| Background: Renin-angiotensin system (RAS) is known to play a role during ischemia/reperfusion (I/R) injury in the heart, which leads to both necrosis and apoptosis of cardiomyocytes as well as the complication of ventricular arrhythmias (VA). As an angiotensin-converting enzyme (ACE) inhibitor, ramipril is commonly used to treat hypertension and heart failure after myocardial infarction. This study was designed to test the hypothesis that ramipril would provide delayed cardioprotection by decreasing the extent of VA during myocardial ischemia and reducing the myocardial damage including necrosis and apoptosis after I/R injury in vivo.Methods and Results: Male Wistar rats were subjected to 30 minutes of myocardial ischemia by left coronary artery occlusion and 2 hours of reperfusion. Rats were randomized to receive vehicle or ramipril (1 mg/kg) orally 24 hours before surgery. A lead II electrocardiogram was monitored throughout the experiment. Myocardial infarct size was measured by using the staining agent 2,3,5-triphenyl tetrazolium chloride (TTC). Cardiomyocyte apoptosis was assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and confirmed by detection of DNA ladder formation. The expression of antiapoptotic gene (Bcl-2) and proapoptotic gene (Bax) was determined by immunohistochemistry. During the period of ischemia, ramipril delayed the onset of ventricular premature contraction (VPC, 397+209 sec vs 99 + 90 sec, P<0.01). It also decreased the amount of VPC (71+43 vs 198 + 91, P<0.01), the duration of ventricular tachycardia (VT, 8+4 sec vs 59+47 sec, P<0.01), the incidence of VT (50 % vs 100 %, PO.001) or ventricular fibrillation (VF, 0 % vs 20 %, P<0.001) and the arrhythmic score (2.10 + 0.99 vs 3.80 + 0.42, P<0.001) compared withvehicle. At the end of reperfusion, infarct size was reduced (0.28 + 0.09 vs 0.43 +0.10, P<0.05) by ramipril. TUNEL assay and DNA-laddering study demonstrated that cardiomyocyte apoptosis was attenuated in ramipril-treated hearts (36.54+7.45 % vs 61.92+4.90 %, P<0.01), correlating with increased expression of Bcl-2 (15.93+4.46 % vs 10.73 + 1.41 %, P<0.05) and ratio of Bcl-2/Bax (0.80 + 0.28 vs 0.44 + 0.15, P<0.05).Conclusions: The results document that ramipril protected myocardium from I/R injury by decreasing the extent of ischemia-induced VA associated with reduced necrosis and apoptosis of cardiomyocytes. This suggests a potentially important role of RAS in myocardial I/R injury and the value of ACE inhibitor for myocardial preservation.
|
PDF Full Text Request