Published online before print August 29, 2002, doi: 10.1161/01.RES.0000035528.00678.D5
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Submitted on December 3, 2001
Revised on August 8, 2002
Accepted on August 20, 2002
Decreasing Cellular Hydrogen Peroxide With Catalase Mimics the Effects of Hypoxia on the Sensitivity of the L-Type Ca2+ Channel to ß-Adrenergic Receptor Stimulation in Cardiac Myocytes
Livia C. Hool * and Peter G. Arthur
From the Departments of Physiology and Biochemistry (L.C.H..), The University of Western Australia, Nedlands, and The Western Australia Institute of Medical Research (P.G.A.).
* To whom correspondence should be addressed. E-mail: lhool{at}cyllene.uwa.edu.au.
Hypoxia inhibits the basal L-type Ca2+ current (ICa-L) and increases the sensitivity of ICa-L to ß-adrenergic receptor stimulation. We investigated whether hydrogen peroxide (H2O2) is involved in the hypoxic response. Guinea pig ventricular myocytes were dialyzed with catalase, which specifically catalyzes the conversion of H2O2 to H2O and oxygen, and then ICa-L was recorded during exposure to isoproterenol (Iso). Catalase decreased the K0.5 for activation of ICa-L by Iso from 2.7±0.3 nmol/L (in cells dialyzed with heat-inactivated catalase) to 0.4±0.1 nmol/L. The increase in sensitivity to Iso by catalase may be attenuated when cells are preexposed to H2O2. A significant increase in sensitivity of ICa-L to Iso has also been recorded when mitochondrial function was inhibited with myxothiazol or FCCP, suggesting that the source of H2O2 was from the mitochondria. Prior exposure of cells to H2O2 attenuated the inhibition of basal ICa-L during hypoxia and the increase in sensitivity of ICa-L to Iso during hypoxia. Additionally, extracellularly applied catalase mimicked the effect of hypoxia on basal ICa-L. Measurement of the rate of production of hydrogen peroxide using 5- (and 6-)chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester indicated that hypoxia was associated with a significant decrease in the production of hydrogen peroxide in the cells. These data suggest that hypoxia mediates changes in channel activity through a lowering in H2O2 levels and that H2O2 is a key intermediate in modifying basal channel activity and the ß-adrenergic responsiveness of the channel during hypoxia.
Key words: catalase • ß-adrenergic receptors • hypoxia • L-type Ca2+ channels
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