POLYAMINE ANALOG ANTIARRHYTHMICS

A group of polyamine analogues was assessed for their ability to preve nt isoproterenol-induced ventricular fibrillation and death in a desox ycorticosterone acetate (DOCA)/saline rodent model. The compounds test ed included polyamine antimetabolites and putrescine mimics. A structu re-activity analysis revealed that tetraamines that are dicationic at physiological pH with their terminal nitrogens incorporated into pyrid ine rings are the most active analogues. It is clear from this study t hat there was no correlation between the compounds' ability to diminis h polyamine metabolism and their effects on the electrical properties of the heart. In fact, the most potent polyamine antimetabolites were among the least effective antiarrhythmics. The most active of the comp ounds investigated, N-1,N-3-bis(4-pyridyl)-1,3-diaminopropane, PYR(3,3 ,3), was shown to both prevent isoproterenol-induced arrhythmias in DO CA/saline-treated rodents and reverse the progression of arrhythmic ev ents that would otherwise culminate in ventricular fibrillation and de ath. Electrocardiographic tracings demonstrated that PYR(3,3,3) and pr opranolol both protect from and reverse the progression of arrhythmic events to ventricular fibrillation. In addition, cardiac pathologies f rom rats treated with both drugs are similar, but are substantially di fferent from the control (isoproterenol)-treated animals. (C) 1998 The Italian Pharmacological Society.