Angiotensin II and ischemic preconditioning synergize to improve mitochondrial function while showing additive effects on ventricular post‐ischemic recovery (667.2)

Abstract

Recent studies indicate that the cardioprotective effects of ischemic preconditioning (IPC) against sustained ischemia/reperfusion (IR) can be replicated by angiotensin II (Ang II). However, it is not clear whether IPC and Ang II‐induced preconditioning (APC) act through similar mechanisms or synergize to enhance cardioprotection. In this study, Langendorff‐perfused rat hearts were subjected to IPC, APC or their combination (IPC/APC) followed by IR. IPC and less potently APC, induced cardioprotection as determined by significant increases in the percent recovery of the left ventricular developed‐pressure (LVDP), the first derivative of developed pressure (+dP/dt), and the rate pressure product (RPP) compared to controls. In absolute values, however, the post‐ischemic increase in +dP/dt and RPP were significantly higher for IPC/APC compared to IPC or APC. These effects were associated with normalization of ischemic contracture and lowered LDH release. IPC and/or APC also reduced infarct size and improved mitochondrial respiration and reduced mPTP opening. Notably, IPC/APC markedly increase the respiratory control index of mitochondria compared to IPC or APC. These effects were abrogated by pretreatment with losartan or chelerythrine. Therefore, our results demonstrate that IPC in combination with APC exerts additional cardioprotective effects on post‐ischemic recovery of cardiac function that are associated with improved mitochondrial respiration and attenuation of mitochondria‐mediated cell death.Grant Funding Source: Supported by NIH Grant SCIHL118669‐01A1 and NIH RCMI Program Grant G12RR‐03051