Excitatory Modulation of the preBötzinger Complex Inspiratory Rhythm Generating Network by Endogenous Hydrogen Sulfide

Hydrogen Sulfide (H(2)S) is one of three gasotransmitters that modulate excitability in the CNS. Global application of H(2)S donors or inhibitors of H(2)S synthesis to the respiratory network has suggested that inspiratory rhythm is modulated by exogenous and endogenous H(2)S. 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 H(2)S. Importantly, site-specific modulation of respiratory nuclei by H(2)S means that targeted, rather than global, manipulation of respiratory nuclei is required to understand the role of H(2)S signaling in respiratory control. Thus, our aim was to test whether endogenous H(2)S, 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 H(2)S 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% O(2), 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-H(2)S system, and that endogenous H(2)S attenuates the secondary hypoxic respiratory depression.