Role of peripheral benzodiazepine receptors in mitochondrial, cellular, and cardiac damage induced by oxidative stress and ischemia-reperfusion.
Mitochondrial dysfunction has been identified as a possible early event in ischemia-reperfusion damage. The peripheral benzodiazepine receptor, a mitochondrial inner membrane protein, has already been proposed to play a role in mitochondrial regulation, although its exact function remains unclear. The aim of this work was to determine the role of peripheral benzodiazepine receptor in ischemia-reperfusion injury and to test the potential beneficial effect of a novel potent peripheral benzodiazepine receptor ligand, 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575). To characterize and link the mitochondrial, cellular, and cardiac consequences of ischemia-reperfusion, we examined the effects of SSR180575 in several in vitro and in vivo models of oxidative stress. Hydrogen peroxide decreased mitochondrial membrane potential, reduced oxidative phosphorylation capacities, and caused cytochrome c release, caspase 3 activation, and DNA fragmentation. SSR180575 (100 nM-1 microM) prevented all these effects. In perfused rat hearts, SSR180575 administered in vitro (100 nM-1 microM) or by oral pretreatment (3-30 mg/kg) greatly reduced the contractile dysfunction associated with ischemia-reperfusion. Furthermore, in anesthetized rats, SSR180575 (3-30 mg/kg p.o.) produced significant reductions in infarct size after coronary artery occlusion/reperfusion. In conclusion, we have demonstrated that peripheral benzodiazepine receptor play a major role in the regulation of cardiac ischemia-reperfusion injury and that SSR180575, a novel peripheral benzodiazepine receptor ligand, is of potential interest in these indications.
Leducq
Nathalie
N
Sanofi-Synthélabo Research, Toulouse, France.
Bono
Françoise
F
Sulpice
Thierry
T
Vin
Valérie
V
Janiak
Philip
P
Fur
Gérard Le
GL
O'Connor
Steve E
SE
Herbert
Jean-Marc
JM
D000758:Anesthesia; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D006335:Heart Injuries / Q000209:etiology* / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D032386:Myoblasts, Cardiac / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000473:pathology; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D014162:Transfection
D011963:Receptors, GABA-A