Abstract
The mechanism mediating the development of ventricular arrhythmia (VA) after acute myocardial infarction (AMI) is still uncertain. Thrombin receptor (TR) activation has been proven to be arrhythmogenic in many other situations, and we hypothesize that it may participate in the genesis of post-AMI VA. Using a left coronary artery ligation rat model of AMI, we found that a local injection of hirudin into the left ventricle (LV) significantly reduced the ratio of VA durations to infarction sizing, whereas injection of thrombin receptor-activating peptide (TRAP) increased the ratios of VA duration to infarction sizing. The effects of TR activation on whole-cell currents were investigated in isolated myocytes. TRAP increased a glibenclamide-sensitive outward current. Pretreatment of rats with glibenclamide (4 mg/kg intraperitoneally) eliminated the effects of a local injection of TRAP on the ratios of VA durations to infarction sizing. TR mRNA and protein expression in the ischemic left ventricle had reached its peak by 20 min postligation in the rat AMI model (P < 0.05). TR-immunoreactive myocytes were observed in infarcted LV but were seldom seen in the right ventricle or in the normal heart. By 60 min, TR transcript levels had returned to control levels. We conclude that increased TR activation and expression in the infarcted LV after AMI may contribute to VA through a mechanism involving glibenclamide-sensitive potassium channels.
Highlights
Acute myocardial infarction (AMI) has been a major public health problem for decades
Our initial studies demonstrated that the thrombin antagonist hirudin decreased the ratios of ventricular arrhythmia (VA) durations to infarction sizing and that thrombin receptor–activating peptide (TRAP) treatment increased the ratios of VA durations to infarction sizing after AMI
Thereafter, we found that TRAP could alter glibenclamide-sensitive KATP and barium-sensitive inward rectifying potassium currents
Summary
Acute myocardial infarction (AMI) has been a major public health problem for decades. Data from the National Registry of Myocardial Infarction and Cooperative Cardiovascular Project indicated that the mortality rate in AMI patients still approaches 20% [2]. Continuous electrocardiogram (ECG) recordings after left coronary artery ligation in a rat model of AMI showed two distinctly active arrhythmogenic periods: one from immediately after ligation (time 0) to 30 min, another extending from 90 min to 9 h postligation. Each period was followed by a quiescent phase of low ectopy [6]. The mechanism underlying these ventricular arrhythmias has not been totally resolved
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