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1 University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK2 Biomedical Sciences, School of Biology, Bute Building, St Andrews KY16 9TS, Scotland, UK
Inhibitors of mitochondrial energy metabolism have long been known to be potent stimulants of the carotid body, yet their mechanism of action remains obscure. We have therefore investigated the effects of rotenone, myxothiazol, antimycin A, cyanide (CN–) and oligomycin on isolated carotid body type I cells. All five compounds caused a rapid rise in intracellular Ca2+, which was inhibited on removal of extracellular Ca2+. Under current clamp conditions rotenone and CN– caused a rapid membrane depolarization and elevation of [Ca2+]i. Voltage clamping cells to –70 mV substantially attenuated this rise in [Ca2+]i. Rotenone, cyanide, myxothiazol and oligomycin significantly inhibited resting background K+ currents. Thus rotenone, myxothiazol, cyanide and oligomycin mimic the effects of hypoxia in that they all inhibit background K+ current leading to membrane depolarization and voltage-gated calcium entry. Hypoxia, however, failed to have any additional effect upon membrane currents in the presence of CN– or rotenone or the mitochondrial uncoupler p-trifluoromethoxyphenyl hydrazone (FCCP). Thus not only do mitochondrial inhibitors mimic the effects of hypoxia, but they also abolish oxygen sensitivity. These observations suggest that there is a close link between oxygen sensing and mitochondrial function in type I cells. Mechanisms that could account for this link and the actions of mitochondrial inhibitors are discussed.
(Received 14 November 2003;
accepted after revision 12 January 2004;
first published online 14 January 2004)
Corresponding author K. J. Buckler: University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK. Email: keith.buckler{at}physiol.ox.ac.uk
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