Campo G M, Squadrito F, Altavilla D, Squadrito G, Avenoso A, Canale P, Ioculano M, Sperandeo A, Caputi A P
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
J Pharmacol Exp Ther. 1996 Apr;277(1):333-40.
We studied the effects of the aminosteroid U-74389G (21-[4-(2, 6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-pregna-1,4,9(11)- triene-3,20-dione(2)-2-butenenedionate), a putative inhibitor of lipid peroxidation, which protects the rat myocardium after ischemia and reperfusion. Pentobarbital-anesthetized (50 mg/kg) rats were subjected to 60 min of occlusion of the left main coronary artery followed by 60 min of reperfusion. Myocardial ischemia/reperfusion produced a large cardiac necrosis (81 +/- 8.6% of the area at risk and 65 +/- 14.8% of the total left ventricle), polymorphonuclear infiltration in the jeopardized tissue (myeloperoxidase activity = 4.2 +/- 2.1 U X 10(-3)/g tissue in the area at risk and 7.0 +/- 3.6 U X 10(-3)/g tissue in the necrotic area), hydroxyl radical (OH.) formation (0.55 +/- 0.16 nmol/ml), increased plasma malonylaldehyde (40.2 +/- 3.9 nmol/ml) and lactate dehydrogenase (431 +/- 30 mIU/ml) and caused a decrease in the survival rate. Treatment with U-74389G (15 and 30 mg/kg i.v.) at the onset of reperfusion caused a reduction of necrotic area expressed as a percentage of either the area at risk (76 +/-7.4% with 15 mg/kg and 69 +/- 13.5% with 30 mg/kg; P < .05) or the total left ventricle (53 +/- 13.6% with 15 mg/kg and 46 +/- 16.8% with 30 mg/kg; P < .05). Treatment U-74389G reduced the myeloperoxidase activity, evaluated as an index of neutrophil infiltration, both in the area at risk (2.7 +/- 1.1 and 2.2 +/- 1.7 U X 10(-3)/g tissue with the doses of 15 and 30 mg/kg, respectively; P < .05) and in the necrotic area (4.3 +/- 2.4 and 3.8 +/- 2.9 U X 10(-3)/g tissue with 15 and 30 mg/kg, respectively; P < .05); decreased OH. formation (measured indirectly by the administration of the trapping agent salicylic acid); and analyzing the hydroxylation product 2,5-dihydroxybenzoic acid during reperfusion (0.35 +/- 0.12 and 0.32 +/- 0.15 nmol/ml with the doses of 15 and 30 mg/kg, respectively; P < .005). Treatment inhibited lipid peroxidation by blunting plasma malonylaldehyde (26.7 +/- 3.1 and 20.8 +/- 3.3 with the doses of 15 and 30 mg/kg, respectively; P < .001), prevented cellular disruption by reducing the increase of plasma lactate dehydrogenase (288.6 +/- 28 and 201.3 +/- 16 mIU/ml with the doses of 15 and 30 mg/kg, respectively; P < .001). Finally, U-74389G enhanced the survival rate evaluated at the end of the experiment (from 40 to 87%). These outcomes suggest that the drug may have potential for cardioprotective use in acute myocardial infarction.
我们研究了氨基甾体U-74389G（21-[4-(2,6-二-1-吡咯烷基-4-嘧啶基)-1-哌嗪基]-孕甾-1,4,9(11)-三烯-3,20-二酮(2)-2-丁烯二酸盐）的作用，它是一种假定的脂质过氧化抑制剂，可在缺血再灌注后保护大鼠心肌。用戊巴比妥麻醉（50mg/kg）的大鼠，使其左主冠状动脉闭塞60分钟，随后再灌注60分钟。心肌缺血/再灌注导致大面积心肌坏死（危险区域面积的81±8.6%，左心室总面积的65±14.8%），受损组织中有多形核白细胞浸润（危险区域组织中髓过氧化物酶活性=4.2±2.1U×10⁻³/g组织；坏死区域中为7.0±3.6U×10⁻³/g组织），形成羟自由基（OH·）（0.55±0.16nmol/ml），血浆丙二醛增加（40.2±3.9nmol/ml）和乳酸脱氢酶增加（431±30mIU/ml），并导致存活率降低。在再灌注开始时用U-74389G（15和30mg/kg静脉注射）治疗，使坏死区域减少，以危险区域面积的百分比表示（15mg/kg时为76±7.4%，30mg/kg时为69±13.5%；P<0.05）或左心室总面积的百分比表示（15mg/kg时为53±13.6%，30mg/kg时为46±16.8%；P<0.05）。U-74389G治疗降低了髓过氧化物酶活性，作为中性粒细胞浸润的指标，在危险区域（分别用15和30mg/kg剂量时为2.7±1.1和2.2±1.7U×10⁻³/g组织；P<0.05）和坏死区域（15和30mg/kg时分别为4.3±2.4和3.8±2.9U×10⁻³/g组织；P<0.05）均降低；减少了OH·的形成（通过给予捕获剂水杨酸间接测量），并在再灌注期间分析羟基化产物2,5-二羟基苯甲酸（15和30mg/kg剂量时分别为0.35±0.12和0.32±0.15nmol/ml；P<0.005）。治疗通过降低血浆丙二醛抑制脂质过氧化（15和30mg/kg剂量时分别为26.7±3.1和20.8±3.3；P<0.001），通过减少血浆乳酸脱氢酶的增加防止细胞破坏（15和30mg/kg剂量时分别为288.6±28和201.3±16mIU/ml；P<0.001）。最后，U-74389G提高了实验结束时评估的存活率（从40%提高到87%）。这些结果表明，该药物在急性心肌梗死中可能具有心脏保护作用的潜力。
