40-ACH but blurred that of reactivity to these agonists. After A 0.75 or A 1.50, solΔG aw V L was similar in N and AST. Except for PD 40, none of the tests recorded could distinguish AST from N. In conclusion, H-induced bronchoconstriction is substantially but not exclusively mediated via ACH pathway. We hypothesize that H and ACH responses anastomose within the cholinergic pathway at a sensitivity and a reactivity level; the former level is ostensibly downstream from and unrelated to the latter. In AST, the reactivity to H and ACH, the bronchodilating, anti-histaminic (DR of H) and antimuscarinic (DR of ACH) effects of atropine are normal and so is ostensibly the anastomosis between H and ACH reactivity levels. The level of H and ACH sensitivity distinguishes AST from N. ACH-sensitivity site may be located at the H->ACH anastomosis.