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This Article Full Text Full Text (PDF) All Versions of this Article: 554/3/743    most recent jphysiol.2003.055442v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hool, L. C. Search for Related Content PubMed PubMed Citation Articles by Hool, L. C.

Physiology, The University of Western Australia, and The Western Australian Institute of Medical Research, Crawley, WA, 6009, Australia

The aim of this study was to examine the effects of acute hypoxia on the slow (I_Ks) and rapid (I_Kr) components of the native delayed rectifier K⁺ channel in the absence and presence of the ß-adrenergic receptor agonist isoproterenol (isoprenaline; Iso) using the whole-cell configuration of the patch-clamp technique. Hypoxia reversibly inhibited basal I_Ks. The effect could be mimicked by exposing the cells to the thiol-specific reducing agent dithiothreitol (DTT) and attenuated upon exposure of cells to the membrane-impermeant thiol-specific oxidizing compound 5,5'-dithio-bis[2-nitrobenzoic acid] (DTNB). In the presence of hypoxia, the K_0.5 for activation of I_Ks by Iso was significantly decreased from 18.3 to 1.9 nM. DTT mimicked the effect of hypoxia on the sensitivity of I_Ks to Iso while DTNB had no effect. Hypoxia increased the sensitivity of I_Ks to histamine and forskolin suggesting that the effect of hypoxia is not occurring at the ß-adrenergic receptor. The increase in sensitivity of I_Ks to Iso could be attenuated with addition of PKCß peptide to the pipette solution. While hypoxia and DTT inhibited basal I_Ks they were without effect on I_Kr. In addition, Iso did not appear to alter the magnitude of I_Kr in the absence or presence of hypoxia. These data suggest that hypoxia regulates native I_Ks through two distinct mechanisms: direct inhibition of basal I_Ks and an increase in sensitivity to Iso that occurs downstream from the ß-adrenergic receptor. Both mechanisms appear to involve redox modification of thiol groups. In contrast native I_Kr does not appear to be regulated by Iso, hypoxia or redox state.

(Received 19 September 2003; accepted after revision 18 November 2003; first published online 21 November 2003)
Corresponding author L. C. Hool: Physiology M311, School of Biomedical and Chemical Sciences, The University of Western Australia, Stirling Highway, Crawley, WA 6009, Australia.  Email: lhool{at}cyllene.uwa.edu.au

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