Effect of two new PBN-derived phosphorylated nitrones against postischaemic ventricular dysrhythmias

• Published in: Fundamental & clinical pharmacology 2003-08, Vol.17 (4), p.433-442
• Main Authors: Vergely, Catherine, Renard, Céline, Moreau, Daniel, Perrin- Sarrado, Caroline, Roubaud, Valérie, Tuccio, Béatrice, Rochette, Luc
• Format: Article
• Language: English
• Subjects: Amiodarone - therapeutic use; Animals; Anti-Arrhythmia Agents - therapeutic use; Arrhythmias, Cardiac - drug therapy; Biological and medical sciences; Cardiovascular system; Cyclic N-Oxides - therapeutic use; Dose-Response Relationship, Drug; dysrhythmias; free radicals; Imines - therapeutic use; ischaemia; Male; Medical sciences; Miscellaneous; Myocardial Reperfusion Injury - drug therapy; Nitrogen Oxides - therapeutic use; Organophosphonates - therapeutic use; PBN; Pharmacology. Drug treatments; phosphorylated spin traps; Rats; Rats, Wistar; reperfusion
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1046/j.1472-8206.2003.00158.x

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 α‐phenyl N‐tert‐butylnitrone (PBN)‐derived β‐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 μmol/kg of the nitrones or 14 μmol/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 β‐phosphorylated nitrones during reperfusion after a regional myocardial ischaemia but also minor antioxidant properties of these spin trapping agents.