The role of nitric oxide in the modulation of breathing during hypoxia; studies in transgenic mice.

摘要

In the present study, the role of nitric oxide (NO) in the modulation of the hypoxic ventilatory response was examined. NO is produced by two constitutive isoforms of NO synthase, i.e., a neuronal (NOS-1) and an endothelial (NOS-3) isoform. Experiments were performed on awake and anesthetized wild-type (Wt) mice, as well as mutant mice deficient in NOS-1 or NOS-3. In awake animals, respiration was monitored by plethysmography. In anesthetized mice, integrated efferent phrenic nerve activity was monitored as an index of neural respiration. Peripheral chemosensitivity was examined by the ventilatory response to cyanide or brief hyperoxia. The respiratory response to acute, episodic or sustained hypoxia was monitored. Under awake as well as anesthetized conditions, the respiratory response to acute hypoxia (5 min, 12% O2) was greater in NOS-1 mutant than Wt mice. The ventilatory responses to cyanide and brief hyperoxia were also augmented in the NOS-1 mutant, suggesting enhanced peripheral chemosensitivity. In contrast to NOS-1 mutant mice, the respiratory response to hypoxia, cyanide and brief hyperoxia was attenuated in NOS-3 mutant mice, compared to Wt mice, suggesting blunted chemosensitivity. Following termination of a hypoxic challenge (7% O2), respiration remained significantly elevated during normoxia in Wt mice, but not in NOS-1 mutant mice. Following episodic hypoxia (3X 7% O2, intermittent with 21% O 2), respiration remained elevated for up to 30 minutes in Wt mice, whereas breathing in NOS-1 mice promptly returned to baseline values. After 90 hrs of sustained hypobaric hypoxia, the ventilatory response to acute hypoxia (12% O2) was significantly elevated in Wt mice, in part due to enhanced peripheral chemosensitivity. By contrast, such an enhanced response to acute hypoxia or peripheral chemosensitivity was not seen in NOS-1 or NOS-3 mutant mice. Taken together, these results support the idea that NO from NOS-1 and NOS-3 is an important physiological modulator of respiration during hypoxia.