Dikow Ralf, Wasserhess Caroline, Zimmerer Katrin, Kihm Lars Philipp, Schaier Matthias, Schwenger Vedat, Hardt Stefan, Tiefenbacher Christiane, Katus Hugo, Zeier Martin, Gross Lisa Marie
Department of Nephrology, University Hospital of Heidelberg, Heidelberg, Germany.
Basic Res Cardiol. 2009 Sep;104(5):571-9. doi: 10.1007/s00395-009-0018-2. Epub 2009 Mar 14.
The post myocardial infarction (MI) mortality rate is high in renal patients. One possible explanation is the reduced ischemia tolerance caused by uraemia. Previous investigations showed larger MI size in uraemic rats when compared with sham-operated controls. To explore a possible link between uraemic insulin resistance syndrome and MI size in uraemia, we studied an intervention model with administration of insulin and glucose during acute MI in subtotally nephrectomized (SNX) rats and sham-operated controls. In 16 SNX rats and 16 sham-operated controls, the left coronary artery was ligated for 60 min, followed by reperfusion for 90 min. To visualize the perfused myocardium, lissamine-green ink was injected. The nonperfused area (lissamine exclusion) and the area of total infarction (TTC stain) were assessed in sections of the left ventricle (LV) using image analysis. While eight SNX rats and eight sham-operated controls were treated with a placebo during the procedure, the other animals received an insulin bolus of 85 mU/kg and then a continuous insulin infusion of 8 mU/kg per minute. Blood glucose levels were clamped to baseline levels with an infusion of 25% glucose. Insulin receptor substrates (IRS-1 and IRS-2) and glucose transporter (GLUT 4) were studied by western blot in another seven SNX and seven sham-operated controls without further intervention. The infarcted area, given as a proportion of the nonperfused risk area, was not different in sham-operated controls treated with a hyperinsulinaemic clamp versus untreated (0.55 +/- 0.07 vs. 0.51 +/- 0.13, p = 0.477). The eight SNX animals treated with the hyperinsulinaemic clamp utilized significantly less glucose to stabilize baseline glucose levels when compared with the sham-operated controls (5,637 vs. 3,207 microl Glc 25%, p = 0.007). The infarcted area was significantly lower in SNX rats treated with the hyperinsulinaemic clamp compared to non-treated SNX animals (0.56 +/- 0.06 vs. 0.79 +/- 0.09, p < 0.001). SNX rats with the insulin clamp had the same infarcted area size as sham-operated controls (0.56 +/- 0.06 vs. 0.51 +/- 0.13, p = 0.357). Western blotting did not show any change in the expression of GLUT 4 and IRS-1/IRS-2 in SNX animals when compared with sham-operated controls. The size of MI in uraemic rats is significantly reduced by a glucose/insulin infusion. The results suggest an insulin resistance in uraemic rats with similar benefits of glucose/insulin application during acute MI, as found in diabetic individuals. Further analysis did not reveal a down regulation in GLUT 4 and IRS-1/IRS-2.
肾衰患者心肌梗死后的死亡率很高。一种可能的解释是尿毒症导致缺血耐受性降低。先前的研究表明，与假手术对照组相比，尿毒症大鼠的心肌梗死面积更大。为了探究尿毒症胰岛素抵抗综合征与尿毒症患者心肌梗死面积之间的可能联系，我们研究了一种干预模型，即在急性心肌梗死期间对次全肾切除（SNX）大鼠和假手术对照组给予胰岛素和葡萄糖。在16只SNX大鼠和16只假手术对照组中，结扎左冠状动脉60分钟，然后再灌注90分钟。为了使灌注心肌可视化，注射了丽丝胺绿墨水。使用图像分析评估左心室（LV）切片中的非灌注区域（丽丝胺排除）和总梗死面积（TTC染色）。在手术过程中，8只SNX大鼠和8只假手术对照组接受安慰剂治疗，其他动物先静脉注射85 mU/kg胰岛素推注，然后以每分钟8 mU/kg的速度持续输注胰岛素。通过输注25%葡萄糖将血糖水平维持在基线水平。在另外7只未进一步干预的SNX大鼠和7只假手术对照组中，通过蛋白质免疫印迹法研究胰岛素受体底物（IRS-1和IRS-2）和葡萄糖转运蛋白（GLUT 4）。接受高胰岛素钳夹治疗的假手术对照组与未治疗组相比，梗死面积占非灌注风险区域的比例没有差异（0.55±0.07对0.51±0.13，p = 0.477）。与假手术对照组相比，接受高胰岛素钳夹治疗的8只SNX动物在稳定基线血糖水平时利用的葡萄糖显著减少（5637对3207微升25%葡萄糖，p = 0.007）。与未治疗的SNX动物相比，接受高胰岛素钳夹治疗的SNX大鼠梗死面积显著降低（0.56±0.06对0.79±0.09，p < 0.001）。接受胰岛素钳夹的SNX大鼠梗死面积与假手术对照组相同（0.56±0.06对0.51±0.13，p = 0.357）。与假手术对照组相比，蛋白质免疫印迹法未显示SNX动物中GLUT 4和IRS-1/IRS-2的表达有任何变化。葡萄糖/胰岛素输注可显著减小尿毒症大鼠的心肌梗死面积。结果表明，尿毒症大鼠存在胰岛素抵抗，在急性心肌梗死期间应用葡萄糖/胰岛素具有与糖尿病个体相似的益处。进一步分析未发现GLUT 4和IRS-1/IRS-2的下调。
