H2S synthesis inhibitor prevents hypoxia‐evoked periodic breathing in spontaneous hypertensive rats

Abstract

An augmented carotid body (CB) response to hypoxia has been implicated as one of the mechanism for evoking periodic breathing (PB). Spontaneous hypertensive (SH) rats exhibit CB hypersensitivity to hypoxia; this hypersensitivity is mediated by H2S produced by cystathionine‐g‐lyase (CSE; Peng et al. PNAS, 2017). Using whole‐body plethysmography, we demonstrate that acute hypoxia evokes PB in unsedated 2–4 month old SH rats; PB was characterized by episodes of hyperventilation and hypoventilation (decreased tidal volume and respiratory rate). The magnitude of PB in SH rats was linked to the severity of hypoxia: exposure to 12% O2 elicited 40 ± 3 episodes/hr of PB, while more severe hypoxia (8–10% O2) elicited 114 ± 4 episodes/hr of PB. Oral administration of the CSE inhibitor, L‐propargylglycine (L‐PAG) prevented CB hypersensitivity to hypoxia and stabilized breathing in dose‐related fashion. L‐PAG is rapidly absorbed after oral dosing (Tmax = 0.25 to 0.5 hr) and oral bioavailability is 100%. These data demonstrate that CSE inhibition provides a viable mechanism for prevention of breathing instability arising from CB hypersensitivity to hypoxiaSupport or Funding Information(Supported by NHLBI grant UH3HL‐123610).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.