丹曲林在心肌再灌注损伤体内和体外模型中的作用。

Effect of dantrolene in an in vivo and in vitro model of myocardial reperfusion injury.

作者信息

Preckel B, Schlack W, Comfère T, Thämer V

机构信息

Institut für Klinische Anaesthesiologie, Heinrich-Heine-Universität, Düsseldorf, Germany.

出版信息

Acta Anaesthesiol Scand. 2000 Feb;44(2):194-201. doi: 10.1034/j.1399-6576.2000.440211.x.

DOI:10.1034/j.1399-6576.2000.440211.x

PMID:10695914

Abstract

BACKGROUND

In skeletal muscle, dantrolene reduces free cytosolic calcium by inhibiting calcium release from the sarcoplasmic reticulum. A similar effect in ischemic-reperfused heart cells would protect myocardial tissue against reperfusion injury. We tested the hypothesis that dantrolene infusion during reperfusion protects the heart against reperfusion injury.

METHODS

Isovolumetric beating rat hearts were subjected to 30 min of ischemia followed by 60 min of reperfusion. Left ventricular (LV) developed pressure (LVDP) and creatine kinase release (CKR) were determined as indices of myocardial performance and cellular injury, respectively. In the treatment groups, dantrolene (25 (DAN25) or 100 (DAN100) micromol l(-1)) was infused during the first 15 min of reperfusion; control hearts received the respective concentration of the vehicle (mannitol (CON25, CON100), each group n=7). To investigate the effects of dantrolene on reperfusion injury in vivo, 18 chloralose-anesthetized rabbits were subjected to 30 min occlusion and 180 min reperfusion of a major coronary artery. LV pressure (LVP), cardiac output (CO), and infarct size were determined. During the last 5 min of ischemia, nine rabbits received 10 mg kg(-1) dantrolene intravenously (DAN). Another nine rabbits received the vehicle (dimethylsulfoxide) and served as controls (CON).

RESULTS

In isolated rat hearts, there was no recovery of LVDP in any group. Total CKR during 1 h of reperfusion was 845+/-76 (CON100) and 550+/-81 U g(-1) dry mass (DAN100, P<0.05). In rabbits in vivo, hemodynamic baseline values were similar between groups (CON vs. DAN: LVP, 99+/-6 (mean+/-SEM) vs. 91+/-6mm Hg, P=0.29; CO, 252+/-26 vs. 275+/-23 ml min(-1), P= 0.53). During coronary artery occlusion, LVP and CO were reduced in both groups (CON: LVP, 89+/-3%; CO, 90+/-5% of baseline values) and LVP did not recover to baseline values during reperfusion (51+/-5% (CON) vs. 67+/-7% (DAN) of baseline, P=0.10). Infarct size was 41+/-4% of the area at risk in controls and 37+/-6% in dantrolene treated hearts (P=0.59).

CONCLUSIONS

Dantrolene reduced CKR, indicating an attenuation of lethal cellular reperfusion injury in isolated rat hearts. However, in the rabbit in vivo, there was no effect on the extent of reperfusion injury after regional myocardial ischemia.

摘要

背景

在骨骼肌中，丹曲林通过抑制肌浆网释放钙来降低胞浆游离钙。在缺血再灌注的心脏细胞中产生类似作用可保护心肌组织免受再灌注损伤。我们检验了再灌注期间输注丹曲林可保护心脏免受再灌注损伤这一假说。

方法

将等容跳动的大鼠心脏进行30分钟缺血，随后60分钟再灌注。分别测定左心室（LV）舒张末压（LVDP）和肌酸激酶释放量（CKR）作为心肌功能和细胞损伤的指标。在治疗组中，于再灌注的最初15分钟内输注丹曲林（25（DAN25）或100（DAN100）微摩尔/升）；对照心脏输注相应浓度的溶媒（甘露醇（CON25、CON100），每组n = 7）。为研究丹曲林对体内再灌注损伤的影响，对18只氯醛糖麻醉的家兔进行主要冠状动脉30分钟阻断和180分钟再灌注。测定LV压力（LVP）、心输出量（CO）和梗死面积。在缺血的最后5分钟，9只家兔静脉注射10毫克/千克丹曲林（DAN）。另外9只家兔注射溶媒（二甲基亚砜）作为对照（CON）。

结果

在离体大鼠心脏中，任何组的LVDP均未恢复。再灌注1小时期间的总CKR在CON100组为845±76，在DAN100组为550±81单位/克干重（P<0.05）。在体内家兔中，各组间血流动力学基线值相似（CON与DAN相比：LVP，99±6（均值±标准误）对91±6毫米汞柱，P = 0.29；CO，252±26对275±23毫升/分钟，P = 0.53）。在冠状动脉阻断期间，两组的LVP和CO均降低（CON：LVP为基线值的89±3%；CO为基线值的90±5%），且再灌注期间LVP未恢复至基线值（CON为基线值的51±5%，DAN为基线值的67±7%，P = 0.10）。梗死面积在对照组中为危险区域面积的41±4%，在丹曲林治疗的心脏中为37±6%（P = 0.59）。