Nitrone spin traps and their pyrrolidine analogs in myocardial reperfusion injury: hemodynamic and ESR implications--evidence for a cardioprotective phosphonate effect for 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide in rat hearts.
Formation of free radicals during reperfusion of the isolated ischemic heart has often been demonstrated by detecting hydroxyl radical spin adducts of the nitrone 5,5-dimethyl-1-pyrroline N-oxide (DMPO) in coronary effluents. However, questions still remain regarding (a) whether the reported cardiovascular effects of nitrone perfusion may affect the formation of spin adducts, and (b) the primary generation of superoxide (O2.-), because of the short persistency of O2.-/DMPO spin adduct. We therefore compared the effects of perfusing 5 mM of two nitrones, DMPO and 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide (DEPMPO) or the two structurally related pyrrolidines, diethyl (2-methyl-2-pyrrolidinyl) phosphonate (DEPMPH) and pyrrolidine (PyH), on postischemic functional recovery of rat hearts subjected to 10 min of low-flow ischemia, 30 min of global ischemia and 60 min of reperfusion. All compounds were added to the perfusate before ischemia, throughout low-flow ischemia and during the initial 10 min of reflow. In one additional group, hearts received DEPMPO only at reflow. Hemodynamic and in vitro ESR evidence is presented indicating that the phosphonate group of DEPMPO and DEPMPH confers these molecules with an enhanced cardioprotective efficacy, unrelated to radical scavenging, acting in synergy with the intrinsic radical trapping effects of the nitronyl group. Continuous-flow ESR spin trapping using 5.7 mM DEPMPO administered at reflow, but not before ischemia, demonstrated for the first time extended formation of O2.- in the reperfused myocardium.
Pietri
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S
Structure et Réactivité des Espèces Paramagnétiques, UMR 6517 du Centre National de la Recherche Scientifique, Universités d'Aix-Marseille I & II, France.
Liebgott
T
T
Fréjaville
C
C
Tordo
P
P
Culcasi
M
M
D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009589:Nitrogen Oxides / Q000494:pharmacology; D063065:Organophosphonates; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013113:Spin Labels
D003497:Cyclic N-Oxides; D005609:Free Radicals; D009589:Nitrogen Oxides; D063065:Organophosphonates; D011759:Pyrrolidines; D013113:Spin Labels; C113107:diethyl(2-methyl-2-pyrrolidinyl)phosphonate; C015388:nitrones; C098505:5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide