Force adaptation through the intravenous route in naïve mice.

Abstract

Aim of the study: Force adaptation is a process whereby the contractile capacity of the airway smooth muscle increases during a sustained contraction (aka tone). Tone also increases the response to a nebulized challenge with methacholine in vivo, presumably through force adaptation. Yet, due to its patchy pattern of deposition, nebulized methacholine often spurs small airway narrowing heterogeneity and closure, two important enhancers of the methacholine response. This raises the possibility that the potentiating effect of tone on the methacholine response is not due to force adaptation but by furthering heterogeneity and closure. Herein, methacholine was delivered homogenously through the intravenous (i.v.) route. Materials and Methods: Female and male BALB/c mice were subjected to one of two i.v. methacholine challenges, each of the same cumulative dose but starting by a 20-min period either with or without tone induced by serial i.v. boluses. Changes in respiratory mechanics were monitored throughout by oscillometry, and the response after the final dose was compared between the two challenges to assess the effect of tone. Results: For the elastance of the respiratory system (E_rs), tone potentiated the methacholine response by 64 and 405% in females (37.4 ± 10.7 vs. 61.5 ± 15.1 cmH₂O/mL; p = 0.01) and males (33.0 ± 14.3 vs. 166.7 ± 60.6 cmH₂O/mL; p = 0.0004), respectively. For the resistance of the respiratory system (R_rs), tone potentiated the methacholine response by 129 and 225% in females (9.7 ± 3.5 vs. 22.2 ± 4.3 cmH₂O·s/mL; p = 0.0003) and males (10.7 ± 3.1 vs. 34.7 ± 7.9 cmH₂O·s/mL; p < 0.0001), respectively. Conclusions: As previously reported with nebulized challenges, tone increases the response to i.v. methacholine in both sexes; albeit sexual dimorphisms were obvious regarding the relative resistive versus elastic nature of this potentiation. This represents further support that tone increases the lung response to methacholine through force adaptation.