title: Nitric oxide deficit in chronic intermittent hypoxia impairs large conductance calcium-activated potassium channel activity in rat hippocampal neurons.
abstract: Sleep apnea associated with chronic intermittent hypoxia (IH) impairs hippocampal functions but the pathogenic mechanisms involving dysfunction of nitric oxide (NO) and ionic channels remain unclear. We examined the hypothesis that hippocampal NO deficit impairs the activity of large conductance calcium-activated potassium (BK) channels in rats with chronic IH, mimicking conditions in patients with sleep apnea. A patch-clamp study was performed on hippocampal CA1 neurons acutely dissociated from IH and control rats. The levels of endogenous NO and intracellular calcium in the CA1 region of the hippocampal slices were measured respectively by electrochemical microsensors and spectrofluorometry. We found that the open probability of BK channels remarkably decreased in the CA1 pyramidal neurons in a time-dependent manner with the IH treatment, without changes in the unitary conductance and reversal potential. NO donors, SNP or DETA/NO, significantly restored the activity of BK channels in the IH neurons, which was prevented by blockade of S-nitrosylation with NEM or MTSES but not by inhibition of the cGMP pathway with ODQ or 8-bromo-cGMP. Endogenous NO levels were substantially lowered in the IH hippocampus during resting and hypoxia. Also, the level of protein expression of neuronal NO synthase was markedly lessened in the IH neurons with decreased intracellular calcium response to hypoxia. Collectively, the results suggest that the IH-induced NO deficit mediated by a down-regulation of the expression of neuronal NO synthase plays a causative role in the impaired activity of BK channels, which could account for the hippocampal injury in patients with sleep apnea.
authors.affiliation: Department of Physiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Yung-Wui
authors.initials: YW
authors.lastname: Tjong
authors.forename: Meifang
authors.initials: M
authors.lastname: Li
authors.forename: Ming-Wai
authors.initials: MW
authors.lastname: Hung
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Man-Lung
authors.initials: ML
authors.lastname: Fung
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D003067:Coenzymes / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000032:analysis; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D003067:Coenzymes; D051036:Large-Conductance Calcium-Activated Potassium Channels; D020030:Nitric Oxide Donors; D014451:Ubiquinone; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C024989:coenzyme Q10; D002118:Calcium