| Objective: Patients of diabetes mellitus(DM) are easy to have many kinds ofcardiovascular diseases, which is seventy percent in death toll. Patients' symptomsusually include asymptomatic myocardial ischemia, myocardial infarction, or suddendeath. Though ischemic preconditioning(IPC) is a powerful endogenouscardioprotective mechanism against ischemia/reperfusion(I/R) injury, transitoryischemia time after time also will lead to myocardial injury. Some drugs may initiatecomplex intracellular signaling pathways by activating endogenous active substancesand may imitate cardioprotection of IPC without ischemia, namely pharmacologicalpreconditioning (PPC). Ramipril is a long-acting and powerfulangiotensin-converting enzyme inhibitior, which protects endothelial cells wall andprevents myocardium from hypertrophy. Clinical application showed that its effectson hypertension, congestive heart failure, and myocardial infraction complicated withheart failure were excellent. There are some controversies about IPC and PPC indiabetes mellitus patients. So the purposes of this study were:①to establish a DMmodel in Wistar rats by Streptozotocin(STZ) in caudal vein;②to establish a IPC andI/R model after given ramipril or normal saline(NS) by oral administration for fourweeks;③to examine I/R injury and cardioprotection of IPC and ramipril in DM rat.Methods: Seventy-five healthy male Wistar rats were divided randomly into sixgroups, included I/R surgery in non-DM rat given NS(same volume of ramipril) forfour weeks (NDM+I/R), IPC surgery in non-DM rat given NS(same volume oframipril) for four weeks (NDM+IPC), FR surgery in DM rat given NS(same volumeof ramipril) for four weeks (DM+I/R), IPC surgery in DM rat given NS(same volumeof ramipril) for four weeks (DM+IPC), I/R surgery in DM rat given ramipril(1mg/kg)for four weeks (RAM+DM+I/R), IPC surgery in DM rat given ramipril(1mg/kg·d) forfour weeks (RAM+DM+IPC). All rats were subjected to open-chest surgery. Aligature was passed below the left anterior descending coronary artery (LAD) to forma snare. In I/R groups, the injury was induced by ligation for 30 minutes followed byreperfusion for 2 hours. In IPC groups, the LAD of rats were occluded three times each for 5 minutes, followed by reperfusion for 5 minutes (IPC) before ischemia 30minutes followed by reperfusion for 2 hours. Arrhythmia corresponding to ischemicinjury, heart rate, blood pressure and ST-segment in ECG were recorded continuously.HE and TTC stainings were performed to determine myocardial necrosis at the end oftest. Ultrastructure of myocardium from three rats randomly of each group, locatedmiddle of one third between Apex of heart and ligature, were examined by electronmicroscope.Results:1. I/R injury and cardioprotection of IPC in non-DM ratsIn NDM+I/R group, the myocardial injury was severe: the ST-segmentcorresponding to ischemic injury was elevated significantly(0.476±0.120 mV). Theonsets of ventricular premature contraction (VPC) were early(1.96±2.36), thedurations of VPC were long(21.03±5.98). The incidence of ventricular tachycardia(VT) and ventricular fibrillation (VF) was high(80%, 60%). The myocardial infarctsize was extensive(34.82±6.93%). Morphological observation on light microscopeshowed that cytoplasm of myocardial cell is eosin deeply, some part of cytoplasmstain light, a little of effusion and many inflammatory cells appear in the matrix. Theultrastructure of myocardium showed: lots of erythrocyte rouleaux and myelin figuresappeard in capillary vessel. The edges of erythrocytes were degradated flocculentlyand adhere with vessel wall. The myocardial membranes were degradated focally andthe tubule systems were dilated. The myocardial fiber arranged disorderly andmitochondrias were degradated focally with some glucogen stacked near them.In NDM+IPC group, compared with that of NDM+I/R group, the onsets of VPCwere delayed(14.17±6.40 vs 1.96±2.36 min, P＜0.001), the durations of VPC wereshortened(8.13±3.66 vs 21.03±5.98 min, P＜0.001). The incidence of VT and VF wasdecreased 10% vs 80%, P＜0.01; 10% vs 60%, P＜0.05). The myocardial infarct sizewere reduced significantly(15.12±3.60% vs 34.82±6.93%, P＜0.001). Morphologicalobservation showed that myocardial injury was more mitigable than that of NDM+I/Rgroup. However, the elevation of ST-segment was decreased appreciably, nodifference in statistics(0.457±0.081 vs 0.476±0.120 mV). In a word, IPC have cardioprotection against I/R injury in non-DM rats.2. I/R injury and cardioprotection of IPC in experimental DM ratsIn experimental DM rats, blood glucose was elevated significantly(24.31±4.99vs 5.86±0.60 mmol/L, P＜0.001), and the mean arterial blood pressure(MAP) waselevated(129.42±15.38 vs 107.90±14.23 mmHg, P＜0.001).In DM+I/R group, the myocardial injury was severe: the ST-segmentcorresponding to ischemic injury was elevated(0.659±0.144 mV). The onsets of VPCwere early(5.54±3.99 min), the durations of VPC were long(17.08±5.51 min). Theincidence of VT and VF was high(80%, 40%). The myocardial infarct size wasextensive(32.29±10.70%). Morphological observation on light microscope showedthat the fragmentation of some myocardium was found, some part of cytoplasmagglomerated, nuclear pyknosis was found, the matrix edema severely, erythrocyte,fibrin and neutrophil was exuded. The ultrastructure of myocardium showed: lots oferythrocyte rouleaux and myelin figures in most of capillary vessel, the basementmembrane incrassated and multiple layers appeared. The edges of erythrocytes weredegradated flocculently and adhere with vessel wall. The myocardial membraneswere degradated focally and lots of myelin figures appeared around them. Z and Ibones of sacromere were disappeared gradually, myofilarnent arranged disorderly.Some of mitochondrial membranes were degradated, cristal and matrix ofmitochondria were indistinct, quantity of cristal decreased, many glucogens stackedaround them.In DM+I/R group, compared with NDM+I/R group, the durations of VPC, theincidence of VT and VF, the myocardial infarct size were no difference in statistics.But MAP and ST-segment were higher than those of NDM+I/R group(103.59±17.90vs 81.43±10.28 mmHg, P＜0.01; 0.659±0.144 vs 0.476±0.120 mV, P＜0.001).Morphological observation showed that myocardial injury was more severe than thatof NDM+I/R group. So I/R injury of experimental DM rats is more severe thannon-DM rats.In DM+IPC group, compared with that of DM+I/R group, the elevation ofST-segment was descended(0.495±0.111 vs 0.659±0.144 mV, P＜0.01). The onsets of VPC were delayed(13.03±8.94 vs 5.54±3.99 min, P＜0.05), the durations of VPC wereshortened(6.67±6.27 vs 17.08±5.51 min, P＜0.001). The incidence of VT and VF wasdecreased(10% vs 80%, P＜0.01; 0 vs 40%, P＜0.01). The myocardial infarct size werereduced significantly(15.54±9.42% vs 32.29±10.70%, P＜0.001). Morphologicalobservation showed that myocardial injury was more mitigable than that of NDM+I/Rgroup. IPC have cardioprotection against I/R injury in experimental DM rats.3. cardioprotection oframipdl in experimental DM rats3.1 PPC of ramiprilIn RAM+DM+I/R group, compared with that of DM+I/R group, the MAP wasdescended significantly(95.35±10.80 vs 103.59±17.90 mmHg, P＜0.05). The elevationof ST-segment was descended(0.407±0.095 vs 0.659±0.144 mV, P＜0.001). Theonsets of VPC were delayed(12.14±5.97 vs 5.54±3.99 min, P＜0.01), the durations ofVPC were shortened(11.11±5.41 vs 17.08±5.51 min, P＜0.05). The incidence of VTand VF was decreased(40% vs 80%, P＜0.01; 10% vs 40%, P＜0.01). The myocardialinfarct size were reduced significantly(14.19±6.53% vs 32.29±10.70%, P＜0.001).Morphological observation showed that myocardial injury was more mitigable thanthat of DM+I/R group. In conclusion Ramipril have cardioprotection against I/Rinjury in experimental DM rats.3.2 Cardioprotection oframipril is same as IPC in experimental DM ratsIn RAM+DM+I/R group, compared with that of DM+IPC group, the elevationof ST-segment only corresponding to ischemic 0 min was decreased significantly(0.196±0.083 vs 0.286±0.118 mV, P＜0.05). But The incidence of VT and VF wasincreased(40% vs 10%, P＜0.01; 10% vs 0, P＜0.01). However, the elevation of MAP,the onsets and durations of VPC, the myocardial infarct size, and morphologicalobservation were no difference in statistics. Cardioprotection of ramipdl is same asIPC in experimental DM rats.3.3 Ramipril and IPC have no synergistic effect in cardioprotection ofexperimental DM ratsIn RAM+DM+IPC group, compared with that of DM+IPC and RAM+DM+I/Rgroup, the elevation of MAP and ST-segment, the onsets and durations of VPC, the incidence of VT and VF, the myocardial infarct size, and morphological observationwere no difference in statistics. Ramipril and IPC have no synergistic effect incardioprotection of experimental DM rats.Conclusions:1. IPC have cardioprotection of I/R injury in experimental 4 wecks-DM rats.2. ramipril(1mg/kg) can imitate cardioprotection of IPC without ischemia inexperimental 4 weeks-DM rats.3. Cardioprotection of ramipril(1mg/kg) is similar with IPC, and they haveno synergistic effect in cardioprotection of experimental DM rats.
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