Disruption of Kir6.2-containing ATP-sensitive potassium channels impairs maintenance of hypoxic gasping in mice.
Hypoxic gasping emerges under severe hypoxia/ischemia in various species, exerting a life-protective role by assuring minimum ventilation even in loss of consciousness. However, the molecular basis of its generation and maintenance is not well understood. Here we found that mice lacking Kir6.2- but not Kir6.1-containing ATP-sensitive potassium (K(ATP)) channels [knockout (KO) mice] exhibited few gaSPS when subjected to abrupt ischemia by decapitation, whereas wild-type mice all exhibited more than 10 gaSPS. Under anesthesia, wild-type mice initially responded to severe hypoxic insult with augmented breathing (tachypnea) accompanied by sighs and subsequent depression of respiratory frequency. Gasping then emerged and persisted stably (persistent gasping); if the hypoxia continued, several gaSPS with distinct patterns appeared (terminal gasping) before cessation of breathing. KO mice showed similar hypoxic responses but both depression and the two types of gasping were of much shorter duration than in wild-type mice. Moreover, in the unanesthetized condition, the onset of terminal gasping in KO mice, which was always earlier than in wild-type mice, was unaltered by decreasing O(2) concentrations within the severe range (4.5-7.0%), whereas onset in wild-type mice became earlier in response to lowered O(2) concentrations. Thus, the mechanism responsible for regulating the hypoxic response in accordance with the severity of the hypoxia was dysfunctional in these KO mice, suggesting that Kir6.2-containing K(ATP) channels are critically involved in the maintenance rather than the generation of hypoxic gasping and depression of respiratory frequency.
Miyake
Akari
A
Department of Physiology, Akita University School of Medicine, Akita, Japan.
Yamada
Katsuya
K
Kosaka
Tomohiro
T
Miki
Takashi
T
Seino
Susumu
S
Inagaki
Nobuya
N
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D000860:Hypoxia; D054086:KATP Channels; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D012119:Respiration; D000099161:Kcnj11 Channel
D000255:Adenosine Triphosphate; D002245:Carbon Dioxide; D054086:KATP Channels; D010100:Oxygen; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel; C092520:uK-ATP-1 potassium channel