S-Nitrosoglutathione reductase is a key enzyme in hypoxic and post-hypoxic ventilatory signaling

The endogenous S-nitrosothiol, S-nitrosoglutathione (GSNO), regulates the activities of cell proteins by S-nitrosylation of key cysteine residues. There is compelling evidence that this S-nitrosothiol plays a role in ventilatory function including that bilateral microinjections of GSNO into the nucleus tractus solitarius of conscious rats, elicit profound increases in minute ventilation (MV). Exposure of mice to a hypoxic challenge elicits a robust increase in MV that declines during the challenge (roll-off) whereas return to room-air results in enhanced ventilation (short-term facilitation, STF). Since GSNOR catalyzes the GSH/NADH-dependent metabolism of GSNO to the disulfide, we hypothesize that increased GSNOR activity and enhanced degradation of GSNO, underlies ventilatory roll-off and diminished expression of STF. The first objective of this study was to examine the hypoxic ventilatory responses of wild-type C57BL6, GSNOR+/− and GSNOR−/− mice during exposure to a hypoxic challenge (10% O2, 90% N2 for 15 min) and upon return to room-air. In brief, ventilatory roll-off was virtually absent in the GSNOR+/− and GSNOR−/− mice whereas, STF was augmented. Our second on-going objective to collect biochemical evidence from WT, GSNOR+/− and GSNOR−/− mice as to whether an increase in GSNOR in the brainstem, lung and diaphragm contribute to the above ventilatory responses. The data includes changes in total S-nitrosothiol abundance, GSNOR activity, GSH/GSSG levels and NADH/NAD+ levels. This study, which is the first pertaining to determination of the hypoxic ventilatory response, roll off and STF in GSNOR+/− or GSNOR−/− mice, provides compelling evidence for key rolls of GSNOR and GSNO in ventilatory responses.