药物后处理对离体大鼠心肌缺血再灌注损伤影响的对比研究

Comparative study of the effect of different drugs on post-conditioning of myocardial ischemia reperfusion injury on isolated rat heart models

目的观察治疗浓度的硝酸甘油、地尔硫艹卓、尼可地尔以及腺苷对离体大鼠心肌缺血再灌注损伤的影响,探讨四种药物发挥心肌保护作用的不同机制以及各个药物的相对优劣。方法66只大鼠随机分为六组:正常对照组(N组)、缺血再灌注组(I-R组)、硝酸甘油组、地尔硫艹卓组、尼可地尔组、腺苷组。N组持续灌流Krebs-Henseleit液(K-H液)150 min;I-R组稳定灌流K-H液30 min后,结扎前降支30 min,继以K-H液再灌注90 min;药物后处理组分别在再灌注即刻给予硝酸甘油(10-8mol/L)、地尔硫艹卓(5μmo/L)、尼可地尔(200μmo/L)以及腺苷(100μmo/L)再灌注15 min,继以K-H液灌流75 min。记录并分析各组左心室发展压(left ventricular developed pressure,LVDP)、左心室内压力最大上升/下降速率(±dp/dtmax)、再灌注心律失常(RA)评分以及心肌梗死面积(myocardial infarct size)。结果 (1)I-R组再灌注30 min及45 min时LVDP均低于各药物后处理组(均P<0.05)。在药物后处理组,再灌注30 min地尔硫艹卓组LVDP[(92.68±5.09)mm Hg比(84.26±3.02)mm Hg比(83.35±2.88)mm Hg]、尼可地尔组LVDP[(88.95±1.75)mm Hg比(84.26±3.02)mm Hg比(83.35±2.88)mm Hg],再灌注45 min地尔硫艹卓组LVDP[(90.39±4.29)mm Hg比(82.09±4.24)mm Hg比(80.98±3.89)mm Hg]、尼可地尔组LVDP[(86.13±2.38)mm Hg比(82.09±4.24)mm Hg比(80.98±3.89)mm Hg]均高于硝酸甘油组与腺苷组,且地尔硫艹卓组高于尼可地尔组,差异均有统计学意义(均P<0.05),但硝酸甘油组与腺苷组比较,差异均无统计学意义(均P>0.05)。(2)I-R组再灌注30 min及45 min的±dp/dtmax均低于各药物后处理组(均P<0.05)。地尔硫艹卓组、尼可地尔组再灌注30 min及45 min的±dp/dtmax均高于硝酸甘油组、腺苷组,且地尔硫艹卓组高于尼可地尔组,差异均有统计学意义(均P<0.05)。但硝酸甘油组与腺苷组比较,差异无统计学意义(P>0.05)。(3)RA评分比较:I-R组评分[5(3,6),57.36]明显高于尼可地尔组[1(1,3),22.05]、地尔硫艹卓组[3(1,4),34.77]、硝酸甘油组[4(1,4),45.41]和腺苷组[2(1,3),23.14],差异均有统计学意义(均P<0.05)。尼可地尔组RA评分最低,但尼可地尔组与腺苷组差异无统计学意义(P=0.771)。(4)心肌梗死面积比较:硝酸甘油组(27.04±2.45)%、地尔硫艹卓组(17.01±1.13)%、腺苷组(47.97±1.22)%以及尼可地尔组(34.95±1.25)%均小于I-R组(55.51±1.43)%,差异均有统计学意义(均P<0.01)。各药物后处理组组间比较差异均有统计学意义(均P<0.01),且地尔硫艹卓组梗死面积最小。结论硝酸甘油、地尔硫艹卓、尼可地尔以及腺苷药物后处理均可以减少心肌缺血再灌注损伤,对缺血心肌起到保护作用。其中,地尔硫艹卓在改善心脏泵功能以及减少心肌梗死面积方面效果最好;在药物后处理RA评分方面,尼可地尔和腺苷效果更好。

Objective To observe and compare the effects of nitroglycerin,diltiazem,nicorandil and adenosin on isolated rat myocardial ischemia reperfusion injury modles,and to investigate the protective effect and related mechanisms of respective agents. Methods Sixty-six Wistar rats were randomly divided into six groups： normal group（ N Group）,ischemia-reperfusion group（ I-R group）,nitroglycerin ＋ischemia-reperfusion group,diltiazem ＋ ischemia-reperfusion group,adenosine ＋ ischemia-reperfusion group,nicorandil ＋ ischemia-reperfusion group. The normal group（ N group） was given continued perfusion of normal liquid for 150 min; the I-R group was given stable perfusion for 30 min followed by ligating the LAD for 30 min and subsequent reperfusion for 90 min. For the drug post-conditioning groups,the models were given reperfusion with nitroglycerin（ 10- 8mol / L）,diltiazem（ 5 μmo / L）,nicorandil（ 200 μmo / L） and adenosine（ 100 μmo / L） for 15 min respectively,and then perfused with K-H liquid for 75 min. Observed and recorded reperfusion arrhythmia（ RA）,Left ventricular developed pressure（ LVDP）,± dp / dtmax by Taimeng（ Chengdu） BL-420 s system and calculated myocardial infarct size. Results（ 1） LVDP was lowest in the I-R group compared with the other groups after 30 min and 45 min of reperfusion（ P 0. 05）. In the drug post-conditioning groups after 30 min reperfusion,LVDP in the diltiazem group [（ 92. 68 ± 5. 09）mm Hg vs.（ 84. 26 ± 3. 02） mm Hg vs.（ 83. 35 ± 2. 88） mm Hg] and in the nicorandil group [（ 88. 95 ±1. 75） mm Hg vs.（ 84. 26 ± 3. 02） mm Hg vs.（ 83. 35 ± 2. 88） mm Hg] was higher than the nitroglycerine and the adenosine treated group. LVDP after 45 min reperfusion in the diltiazem group [（ 90. 39 ± 4. 29）mm Hg vs.（ 82. 09 ± 4. 24） mm Hg vs.（ 80. 98 ± 3. 89） mm Hg] and in the nicorandil group [（ 86. 13 ±2. 38） mm Hg vs.（ 82. 09 ± 4. 24） mm Hg vs.（ 80. 98 ± 3. 89） mm Hg]was higher than the nitroglycerin and adenosine groups respectively. The diltiazem group has higher LVDP than the nicorandil group after reperfusion（ P 0. 05）. The difference between the nitroglycerin group and the adenosine group was not statistically significant（ P 0. 05）.（ 2） ± dp / dtmax was lowest in the I-R group than the other groups after30 min and 45 min reperfusion（ P 0. 05）. ± dp / dtmax in the diltiazem group and the nicorandil group were significantly higher than those in the nitroglycerin group and the adenosine group at 30 min and 45 min after reperfusion. ± dp / dtmax of the diltiazem group was higher than the nicorandil group,and the difference was significant（ P 0. 05）. There was no difference between the nitroglycerin group and the adenosine group（ P 0. 05）.（ 3） Comparison of the RA score showed the score of the IR group [5（ 3,6）,57. 36]was significantly higher than all the drug post-conditioning groups as nicorandil group [1（ 1,3）,22. 05 ],diltiazem group [3（ 1,4）,34. 77],nitroglycerin group [4（ 1,4）,45. 41] and adenosine group [2（ 1,3）,23. 14]（ P = 0. 000,P = 0. 000,P = 0. 004,P = 0. 000）. The nicorandil group had the lowest score. There was no significant difference between the nicorandil group and the adenosine group（ P = 0. 771）.（ 4）Myocardial infarct size was（ 27. 04 ± 2. 45） % in the nitroglycerin group,（ 17. 01 ± 1. 13） % in the diltiazem group,（ 47. 97 ± 1. 22） % in the adenosine group and（ 34. 95 ± 1. 25） in the nicorandil group. IR group（ 55. 51 ± 1. 43） % had the largest infarct size among all the groups statistical difference（ all P 0. 01）. The infarct size in the diltiazem group was the smallest. Conclusions In the treatment of myocardial ischemia and reperfusion,all of the four drugs（ nitroglycerin,diltiazem,nicorandil and adenosine） can reduce myocardial ischemia-reperfusion injury,and play a protective role in ischemic myocardium. Diltiazem showed promising improvement in cardiac pump function and reducing the area of myocardial infarction. In the post-conditioning for RA,nicorandil and adenosine showed better performance.