Gaseotransmitters Modulate Inspiratory Drive from the Hypoglossal Nucleus

Gaseotransmitters, carbon monoxide (CO) and hydrogen sulfide (H2 S), play an important role in maintaining proper function of cardio-respiratory systems. Previous work has demonstrated that Heme Oxygenase-2 knock out mice (HO-2-/- ) develop a sleep apnea phenotype characterized predominantly by obstructive apneas, which could be normalized by either treating HO-2-/- with L-propargylglycine (L-PAG) an inhibitor of cystathionine gamma-lysase (CSE) and H2S synthesizing enzyme or in HO-2+ CSE double null mice. Obstructive apneas are often caused by a loss in upper airway tone, we sought to examine how H2 S and CO signaling impacts inspiratory activity from the preBötC and the hypoglossal nucleus (XIIn). We hypothesized that HO-2 and CSE are involved in the regulation of inspiratory motor output from XIIn. Immunohistochemical analysis revealed many ChAT+ cells of XIIn are positive for HO-2 and CSE. Biochemical analysis showed elevated H2 S abundance in XIIn of HO-2-/- mice. Electrophysiological recordings demonstrated transmission failure from preBötC to XIIn in response to NaHS, a H2S donor or Cr (III) Mesoporphyrin IX chloride (ChrMP459), an inhibitor of HO in brain slices from wild type mice. Furthermore, ChrMP459 reduced inspiratory drive currents received by XIIn neurons and suppressed excitability in XIIn neurons. Brain slices from HO-2-/- mice showed: (1) a larger rate of transmission failure between preBötC and XIIn motor pools; and (2) smaller drive currents from individual XIIn neurons. Brain slices from HO-2+ CSE double null mice displayed reduced transmission failures from preBötC to XIIn. Furthermore, L-PAG mitigated transmission failures and increased the magnitude of inspiratory drive currents in XIIn neurons in HO-2-/- mice. These findings demonstrate that HO-2 and CSE regulate inspiratory drive from XIIn and suggest potential role for gaseotransmitters in regulating upper airway tone.