Nitric Oxide and ATP-Sensitive Potassium Channels Mediate Lipopolysaccharide-Induced Depression of Central Respiratory-Like Activity in Brain Slices

Abstract

Infection may result in early abnormalities in respiratory movement, and the mechanism may involve central and peripheral factors. Peripheral mechanisms include lung injury and alterations in electrolytes and body temperature, but the central mechanisms remain unclear. In the present study, brainstem slices harvested from rats were stimulated with lipopolysaccharide at different doses. Central respiratory activities as demonstrated by electrophysiological activity of the hypoglossal rootlets were examined and the mechanisms were investigated by inhibiting nitric oxide synthase and ATP-sensitive potassium channels. As a result, 0.5 µg/ml lipopolysaccharide mainly caused inhibitory responses in both the frequency and the output intensity, while 5 µg/ml lipopolysaccharide caused an early frequency increase followed by delayed decreases in both the frequency and the output intensity. At both concentrations the inhibitory responses were fully reversed by inhibition of nitric oxide synthase with Nω-nitro-L-arginine methyl ester hydrochloride (20 µM), and by inhibition of ATP- sensitive potassium channels with glybenclamide (100 µM). These results show that direct lipopolysaccharide challenge altered central respiratory activity in dose- and time- related manners. Nitric oxide synthase and ATP-sensitive potassium channels may be involved in the respiratory changes.

Time and dose-dependent impairment of neonatal respiratory motor activity after systemic inflammation

“…Continuous bath application of LPS decreased respiratory activity in rhythmic slice preparations (Camacho-Hernández et al, 2019;Lorea-Hernández et al, 2016;Lu et al, 2012), although the effects on amplitude and frequency depended on the concentration. Similar to the results shown here, respiratory amplitude decreased after bath application of LPS (200 ng/ml LPS, Lorea-Hernández et al, 2016), while frequency decreased after 5 μg/ml bath-applied LPS (Lu et al, 2012), also demonstrating dose-dependent impairment in respiratory activity. Additionally, bath-applied LPS prior to intermittent anoxia attenuated intermittent anoxia-induced LTF (Camacho-Hernández et al, 2019).…”

“…To understand the temporal and dose-dependency of systemic neonatal inflammation on respiratory activity, we investigated the effect of increasing LPS dose (0.1-10mg /kg) at 1h and 3h on fictive respiratory activity. Although neonatal infections can have deadly consequences (Heron, 2018) and neonatal respiratory impairment during infection is common (Campion et al, 2006;Fetter et al, 1995;Hofstetter et al, 2008;Ollikainen et al, 1993), the effect of neonatal inflammation on neural circuitry controlling breathing remains poorly understood (Camacho-Hernández et al, 2019;Lorea-Hernández et al, 2016;Lu et al, 2012). Further, we know little about the impact of timing and magnitude of early life inflammation on neonatal respiratory activity.…”

“…An important contrast between the previous studies and our study is the method of LPS exposure. Bath application of LPS is directly inducing CNS inflammation (Camacho-Hernández et al, 2019;Lorea-Hernández et al, 2016;Lu et al, 2012), while intraperitoneal injections of LPS induces peripheral inflammation and indirectly central inflammation. As LPS does not cross the blood-brain barrier (Banks & Robinson, 2010), the profile of the inflammatory response and associated respiratory impairment after direct application of the LPS to the CNS likely differs from the indirect effects of activating the peripheral inflammatory signaling.…”