Magnesium orotate elicits acute cardioprotection at reperfusion in isolated and in vivo rat hearts

Orotic acid and its salts chronically administered have been shown to significantly improve cardiac function in pathological settings associated with ischemia-reperfusion (I/R) injury. The aim of our study was to investigate the effect of magnesium orotate (Mg-Or) administration at the onset of post-ischemic reperfusion on myocardial function and infarct size (IS). Ex-vivo experiments performed on isolated perfused rat hearts were used to compare Mg-Or administration with a control group (buffer treated), ischemic post-conditioning, orotic acid treatment, and Mg[Cl.sub.2] treatment. Mg-Or administration was also investigated in an in-vivo model of regional I/R performed in rats undergoing reversible coronary ligation. The effect of Mg-Or on mitochondrial permeability transition pore (mPTP) opening after I/R was investigated in vitro to gain mechanistic insights. Both ex-vivo and in-vivo experiments showed a beneficial effect from Mg-Or administration at the onset of reperfusion on myocardial function and IS. In-vitro assays showed that Mg-Or significantly delayed mPTP opening after I/R. Our data suggest that Mg-Or administered at the very onset of reperfusion may preserve myocardial function and reduce IS. This beneficial effect may be related to a significant reduction of mPTP opening, a usual trigger of cardiac cell death following I/R. Key words: magnesium orotate, cardioprotection, ischemia-reperfusion, ischemic post-conditioning, in vivo. L'administration au long cours d'acide orotique ou de ses sels a montre un effet benefique sur la fonction cardiaque dans plusieurs situations pathologiques associees aux lesions d'ischemie-reperfusion (I/R). L'objectif de notre etude etait d'evaluer l'effet de l'orotate de magnesium (Mg-Or) administre en tout debut de reperfusion myocardique post ischemique sur la taille d'infarctus (TI) et la fonction cardiaque. Un modele ex vivo d'I/R sur cceur isole perfuse de rats a compare l'administration de Mg-Or avec les groupes experimentaux control (tampon), post conditionnement ischemique, acide orotique, et Mg[Cl.sub.2]. L'effet de Mg-Or a egalement ete evalue sur un modele in vivo d'I/R myocardique regional par ligature coronaire chez le rat. Une etude mecanistique a evalue l'effet de Mg-Or sur l'ouverture du port de permeabilite de transition mitochondriale (mPTP). L'administration de Mg-Or en debut de reperfusion sur les modeles ex vivo et in vivo entrame une diminution de la TI et une preservation de la fonction cardiaque. L'etude mecanistique montre que Mg-Or retarde l'ouverture du mPTP apres I/R myocardique. Nos resultats suggerent que Mg-Or administre en debut de reperfusion est susceptible de diminuer la TI et de preserver la fonction cardiaque. Cet effet est vraisemblablement lie a son action inhibitrice sur l'ouverture du mPTP, phenomene implique dans les processus de mort cellulaire post I/R myocardique. Mots-cles: orotate de magnesium, cardioprotection, ischemie-reperfusion, post conditionnement ischemique, in vivo.
Introduction Myocardial infarction represents a major cause of morbidity and mortality worldwide. The cornerstone of treatment is represented by timely restoration of coronary reperfusion achieved either pharmacologically by thrombolysis and [...]