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

Abstract

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% O(2), 90% N(2)) 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.

Fig. 1

Changes in frequency of breathing (top panels), tidal volume (middle panels) and ventilation (bottom panels) during exposure to hypoxia (10% O₂, 90% N₂ for 15 min) and following return to room-air (normoxia). Left-hand panels: Conscious female C57BL6 mice (n=16), GSNOR+/− mice (n=9) and GSNOR−/− mice (n=17). Right-hand panels: Conscious male C57BL6 mice (n=16), GSNOR+/− mice (n=7) and GSNOR−/− mice (n=5).The stippled horizontal lines denote the average resting values immediately before exposure to hypoxia. The data are presented as mean ± SEM.

Fig. 2

Changes in Inspiratory time (top panels) and Expiratory Time (middle panels) and Tidal volume/Inspiratory time (V_T/T_I, index of respiratory drive) (bottom panels) during exposure to hypoxia (10% O₂, 90% N₂ for 15 min) and following return to room-air (normoxia). Left-hand panels: Conscious female C57BL6 mice (n=16), GSNOR+/− mice (n=9) and GSNOR−/− mice (n=17). Right-hand panels: Conscious male C57BL6 mice (n=16), GSNOR+/− mice (n=7) and GSNOR−/− mice (n=5). The stippled horizontal lines denote the average resting values immediately before exposure to hypoxia. The data are presented as mean ± SEM.

Fig. 3

Changes in peak inspiratory flow (top panels) and peak expiratory flow (bottom panels) during exposure to hypoxia (10% O₂, 90% N₂ for 15 min) and following return to room-air (normoxia). Left-hand panels: Conscious female C57BL6 mice (n=16), GSNOR+/− mice (n=9) and GSNOR−/− mice (n=17). Right-hand panels: Conscious male C57BL6 mice (n=16), GSNOR+/− mice (n=7) and GSNOR−/− mice (n=5). The stippled horizontal lines denote the average resting values immediately before exposure to hypoxia. The data are presented as mean ± SEM.