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% 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 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.

Hypoxia-Induced Changes in Protein S-Nitrosylation in Female Mouse Brainstem

“…As reviewed by Palmer and colleagues (11,18), studies in humans found that HVRs are greater in females, equal in females and males, or that women have a lower HVR and hypercapnic drive than men. Disparate findings have also been generated in rats.…”

“…First, the expression of HVR and shortterm potentiation (STP) are absent in conscious mice with bilateral carotid sinus nerve transection (39), supporting a role of carotid body primary glomus cells/ chemoafferents in these responses. As such, the potential release of S-nitrosothiols from eNOS-positive glomus cells (11) and subsequent activation of chemoafferent terminals may contribute to the initiation of HVR, whereas S-nitrosothiols generated from red blood cell hemoglobin (see subsequent text) do not appear to be vital for initiation of the HVR (39). Second, ventilatory roll-off during the hypoxic challenge is absent in conscious GSNOR 1/2 or GSNO 2/2 mice (11), clearly suggesting that roll-off is due to enhanced catabolism of GSNO in the carotid body and/or central structures.…”

“…Female GSNOR 1/2 and GSNOR 2/2 mice (10-12 wk old) were from breeding colonies maintained at the University of Virginia. The status of the menstrual cycle was not taken into account, because its effects on hypoxic ventilatory response (HVR) in mice are minor, and range from an increased HVR in the luteal phase by 10-20% compared with the follicular phase, because of the lack of correlation between the ratio of progesterone and estradiol and the HVR response, and because sex differences in HVR in rats are due to mechanisms independent of ovarian hormones (11,18).…”

“…The ventilatory responses elicited during hypoxic challenge (10% O 2 , 90% N 2 for 15 min) were recorded as described previously (11,18). These mice were taken randomly from the pool that also provided mice for the in vitro tissue studies described in this article.…”

“…S-nitrosothiols (SNOs) are involved in ventilatory control processes (11,12), and microinjections of these compounds, including GSNO, into the NTS of conscious rats elicit marked increases in VM (12). The finding that ventilatory roll-off does not occur in male and female mice deficient in GSNOR (11) suggests that mechanisms decreasing GSNO abundance and protein S-nitrosylation contribute to this phenomenon.…”