Abstract
Hydrogen Sulfide (H2S) is one of three gasotransmitters that modulate excitability in the CNS. Global application of H2S donors or inhibitors of H2S synthesis to the respiratory network has suggested that inspiratory rhythm is modulated by exogenous and endogenous H2S. However, effects have been variable, which may reflect that the RTN/pFRG (retrotrapezoid nucleus, parafacial respiratory group) and the preBötzinger Complex (preBötC, critical for inspiratory rhythm generation) are differentially modulated by exogenous H2S. Importantly, site-specific modulation of respiratory nuclei by H2S means that targeted, rather than global, manipulation of respiratory nuclei is required to understand the role of H2S signaling in respiratory control. Thus, our aim was to test whether endogenous H2S, which is produced by cystathionine-β-synthase (CBS) in the CNS, acts specifically within the preBötC to modulate inspiratory activity under basal (in vitro/in vivo) and hypoxic conditions (in vivo). Inhibition of endogenous H2S production by bath application of the CBS inhibitor, aminooxyacetic acid (AOAA, 0.1–1.0 mM) to rhythmic brainstem spinal cord (BSSC) and medullary slice preparations from newborn rats, or local application of AOAA into the preBötC (slices only) caused a dose-dependent decrease in burst frequency. Unilateral injection of AOAA into the preBötC of anesthetized, paralyzed adult rats decreased basal inspiratory burst frequency, amplitude and ventilatory output. AOAA in vivo did not affect the initial hypoxia-induced (10% O2, 5 min) increase in ventilatory output, but enhanced the secondary hypoxic respiratory depression. These data suggest that the preBötC inspiratory network receives tonic excitatory modulation from the CBS-H2S system, and that endogenous H2S attenuates the secondary hypoxic respiratory depression.
Highlights
Hydrogen sulfide (H2S) is a gasotransmitter that modulates neuronal excitability and synaptic transmission in the peripheral and central nervous systems (Kimura, 2014)
Exogenous H2S applied via donors is reported to inhibit inspiratory rhythm in vitro through actions in the RTN/pFRG and excite inspiratory rhythm in the preBötzinger Complex (preBötC)
To test the hypothesis that endogenous H2S modulates inspiratory activity in vitro, and that the net effect of H2S results from an interaction between differential actions in the preBötC and RTN/pFRG, we compared the effects on baseline inspiratory frequency and amplitude in brainstem spinal cord (BSSC) and rhythmic slice preparations of inhibiting H2S production via bathapplication of incrementing concentrations of the CBS inhibitor, aminooxyacetic acid (AOAA)
Summary
Hydrogen sulfide (H2S) is a gasotransmitter that modulates neuronal excitability and synaptic transmission in the peripheral and central nervous systems (Kimura, 2014). High concentrations decrease frequency and are associated with respiratory and cardiac irregularities and coma (Beauchamp et al, 1984; Reiffenstein et al, 1992). High doses inhibit the activity of inspiratory networks isolated in vitro (Greer et al, 1995) and cause apnea and death within minutes. The lethal actions of exogenous H2S are not due to its direct inhibition of the central respiratory network because the brainstem inspiratory network, when isolated in vitro, continues to generate rhythm when exposed to levels of H2S that are lethal in vivo (Greer et al, 1995)
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