| Research Abstract |
Application of brief periods (2-4 min) of a medium equilibrated with 95% N_2-5% CO_2 produced a membrane hyperpolarization, generated by an increase in K^+ conductance, in CA1 neurons in hippocampal slices from adult Wistar rats. The anoxic hyperpolarization appeared to be constituted of two different mechanisms. The anoxic hyperpolarization was partially depressed by glybenclamide (30-100muM), tolbutamide (20-100muM), quinidine (3muM) or TEA (10mM) and was mimicked by application of diazoxide (1mM) or nicorandil (1mM). These results suggest that the anoxic hyperpolarization, in part, is due to an activation of ATP-sensitive K^+ channels (K^+ ATP channels). The remaining membrane hyperpolarization in the presence of bolbutamide (100muM) was also accompanied by a decrease in input resistance. The tolbutamide-resistant hyperpolarization was markedly depressed by reduction or elevation of extracellular Ca^<2+> or by addition of BAPTA/AM (50-100muM), ryanodine (10muM) or procaine (300muM), but was not significantly affected by 4-AP (1.5mM) or apamin (1muM). Trifluoperazine (50muM), W-7(50muM), KN-62 (20muM), H-7 (20muM) or staurosporine (0.1muM)) suppressed the hyperpolarization, while ML-7 (10muM) or H-89 (1muM) did not affect the hyperpolarization. These findings indicate that the tolbutamide-resistant hyperpolarization is due to activation of Ca^<2+> -dependent K^+ channels (K^+(Ca^<2+>)channels) that may be mediated intracellularly by calmodulin kinase II and C kinase. The hyperpolarization was depressed by dTC (100muM) or Ba^<2+> (0.1mM). It is likely, therefore, that the pharmacological characteristic of the K^+ (Ca^<2+>) channels activated by hypoxia is similar, but not identical, to that of the voltage-dependent K^+ (Ca^<2+>) channels being endowed with hippocampal and other neurons.
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