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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

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

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Submitted 27 April 2008 ; accepted in final form 3 September 2008

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% N₂-5% CO₂ vs. 95% O₂-5% CO₂ 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 µM). Bath application of the K_ATP channel opener diazoxide (200 µM, 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.

chemoreflex; electrophysiology; respiration

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				W. Zhang, F. R. Carreno, J. T. Cunningham, and S. W. Mifflin Chronic Sustained Hypoxia Enhances Both Evoked EPSCs and Norepinephrine Inhibition of Glutamatergic Afferent Inputs in the Nucleus of the Solitary Tract J. Neurosci., March 11, 2009; 29(10): 3093 - 3102. [Abstract] [Full Text] [PDF]