Khan Tanveer A, Ruel Marc, Bianchi Cesario, Voisine Pierre, Komjáti Katalin, Szabo Csaba, Sellke Frank W
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
J Am Coll Surg. 2003 Aug;197(2):270-7. doi: 10.1016/S1072-7515(03)00538-6.
Poly(ADP-ribose) polymerase activation has been shown to contribute to the pathogenesis of myocardial ischemia-reperfusion injury. We hypothesized that a novel poly(ADP-ribose) polymerase inhibitor, INO-1001, provides myocardial protection and improves cardiac function after regional ischemia and cardioplegia-cardiopulmonary bypass (CPB).
Pigs were subjected to 30 minutes of regional ischemia by distal left anterior descending coronary artery ligation followed by CPB (60 minutes) with hyperkalemic cardioplegia (45 minutes). The myocardium then was reperfused post-CPB for 90 minutes. After 15 minutes of ischemia, the treatment group (n = 6) received an INO-1001 bolus (1mg/kg) before a continuous infusion (1mg/kg/hour). Control pigs (n = 6) received vehicle solution. Left ventricular pressure was monitored, from which the maximum, positive first derivative of left ventricular pressure over time (+dP/dt) was calculated. Regional myocardial function in the ischemic area was determined by sonomicrometric analysis. Infarct size was measured as the percent of the ischemic area by tetrazolium staining. Myocardial sections were immunohistochemically stained for poly(ADP-ribose) as a measure of poly(ADP-ribose) polymerase activity and inhibition.
Pigs treated with INO-1001 showed improvements in the +dP/dt at 60 and 90 minutes of post-CPB reperfusion (both p = 0.03) and percent segmental shortening at 30, 60, and 90 minutes of post-CPB reperfusion (p = 0.03, 0.009, and 0.03, respectively). Infarct size was decreased in the treatment group (18.5 +/- 5.7% versus 52.0 +/- 7.7%, INO-1001 versus control, p = 0.03). Poly(ADP-ribose) was reduced in myocardial sections from INO-1001-treated animals compared with controls.
These results suggest that INO-1001 provides myocardial protection by reducing the extent of infarction and improves cardiac function after regional ischemia and cardioplegia-CPB.
聚（ADP - 核糖）聚合酶激活已被证明与心肌缺血 - 再灌注损伤的发病机制有关。我们假设一种新型聚（ADP - 核糖）聚合酶抑制剂INO - 1001可在局部缺血及心脏停搏 - 体外循环（CPB）后提供心肌保护并改善心脏功能。
通过结扎左前降支冠状动脉远端使猪经历30分钟局部缺血，随后进行CPB（60分钟）并使用高钾心脏停搏液（45分钟）。然后在CPB后使心肌再灌注90分钟。缺血15分钟后，治疗组（n = 6）在持续输注（1mg/kg/小时）前接受INO - 1001推注（1mg/kg）。对照猪（n = 6）接受溶媒溶液。监测左心室压力，并据此计算左心室压力随时间的最大正向一阶导数（+dP/dt）。通过超声心动图分析确定缺血区域的局部心肌功能。通过四氮唑染色测量梗死面积，以缺血区域的百分比表示。对心肌切片进行免疫组织化学染色以检测聚（ADP - 核糖），作为聚（ADP - 核糖）聚合酶活性及抑制作用的指标。
接受INO - 1001治疗的猪在CPB再灌注60分钟和90分钟时的 +dP/dt有所改善（均p = 0.03），在CPB再灌注30分钟、60分钟和90分钟时的节段缩短百分比也有所改善（分别为p = 0.03、0.009和0.03）。治疗组的梗死面积减小（INO - 1001组为18.5±5.7%，对照组为52.0±7.7%，p = 0.03）。与对照组相比，INO - 1001治疗动物的心肌切片中聚（ADP - 核糖）减少。
这些结果表明，INO - 1001通过减少梗死范围提供心肌保护，并在局部缺血及心脏停搏 - CPB后改善心脏功能。
