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

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 Ca2+ levels, decreases in K+ and Mg2+ 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 microM 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+, Ca2+ and Mg2+ 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 Ca2+ overload in cardiac cells may be the mechanism underlying the improvement of post-ischemic contractile function of perfused hearts by these agents.