Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury

Inhibition of the renin-angiotensin system (RAS) has been shown to be benef icial in providing cardioprotective effects in humans, but the mechanism of these effects is not well understood. In this study, we examined the effec ts and mechanism of RAS inhibitors on ischemia/reperfusion (IR) induced myo cardial injury in rats. Rats were randomly divided into five groups and tre ated with vehicle (C), angiotensin converting enzyme inhibitor (ACE-I), ang iotensin II type 1 receptor antagonist (AT(1)-A), angiotensin II type 2 rec eptor antagonist (AT(2)-A) or ACE-I plus bradykinin B-2 antagonist. Ten min utes after administration, the left main coronary artery was ligated for 45 min, and then reperfused for 120 min, IR-induced cardiomyocyte apoptosis w as assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick -end labeling (TUNEL) assay and confirmed by typical DNA laddering. Mitogen -activated protein kinase, extracellular signal-regulated protein kinase (E RK) and c-Jun NH2-terminal protein kinase (JNK) activity in the ischemic zo ne were measured by an in vitro kinase assay. The duration of ventricular t achycardia (VT) during ischemia was reduced by AT(2)-A and ACE-I, and incre ased by AT(1)-A and ACE-I+icatibant. ACE-I and AT(2)-A reduced apoptosis (b y 54% and 53%) and infarct size (by 42% and 41%), while AT(1)-A increased a poptosis (by 86%) and infarct size (by 45%). These changes were negatively correlated with the change in ERK activity. The effects of ACE-I on apoptos is and infarct size were abolished by the coadministration of icatibant, Ap optosis was correlated with the occurrence of VT (r=0.837, p<0.001). These results suggest that both the accumulation of bradykinin and inhibition of AT(2) receptor are cardioprotective against IR injury through the activatio n of ERK, but not JNK.