| Myocardial ischemic preconditioning (IPC) is a powerful endogenous cardioprotective mechanism against ischemia-reperfusion (I/R) injury. The second window of IPC, or delayed preconditioning (DPC), has more advantageous protection and longer duration than early preconditioning, therefore DPC may ultimately have greater clinical usage. Some drugs may initiate complex intracellular signaling pathways by activating endogenous active substances and may imitate cardioprotection of DPC without ischemia, namely pharmacological preconditioning (PPC). Ramipril is a long-acting, powerful angiotensin-converting enzyme inhibitor, which protects endothelial cells well and prevents myocardium from hypertrophy. Clinical application showed that its effects on hypertension, congestive heart failure, and myocardial infarction complicated with heart failure were excellent. The purposes of this study were: (1) to establish a DPC model in rat and to determine whether ramipril induces delayed PPC against I/R injury in rats; and (2) to examine the possible mechanism of such delayed cardioprotection using the technique of proteomics, thereby to detect new target for the development of new drugs.Thirty-nine healthy male Wistar rats were divided randomly into 3 groups and subjected to different treatments. A two-day protocol was used. On dayl, ramipril (Img/kg) was given to rats in RAM group by oral injection, while the same volume of normal saline was given to rats in NS and IP groups. All rats were subjected to open-chest surgery. A ligature was passed below the left anterior descending coronary artery (LAD) to form a snare. In IP group, the LAD of rats were occluded three times each for 5 minutes, followed by reperfusion for 5 minutes (IPC); while rats in NS and RAM groups were subjected to no treatment for 30 minutes before the chest was closed. Twenty-four hours later (i.e. day2), the I/R injury was inducedby ligation for 30 minutes followed by reperfusion for 2 hours. Arrhythmia corresponding to ischemic injury, heart rate, blood pressure and ST-segment in ECG were recorded continuously throughout the whole test on day2. The activity of plasma creatine kinase (CK) was measured after anesthesia on dayl and day 2, 30 minutes after ischemia and 2 hours after reperfusion. HE and TTC stainings were performed to determine myocardial necrosis at the end of test. A pilot study on investigating the mechanisms of DPC and ramipril was carried out through performing two-dimensional electrophoresis to whole proteins samples of ventricular tissue and a following analysis on differential proteins by mass spectrometry.ResultsI . Study on delayed pharmacogical preconditioning induced by ramipril in rat heart(l)In NS group, the myocardial injury was severe: the ST-segment corresponding to ischemic injury was elevated significantly (0.457 + 0.124mV). The onsets of ventricular premature contraction (VPC) and ventricular tachycardia (VT) were early (2.00 +1.89min, 4.40 + 2.01min, respectively), the durations of VPC and VT were long (20.66?.9min, 16.58?.92min, respectively ) and the incidence of ventricular fibrillation (VF) was high (81.82%). The elevation of plasma CK corresponding to reperfusion injury was increased remarkably (97.36 ?31.58U/L). The myocardial infarct size was extensive (41.03 ?9.40%). Morphological observation on HE staining slides showed that interstitial hyperemia was severe, the cloudy swelling of cardiac myocytes was moderate to severe, and the fragmentation of myocardium was found.(2) Compared with that of NS group, the elevation of ST-segment was decreased (0.457 + 0.124 vs 0.241+0.115 mV, P<0.01). The onsets of VPC and VT were delayed (2.00+1.89 vs. 10.09 + 3.72 min, P<0.001; 4.40 +2.01 vs 11.28 +4.45 min, P<0.01, respectively), the durations of VPC and VT were shortened (20.66+5.9 vs 10.37+5.86 min, ?<0.001; 16.58+4.92 vs 7.43 + 4.05 min, .P<0.001, respectively) and the incidence of VF was decreased (81.82% vs 0, P<0.001) remarkably in IP group. The elevation of plasma CK corresponding to... |
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