Chronic sustained and intermittent hypoxia reduce function of ATP-sensitive potassium channels in nucleus of the solitary tract.

Activation of neuronal ATP-sensitive potassium (K(ATP)) channels is an important mechanism that protects neurons and conserves neural function during hypoxia. We investigated hypoxia (bath gassed with 95% N(2)-5% CO(2) vs. 95% O(2)-5% CO(2) in control)-induced changes in K(ATP) current in second-order neurons of peripheral chemoreceptors in the nucleus of the solitary tract (NTS). Hypoxia-induced K(ATP) currents were compared between normoxic (Norm) rats and rats exposed to 1 wk of either chronic sustained hypoxia (CSH) or chronic intermittent hypoxia (CIH). Whole cell recordings of NTS second-order neurons identified after 4-(4-(dihexadecylamino)styryl)-N-methylpyridinium iodide (DiA) labeling of the carotid bodies were obtained in a brain stem slice. In Norm cells (n = 9), hypoxia (3 min) induced an outward current of 12.7 +/- 1.1 pA with a reversal potential of -73 +/- 2 mV. This current was completely blocked by the K(ATP) channel blocker tolbutamide (100 muM). Bath application of the K(ATP) channel opener diazoxide (200 muM, 3 min) evoked an outward current of 21.8 +/- 5.8 pA (n = 6). Hypoxia elicited a significantly smaller outward current in both CSH (5.9 +/- 1.4 pA, n = 11; P < 0.01) and CIH (6.8 +/- 1.7 pA, n = 6; P < 0.05) neurons. Diazoxide elicited a significantly smaller outward current in CSH (3.9 +/- 1.0 pA, n = 5; P < 0.05) and CIH (2.9 +/- 0.9 pA, n = 3; P < 0.05) neurons. Western blot analysis showed reduced levels of K(ATP) potassium channel subunits Kir6.1 and Kir6.2 in the NTS from CSH and CIH rats. These results suggest that hypoxia activates K(ATP) channels in NTS neurons receiving monosynaptic chemoreceptor afferent inputs. Chronic exposure to either sustained or intermittent hypoxia reduces K(ATP) channel function in NTS neurons. This may represent a neuronal adaptation that preserves neuronal excitability in crucial relay neurons in peripheral chemoreflex pathways.