Journal du métabolisme des médicaments et de la toxicologie
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Effects of Long-Acting β2-Agonist and Corticosteroid Inhalation on Diaphragm Muscle in Mice

Chiyohiko Shindoh, Rie Shishido, Natsu Narumi, Hiroshi Takano and Masahito Miura

Background and Objective: Although a combination of inhaled corticosteroid (ICS) and inhaled long-acting β2- agonist (LABA) reduces exacerbation of asthma, whether these affect diaphragm muscle contraction is still unclear. Methods: We investigated the effects of ICS and LABA inhalation separately, endotoxin injection-only, and ICS or LABA inhalation plus endotoxin injection on diaphragm contractile properties and nitric oxide (NO) production during 4 h, using BALB/c mice (n=84). In this study, budesonide was used as the ICS, and formoterol fumarate dehydrate was used as the LABA. After administrations of these drugs, the diaphragm muscles were dissected, and their contractile properties, including force/frequency (F/f) curves and twitch contraction, were measured by electrical pulse stimulation in an isometric condition. A reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry was performed to assess NO production, which induces cellular damages in diaphragm muscle fibers. Results: The ICS inhalation did not significantly shift the F/f curves; but the LABA inhalation significantly shifted them upward compared with shams at 1 h (p < 0.01), 2 h (p < 0.01), and 4 h (p < 0.05) after inhalation, that is, it showed an inotropic effect. Although endotoxin injection resulted in a downward shift in F/f curves at 4 h (p < 0.01) and induced NO production, the endotoxin plus either ICS or LABA inhalation prevented downward shifts of the F/f curves and inhibited NO production. Conclusions: These results indicate that the inhalation of LABA potentiates diaphragm muscle contractility more than ICS inhalation and that both ICS and LABA inhalation inhibit NO production induced by endotoxin injection.