Role of NAD(P)H oxidase in the regulation of cardiac L-type Ca2+ channel function during acute hypoxia

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Abstract

Objective: The role of NAD(P)H oxidase in regulating cellular production of reactive oxygen species (ROS) and the L-type Ca2+ channel during acute hypoxia was examined in adult ventricular myocytes from guinea pig.Methods: The fluorescent indicator dihydroethidium (DHE) was used to detect superoxide and the response of the L-type Ca2+ channel to adrenergic receptor stimulation was used as a functional reporter since hypoxia increases the sensitivity of the L-type Ca2+ channel (ICa-L) to isoproterenol (Iso).Results: Hypoxia caused a 41.2 +/- 5.2% decrease in the rate of the DHE signal (n=21; p < 0.01). Of the classical NAD(P)H oxidase inhibitors, DPI but not apocynin mimicked the effect of hypoxia on the sensitivity Of ICa-L to Iso. However, the potent NAD(P)H oxidase agonist angiotensin 11 had no effect on cellular superoxide or the sensitivity Of ICa-L to Iso. Although DPI inhibits NAD(P)H oxidase, it also decreased superoxide in isolated mitochondria in a concentration-dependent manner. Partial inhibition of mitochondrial function with nanomolar concentrations of FCCP or myxothiazol mimicked the effect of hypoxia on cellular superoxide and the sensitivity Of ICa-L to Iso. In addition, hypoxia caused a 69.3 +/- 0.8% decrease in superoxide in isolated mitochondria (n=4; p < 0.01), providing direct evidence for a role for the mitochondria.Conclusions: Our data suggest that mitochondria appear to be involved in oxygen sensing, regulation of cellular ROS, and the function of ICa-L during acute hypoxia in cardiac myocytes and NAD(P)H oxidase does not appear to contribute substantially. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Original languageEnglish
Pages (from-to)624-635
JournalCardiovascular Research
Volume67
Issue number4
DOIs
Publication statusPublished - 2005

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