Adriamycin-Induced Mitochondrial Toxicity in Rat Heart is Exacerbate by Angiotensin

Abstract

Adriamycin (ADR) increases the production of reactive oxygen species, which diminishes mitochondrial function. Angiotensin-II stimulates mitochondrial-ROS generation. The aim of the study was to examine whether angiotensin converting enzyme (ACE) or renin inhibitors (captopril and/or aliskiren) protect against ADR-induced mitochondrial function impairment. Rats were divided into five groups (n=14 each). The control group was treated with saline. ADR was administered to the four other groups every 2 days (4 mg/kg i.p). One of these was co-administered captopril (10 mg/kg/daily) and the other was co-treated with aliskiren (50 mg/kg/daily), while another was co-treated with both captopril and aliskiren (captopril and aliskiren were gavage administration daily for 8 days). Left ventricular function, ECG variables and blood pressure were assessed at the end of treatment period. The hearts were homogenized and biochemical measurements were made in mitochondria, cytosol and plasma. Mitochondria membrane potential (MMP), ATP levels were determined. ADR decreased in the left ventricular developed pressure (LVDP), the maximal rate of rise of pressure (+dP/dt), and increased in the left ventricular end-diastolic pressure (LVEDP). ADR increased ST interval and decreased mean blood pressure. ADR increased oxidative stress in mitochondrial, cytosolic and plasma. ADR decreased MMP and ATP level in myocyte mitochondria. ADR co-administration with renin and ACE inhibitors improved the dissipation of MMP. The decreased in ATP level was restored by treatment with inhibitors of ACE and renin. By maintaining normal levels of mitochondrial MMP and ATP, captopril and aliskiren treatment prevented the pathologic changes in ECG, blood pressure and left ventricular function. We concluded that inhibitors of angiotensin II are effective against ADR cardiotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.