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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

From the Departments of Physiology (L.C.H.) and Biochemistry (P.G.A.), The University of Western Australia, Crawley, and The Western Australia Institute of Medical Research (L.C.H., P.G.A.).

Correspondence to Dr Livia Hool, Department of Physiology, The University of Western Australia, Stirling Highway, Crawley, WA 6009, Australia. E-mail lhool{at}cyllene.uwa.edu.au

In cardiac myocytes, hypoxia inhibits the basal L-type Ca²⁺ current (I_Ca-L) and increases the sensitivity of I_Ca-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 I_Ca-L was recorded during exposure to isoproterenol (Iso). Catalase decreased the K_0.5 for activation of I_Ca-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 I_Ca-L to Iso was 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 I_Ca-L during hypoxia and the increase in sensitivity of I_Ca-L to Iso during hypoxia. Additionally, extracellularly applied catalase mimicked the effect of hypoxia on basal I_Ca-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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