TASK-1 regulates mitochondrial function under hypoxia.

TASK-1, TWIK-related acid-sensitive potassium channel 1, is a member of the two-pore- domain potassium channel family. It is constitutively active at resting potentials and strongly expressed in the heart. However, little is known about the role of TASK-1 channels in hypoxia. A cellular model of hypoxia and reoxygenation from rat heart-derived H9c2 cells or TASK-1 deficient HEK293T cells was employed to explore the role of TASK-1 channels in cytoprotection against hypoxia. The cell viability assay revealed that TASK-1 expression increased the number of viable cells subjected to 2 h of hypoxia followed by 2 h of reoxygenation (H/R). To dissect the protective role of TASK-1 on mitochondrial function, mitochondrial membrane potential (MMP) was assessed by tetramethylrhodamine fluorescence. It was demonstrated that MMP was significantly decreased by H/R, but it was maintained by TASK-1 expression or pretreatment with cyclosporin A, an inhibitor of mitochondrial permeability transition pore (mPTP). The effect of cyclosporin A on MMP was not further altered by TASK-1 expression. Moreover, TASK-1 expression significantly blocked cytochrome c release induced by H/R. While a small fraction of endogenous TASK-1 was found to colocalize with the mitochondrial marker MitoTracker in H9c2 cells, H/R did not alter the extent of colocalization of TASK-1 with MitoTracker. The total TASK-1 protein level was not significantly affected by H/R. In summary, we provided the evidence that TASK-1 channels confer cytoprotection against hypoxia-reoxygenation injury, possibly by their capacity of maintaining the mitochondrial membrane potential via inhibiting MPTP opening.

Retrospective evaluation of dexmedetomidine dosing in a cohort of neurologically injured obese critically ill patients.

Background: Dexmedetomidine is used in neurocritical care units (NCCUs) due to the light, dose-dependent sedation, and anxiolysis provided. It is unknown how to dose dexmedetomidine in obese patients. The primary objective is to assess the ability to achieve the goal Richmond Agitation Sedation Scale (RASS) measurements in obese patients with a neurological injury who are solely on dexmedetomidine before and after an institutional dosing change from actual body weight (ABW) to adjusted body weight (AdjBW). Methods: This study included patients admitted to the NCCU with a neurological condition, required dexmedetomidine for at least 8 h as a sole sedative, and weighed ≥120% of ideal body weight. Percentage of RASS measurements within the goal range (-1 to +1) during the first 48 h while on dexmedetomidine were compared between patients dosed on ABW and on AdjBW. Results: Sixty-eight patients in the ABW cohort and 72 patients in the AdjBW cohort were included. There were no statistical differences between the two groups (ABW vs. AdjBW) in the percent of RASS measurements in the goal range (53.2% ± 34.8% vs. 55% ± 37%; P = 0.78), mean weight (99.2 ± 26 vs. 96.8 ± 20.9 kg; P = 0.55), or the average dose of dexmedetomidine required to achieve first goal RASS score (0.4 ± 0.3 vs. 0.4 ± 0.3 mcg/kg/h; P = 0.98). Conclusions: Dosing dexmedetomidine using AdjBW in obese critically ill neurologically injured patients for ongoing sedation resulted in no statistical difference in the percent of RASS measurements within the goal when compared to ABW dosing. Further studies are warranted.