ROS and NO trigger early preconditioning: relationship to mitochondrial K ATP channel

Reactive oxygen species (ROS) and nitric oxide (NO) are implicated in induction of ischemic preconditioning. However, the relationship between these oxidant signals and opening of the mitochondrial ATP-dependent potassium (K ATP ) channel during early preconditioning is not fully understood. We obse...

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Published in:American journal of physiology. Heart and circulatory physiology 2003-01, Vol.284 (1), p.H299-H308
Main Authors: Lebuffe, Gilles, Schumacker, Paul T., Shao, Zuo-Hui, Anderson, Travis, Iwase, Hirotoro, Vanden Hoek, Terry L.
Format: Article
Language:English
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Summary:Reactive oxygen species (ROS) and nitric oxide (NO) are implicated in induction of ischemic preconditioning. However, the relationship between these oxidant signals and opening of the mitochondrial ATP-dependent potassium (K ATP ) channel during early preconditioning is not fully understood. We observed preconditioning protection by hypoxia, exogenous H 2 O 2 , or PKC activator PMA in cardiomyocytes subjected to 1-h ischemia and 3-h reperfusion. Protection was abolished by K ATP channel blocker 5-hydroxydecanoate (5-HD) in each case, indicating that these triggers must act upstream from the K ATP channel. Inhibitors of NO synthase abolished protection in preconditioned cells, suggesting that NO is also required for protection. DAF-2 fluorescence (NO sensitive) increased during hypoxic triggering. This was amplified by pinacidil and inhibited by 5-HD, indicating that NO is generated subsequent to K ATP channel activation. Exogenous NO during the triggering phase conferred protection blocked by 5-HD. Exogenous NO also restored protection abolished by 5-HD or N ω -nitro-l-arginine methyl ester in preconditioned cells. Antioxidants given during pinacidil or NO triggering abolished protection, confirming that ROS are generated by K ATP channel activation. Coadministration of H 2 O 2 and NO restored PMA-induced protection in 5-HD-treated cells, indicating that ROS and NO are required downstream from the K ATP channel. We conclude that ROS can trigger preconditioning by causing activation of the K ATP channel, which then induces generation of ROS and NO that are both required for preconditioning protection.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00706.2002