Hemodynamic and metabolic effects of the beta-phosphorylated nitroxide 2-diethoxyphosphoryl-2,5,5-trimethylpyrrolidinoxyl during myocardial ischemia and reperfusion.
In vitro, the stable six-membered ring nitroxide 2,2,6,6-tetramethyl-1-piperidine-N-oxyl (TEMPO) is known to protect the ischemic and reperfused myocardium through a mechanism likely to involve the limitation of free radical damage. In vivo, TEMPO's high rate of reduction into diamagnetic nonactive compounds could limit its pharmacological use and its potential as an ESR probe in oxymetry studies. Recently, beta-phosphorylated nitrones and pyrrolidines have been reported to protect against myocardial reperfusion injury better than their nonphosphorylated analogs. Using hemodynamic, metabolic, and enzymatic indices of reperfusion injury, the efficacy of 2-diethoxyphosphoryl-2,5,5-trimethylpyrrolidinoxyl (TMPPO), a five-membered ring beta-phosphorylated nitroxide, has been compared to that of TEMPO when added at a nontoxic concentration (1 mM) in buffer-perfused isolated rat hearts during low-flow ischemia, total ischemia, and reflow. TMPPO, which is five times as hydrophilic and eight times as resistant to reduction in a biological medium as TEMPO, was more effective in reducing postischemic contracture and myocardial enzymatic leakage. Since a diamagnetic analog of TMPPO was far less protective and both nitroxides showed an antilipoperoxidant effect and acted mainly when administered only at reflow, it was proposed that beta-phosphorylated nitroxides such as TMPPO could be interesting alternatives in pharmacological and ESR applications.
Pietri
Sylvia
S
Laboratoire Structure et Réactivité des Espèces Paramagnétiques UMR 6517 du Centre National de la Recherche Scientifique, Universités d'Aix-Marseille I et III, France. pietri@srepir1.univ-mrs.fr
Mercier
Anne
A
Mathieu
Corinne
C
Caffaratti
Sophie
S
Culcasi
Marcel
M
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar
C488053:2-diethoxyphosphoryl-2,5,5-trimethylpyrrolidinoxyl; D002316:Cardiotonic Agents; D003497:Cyclic N-Oxides; D003517:Cyclopentanes; C488054:diethyl cyclopentylphosphonate; D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; C003959:TEMPO