Involvement of nitric oxide in reduced large conductance calcium-activated potassium channel activity in rat hippocampal CA1 neurons in intermittent hypoxia

Abstract

The aim of our study is to test the hypothesis that endogenous nitric oxide (NO) production is involved in the change of large conductance calcium-activated (BKca) channel activity in rat hippocampal CA1 neurons in intermittent hypoxia (IH). SpragueDawley rats (ca. 90 g) were exposed to IH (inspired oxygen levels cyclic between 5% and 21% at 60 cycle/h for 8 h diurnally for 3–10 days) or normoxia (N, in room air). The level of NO in hippocampal CA1 region was measured by NO microsensor with electrochemical method. Patch-clamping study with the excised inside-out configuration was performed on CA1 pyramidal neurons freshly dissociated from the hippocampal slices of IH or N rats. The effect of NO synthase inhibitor L-NMMA (100 lM) on the NO level was significantly less in the IH group than that of the N group, suggesting that the endogenous NO production decreased in the IH. There were no differences in unitary conductance between the IH and N groups with symmetrical 140/140 K+ on both sides of the excised membrane. The open probability of BKca channel activity reduced in the IH compared with that of the N group, due to a shortening of mean open time and prolongation of mean close time. NO donor SNP (100 lM) partially recovered the decrease in BKca channel activity in the IH group. The SNP action was prevented by pretreatment of thiol-specific alkylating agent NEM (1 mM), confirming an involvement of the NO mechanism. Taken together, our results suggest that lowering of NO level can cause a decrease in BKca channel activity in the hippocampal neuron during IH, which may lead to the neuronal hyperexcitability and hippocampal injuries in patients with severe sleep apnea. Acknowledgement: Study was supported by research grants from Research Grants Council, HKSAR, and the University Research Council of the University of Hong Kong.