Blunted respiratory responses to hypoxia in mutant mice deficient in nitric oxide synthase-3

In the present study, the role of nitric oxide (NO) generated by endothelia l nitric oxide synthase (NOS-3) in the control of respiration during hypoxi a and hypercapnia was assessed using mutant mice deficient in NOS-3. Experi ments were performed on awake and anesthetized mutant and wild-type (WT) co ntrol mice. Respiratory responses to 100, 21, and 12% O-2 and 3 and 5% CO2- balance O-2 were analyzed. In awake animals, respiration was monitored by b ody plethysmography along with O-2 consumption ((V) over dot O-2) and CO2 p roduction ((V) over dot CO2). In anesthetized, spontaneously breathing mice , integrated efferent phrenic nerve activity was monitored as an index of n eural respiration along with arterial blood pressure and blood gases. Under both experimental conditions, WT mice responded with greater increases in respiration during 12% O-2 than mutant mice. Respiratory responses to hyper oxic hypercapnia were comparable between both groups of mice. Arterial bloo d gases, changes in blood pressure, (V) over dot O-2, and (V) over dot CO2 during hypoxia were comparable between both groups of mice. Respiratory res ponses to cyanide and brief hyperoxia were attenuated in mutant compared wi th WT mice, indicating reduced peripheral chemoreceptor sensitivity. cGMP l evels in the brain stem during 12% On, taken as an index of NO production, were greater in mutant compared with WT mice. These observations demonstrat e that NOS-3 mutant mice exhibit selective blunting of the respiratory resp onses to hypoxia but not to hypercapnia, which in part is due to reduced pe ripheral chemosensitivity. These results support the idea that NO generated by NOS-3 is an important physiological modulator of respiration during hyp oxia.