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.
Kamiyama
T
T
Department of Pharmacology, Tokyo College of Pharmacy, Japan.
Tanonaka
K
K
Harada
H
H
Nakai
K
K
Takeo
S
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology*; D008801:Mexiletine / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D010477:Perfusion; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism
D008801:Mexiletine; D000255:Adenosine Triphosphate; D008012:Lidocaine; D012964:Sodium; D003402:Creatine Kinase; D011188:Potassium; D002118:Calcium