Effect of two new PBN-derived phosphorylated nitrones against postischaemic ventricular dysrhythmias.
Spin traps might exert antioxidant cardioprotective effects during myocardial ischaemia-reperfusion where free radicals are thought to be responsible for the occurrence of reperfusion injury. The aim of our study was to investigate the effects of two new alpha-phenyl N-tert-butylnitrone (PBN)-derived beta-phosphorylated nitrones: 2-N-oxy-N-[benzylidène amino] diéthyl propyl-2-phosphate (PPN) and 1-diethoxyphosphoryl-1-methyl-N-[(1-oxido-pyridin-1-ium-4-yl) methylidene] ethylamine N-oxide (4-PyOPN) compared with PBN on (1) the evolution of cardiovascular parameters and (2) the postischaemic recovery. Anaesthetized rats were injected with 120 micro mol/kg of the nitrones or 14 micro mol/kg of amiodarone, used as a reference antidysrhythmic drug. Ischaemia was induced in vivo through ligation of the left anterior descending coronary artery for 5 min followed by 15 min of reperfusion after release. Cardiovascular parameters and occurrence of ventricular premature beats (VPB), ventricular tachycardia (VT) and fibrillation (VF) were recorded throughout the experiment. Under nonischaemic conditions, none of the three spin traps was shown to modify cardiovascular parameters during the 25-min measurement period. Solvent-treated (NaCl 0.9%) animals challenged with ischaemia-reperfusion exhibited 39 +/- 10 VPB, 156 +/- 39 s of VT and 60% mortality caused by sustained VF. Nitrones improved slightly postischaemic recovery, reducing the occurrence of VF and mortality to 33% whereas amiodarone injection totally suppressed rhythm disturbances and mortality. Our study has shown only limited antidysrhythmic cardioprotective effects of PBN-derived beta-phosphorylated nitrones during reperfusion after a regional myocardial ischaemia but also minor antioxidant properties of these spin trapping agents.
Vergely
Catherine
C
Laboratoire de Physiopathologie et Pharmacologie Cardio-vasculaires Expérimentales (LPPCE), Facultés de Médecine and Pharmacie, Dijon, France. catherine.vergely@u-bourgogne.fr
Renard
Céline
C
Moreau
Daniel
D
Perrin- Sarrado
Caroline
C
Roubaud
Valérie
V
Tuccio
Béatrice
B
Rochette
Luc
L
D000638:Amiodarone / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D007097:Imines / Q000627:therapeutic use*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D009589:Nitrogen Oxides / Q000627:therapeutic use; D063065:Organophosphonates / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
C480690:1-diethoxyphosphoryl-1-methyl-N-((1-oxidopyridin-1-ium-4-yl)methylidene)ethylamine N-oxide; D000889:Anti-Arrhythmia Agents; D003497:Cyclic N-Oxides; D007097:Imines; C480689:N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide; D009589:Nitrogen Oxides; D063065:Organophosphonates; C029217:phenyl-N-tert-butylnitrone; D000638:Amiodarone