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Physiopathologie du cœur embryonnaire soumis à l'anoxie-réoxygénation: Rôle protecteur du NO et des canaux KATP.

Abstract : Aim: In the adult heart, the electrical, mechanical, biochemical and structural disturbances induced by ischemia and reperfusion lead to reversible or irreversible damages depending on the severity and duration of ischemia. In spite of recent advances in fetal cardiology and surgery, little is known regarding the cellular mechanisms involved in hypoxia-induced dysfunction in the developing heart. The aim of this study was to precisely characterize the chrono-, dromo- and inotropic disturbances associated with anoxia-reoxygenation in an embryonic heart model. Furthermore, the roles that nitric oxide (NO), reactive oxygen species (ROS), mitochondrial KATP (mitoKATP) channel and MAP Kinases could play in the stressed developing heart have been investigated.

Methods: Embryonic chick hearts (4-day-old) were isolated and submitted in vitro to 30 min anoxia followed by 60 min reoxygenation. Electrical (ECG) and contractile activities of atria, ventricle and conotruncus (photometric detection), ROS production (DCFH fluorescence) and ERK and JNK activity were determined in the ventricle throughout anoxia-reoxygenation. Hearts were treated with NO synthase inhibitor (L-NAME), NO donor (DETA-NONOate), mitoKATP channel opener (diazoxide) or blocker (5-HD), PKC inhibitor (chelerythrine) and ROS scavenger (MPG).

Results: Anoxia and reoxygenation provoked arrhythmias (mainly originating from atrial region), troubles of conduction (1st, 2nd, and 3rd degree atrio-ventricular blocks) and disturbances of excitation-contraction (E-C) coupling. In addition to these types of arrhythmias, reoxygenation triggered Wenckebach phenomenon and rare ventricular escape beats. No fibrillations, no ventricular ectopic beats and no electromechanical dissociation were observed. Myocardial stunning was observed during the first 30 min of reoxygenation. All hearts fully recovered their electrical and mechanical functions after 30-40 min of reoxygenation. Exogenous NO improved while NOS inhibition delayed E-C coupling recovery. MitoKATP channel opening increased reoxygenation-induced ROS production and improved E-C coupling and conduction (PR) recovery. MPG, chelerythrine or L-NAME reversed this effect. Reoxygenation increased ERK and JNK activities 2- and 4-fold, respectively, while anoxia had no effect. MitoKATP channel opening abolished the reoxygenation-induced activation of JNK but had no effect on ERK activity. This inhibitory effect was partly reversed by mitoKATP channel blocker but not by MPG.

Conclusion: In the developing heart, ventricular E-C coupling was found to be specially sensitive to hypoxia-reoxygenation and its postanoxic recovery was improved by mitoKATP channel activation via a ROS-, PKC- and NO-dependent pathway. JNK inhibition appears to be involved in this protection. Thus, mitochondria can play a pivotal role in the cellular signalling pathways, notably under critical metabolic conditions. The model of isolated embryonic heart appears to be useful to better understand the mechanisms underlying the myocardial dysfunction induced by an in utero hypoxia and to improve therapeutic strategies in fetal cardiology and surgery.
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Contributor : Alexandre Sarre <>
Submitted on : Tuesday, April 1, 2008 - 4:26:53 PM
Last modification on : Tuesday, April 1, 2008 - 4:30:19 PM
Long-term archiving on: : Tuesday, September 21, 2010 - 3:48:05 PM


  • HAL Id : tel-00268858, version 2


Alexandre Sarre. Physiopathologie du cœur embryonnaire soumis à l'anoxie-réoxygénation: Rôle protecteur du NO et des canaux KATP.. Physiologie [q-bio.TO]. Université de Lausanne, 2006. Français. ⟨tel-00268858v2⟩



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