Disruption of Kir6.2‐containing ATP‐sensitive potassium channels impairs maintenance of hypoxic gasping in mice

Abstract

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.

Assessment of a New Piezoelectric Transducer Sensor for Noninvasive Cardiorespiratory Monitoring of Newborn Infants in the NICU

“…It was reported that respiratory activity monitoring by a similar PZT sensor was in good agreement with that by a CO 2 respiratory monitor [24] or a thermistor airflow sensor [7] in mice. However, a large deformation of respiratory signal due to motion artifacts, routine care and artificial ventilation made BR evaluation impossible in about 30% of the total recording time in the present study ( table 3 ).…”

Neuronal network properties underlying the generation of gasping

“…Recently, it was shown that a transgenic mouse lacking the K + channel responsible for the ATP‐sensitive K + current exhibited an exacerbated initial augmentation, along with a weaker secondary depression, in response to hypoxia 60 . In a similar report, using another mouse lacking ATP‐sensitive K + currents, it was found that those animals exhibited an exacerbated initial augmentation along with shortened duration of gasping rhythm generation 61 …”

The Cellular Building Blocks of Breathing

“…These include apamin-sensitive SK3 potassium channels (34), neuronal ATP-sensitive potassium (K ATP ) channels formed by Kir6.2 (343, 353) and SUR1 subunits (4, 230), and pH-sensitive inward rectifier (Kir2.2; 387) and “two-pore” potassium channels [TASK1, TASK3; (363); TASK2, (172)]. In general, none of these genetic manipulations of single potassium channel genes yielded overtly catastrophic respiratory phenotypes, as all strains were viable, even if mutant phenotypes were observed in the context of isolated preBötC slices or single neuronal recordings.…”

“…The role for K ATP channels was also examined at the behavioral level using a mouse strain in which Kir6.2 was genetically deleted (353, 386). Deletion of Kir6.2 was found to clearly abolish the gasping response induced by decapitation.…”