Ventilatory responses during and following exposure to a hypoxic challenge in conscious mice deficient or null in S-nitrosoglutathione reductase

Exposure to a hypoxic challenge increases ventilation in wild-type (WT) mice that diminish during the challenge (roll-off) whereas return to room air causes an increase in ventilation (short-term facilitation, STF). Since plasma and tissue levels of ventilatory excitant S-nitrosothiols such as S-nitrosoglutathione (GSNO) increase during hypoxia, this study examined whether (1) the initial increase in ventilation is due to generation of GSNO, (2) roll-off is due to increased activity of the GSNO degrading enzyme, GSNO reductase (GSNOR), and (3) STF is limited by GSNOR activity. Initial ventilatory responses to hypoxic challenge (10% O₂, 90% N₂) were similar in WT, GSNO+/? and GSNO?/? mice. These responses diminished markedly during hypoxic challenge in WT mice whereas there was minimal roll-off in GSNOR+/? and GSNOR?/? mice. Finally, STF was greater in GSNOR+/? and GSNOR?/? mice than in WT mice (especially females). This study suggests that GSNOR degradation of GSNO is a vital step in the expression of ventilatory roll-off and that GSNOR suppresses STF.