Does the antiarrhythmic effect of DMPO originate from its oxygen radical trapping property or the structure of the molecule itself?
Using the isolated perfused rat heart with transient (30 min) normothermic global ischemia, it was shown that DMPO (5,5-dimethyl-pyrroline-N-oxide), an organic spin trap agent designed specifically to trap free radicals, dramatically reduced the vulnerability of the myocardium to reperfusion-induced ventricular fibrillation (VF) and ventricular tachycardia (VT). DMPO (concentration range 30-500 mumol/l) infused in the heart at the moment and during the first 10 min of reperfusion exerted a dose-dependent antiarrhythmic effect. Thus, the doses of 30, 100, and 500 mumol/l of DMPO reduced the incidence of reperfusion-induced VF and VT from their control values of 100% and 100% to 83% and 91%, 50% (p < 0.05) and 67%, 25% (p < 0.01) and 50% (p < 0.05), respectively. Furthermore, the recovery of myocardial function was improved during postischemic reperfusion. A modification in the molecular structure of DMPO leading to HMIO (1,2,2,4,5,5-hexamethyl-3-imidazoline-oxide), so-called inactive DMPO which does not trap free radicals in the presence of a radical generating system or in the effluent of reperfused hearts, failed to reduce the incidence of reperfusion-induced arrhythmias or improve the recovery of postischemic reperfused myocardium. These findings suggest that the free radical trapping properties of DMPO or the effects of the formed DMPO-OH, a stable nitroxyl radical adduct, are responsible for the reduction of reperfusion-induced arrhythmias, and not the molecular structure of DMPO itself. Finally, it is of interest to note that the detection of free radicals was observed in fibrillating hearts, but not in nonfibrillating hearts. This consideration should be taken into account when making therapeutic interventions and risk assessments of a radical scavenger in this setting.
Tosaki
A
A
Biological Research Center, Szeged, Hungary.
Haseloff
R F
RF
Hellegouarch
A
A
Schoenheit
K
K
Martin
V V
VV
Das
D K
DK
Blasig
I E
IE
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D048289:Imidazolidines; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013113:Spin Labels; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; D048289:Imidazolidines; D017382:Reactive Oxygen Species; D013113:Spin Labels; C079221:1,2,2,4,5,5,-hexamethyl-3-imidazolidine oxide; C017245:5,5-dimethyl-1-pyrroline-1-oxide