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This Article Full Text Full Text (PDF) All Versions of this Article: 288/4/H1611    most recent 00942.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Sarre, A. Articles by Raddatz, E. Search for Related Content PubMed PubMed Citation Articles by Sarre, A. Articles by Raddatz, E.

mitoK_ATP channel activation in the postanoxic developing heart protects E-C coupling via NO-, ROS-, and PKC-dependent pathways

¹Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne; and ²Laboratory of Pharmaceutical Technology, School of Pharmacy Geneva-Lausanne, Geneva, Switzerland

Submitted 9 September 2004 ; accepted in final form 13 November 2004

Whereas previous studies have shown that opening of the mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channel protects the adult heart against ischemia-reperfusion injury, it remains to be established whether this mechanism also operates in the developing heart. Isolated spontaneously beating hearts from 4-day-old chick embryos were subjected to 30 min of anoxia followed by 60 min of reoxygenation. The chrono-, dromo-, and inotropic disturbances, as well as alterations of the electromechanical delay (EMD), reflecting excitation-contraction (E-C) coupling, were investigated. Production of reactive oxygen species (ROS) in the ventricle was determined using the intracellular fluorescent probe 2',7'-dichlorofluorescin (DCFH). Effects of the specific mitoK_ATP channel opener diazoxide (Diazo, 50 µM) or the blocker 5-hydroxydecanoate (5-HD, 500 µM), the nitric oxide synthase (NOS) inhibitor N^G-nitro-L-arginine methyl ester (L-NAME, 50 µM), the antioxidant N-(2-mercaptopropionyl)glycine (MPG, 1 mM), and the PKC inhibitor chelerythrine (Chel, 5 µM) on oxidative stress and postanoxic functional recovery were determined. Under normoxia, the baseline parameters were not altered by any of these pharmacological agents, alone or in combination. During the first 20 min of postanoxic reoxygenation, Diazo doubled the peak of ROS production and, interestingly, accelerated recovery of ventricular EMD and the PR interval. Diazo-induced ROS production was suppressed by 5-HD, MPG, or L-NAME, but not by Chel. Protection of ventricular EMD by Diazo was abolished by 5-HD, MPG, L-NAME, or Chel, whereas protection of the PR interval was abolished by L-NAME exclusively. Thus pharmacological opening of the mitoK_ATP channel selectively improves postanoxic recovery of cell-to-cell communication and ventricular E-C coupling. Although the NO-, ROS-, and PKC-dependent pathways also seem to be involved in this cardioprotection, their interrelation in the developing heart can differ markedly from that in the adult myocardium.

diazoxide; mitochondria; chick; hypoxia-reoxygenation; atrioventricular coupling

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