PROTECTIVE EFFECTS OF ALL-TRANS-RETINOIC ACID AGAINST CARDIAC-ARRHYTHMIAS INDUCED BY ISOPROTERENOL, LYSOPHOSPHATIDYLCHOLINE OR ISCHEMIA ANDREPERFUSION

Previous studies have shown that free polyunsaturated fatty acids (PUF A) reduce the excitability of cardiac myocytes and exert antiarrhythmi c effects. Therefore, we hypothesized that retinoic acid (RA, vitamin A acid), which has structural characteristics similar to those of PUFA , may have similar antiarrhythmic effects, To test this hypothesis, we used an isolated, spontaneously beating, neonatal rat cardiac myocyte preparation to examine the effects of RA, added to the perfusion solu tion, on the cell contraction and arrhythmias induced by isoproterenol (ISO) or lysophosphatidylcholine (LPC). All-trans-PA (10-20 mu M) ind uced a marked and reversible reduction in the contraction rate of the cell in 2-5 min without changing the amplitude of the contractions. Su perfusion of the myocytes with either ISO (3 mu M) or LPC (5 mu M) ind uced sustained tachyarrhythmias characterized by spasmodic contracture s and fibrillation. Addition of 15-20 mu M all-trans-PA to the perfusi on solution effectively prevented as well as terminated the arrhythmia s induced by ISO and LPC. Furthermore, in a whole-animal model of arrh ythmia in which the left anterior descending coronary artery (LAD) of the anesthetized rat was occluded for 15 min followed by reperfusion, both the incidence and severity of ventricular tachycardia and fibrill ation (VT, VF) were significantly reduced during the ischemic and repe rfusion periods by intravenous infusion of all-trans-RA. In contrast, other analogues, including retinol and retinal, and other fat-soluble vitamins, including vitamin D, E, and K, did not have such effects. Ou r results demonstrate that all-trans-RA can produce antiarrhythmic eff ects similar to those of PUFA, suggesting a novel role of RA as a pote ntial antiarrhythmic agent.