Mexiletine and lidocaine reduce post-ischemic functional and biochemical dysfunction of perfused hearts

Abstract

The present study was undertaken to determine whether class Ib antiarrhythmic agents, mexiletine and lidocaine, exert beneficial effects on ischemia/reperfusion-induced cardiac contractile dysfunction. Isolated rat hearts were subjected to 35-min global ischemia, followed by 60-min reperfusion and the functional and metabolic alterations were examined with and without mexiletine or lidocaine treatment. Ischemia/reperfusion resulted in a lack of recovery of contractile function, a sustained rise in left ventricular end-diastolic pressure and increased coronary perfusion pressure of the perfused heart during reperfusion. Contractile dysfunction was associated with increases in tissue Na + and Ca 2+ levels, decreases in K + and Mg 2+ levels, and release of creatine kinase and purine nucleosides and bases (ATP metabolites) from the heart. Treatment of the perfused heart with either 10–100 μM of either mexiletine or lidocaine during pre-ischemia resulted in an enhancement of post-ischemic contractile recovery, a suppression of changes in tissue Na +, K +, Ca 2+ and Mg 2+ contents and an attenuation of the release of creatine kinase and ATP metabolites in an almost concentration-dependent manner. Tissue sodium accumulation was observed at the end of ischemia, which was also attenuated by pretreatment with these agents. The prevention of Na + overload and accompanying Ca 2+ overload in cardiac cells may be the mechanism underlying the improvement of post-ischemic contractile function of perfused hearts by these agents.