Frolkis I, Gurevitch J, Yuhas Y, Iaina A, Wollman Y, Chernichovski T, Paz Y, Matsa M, Pevni D, Kramer A, Shapira I, Mohr R
Department of Thoracic and Cardiovascular Surgery, Tel Aviv Medical Center, Israel.
J Am Coll Cardiol. 2001 Jan;37(1):316-22. doi: 10.1016/s0735-1097(00)01055-x.
The purpose of this study was to explore interactions between paracrine angiotensin II (Ang-II) and tumor necrosis factor-alpha (TNF-alpha) during myocardial ischemia.
Ischemic myocardium releases significant amounts of TNF-alpha. This paracrine release correlated with postischemic myocardial injury. Other studies showed myocardial protection obtained by the use of angiotensin-converting enzyme inhibitors (i.e., captopril) and the Ang-II type 1 receptor antagonist losartan after ischemia. The possibility that these agents decrease TNF-alpha synthesis has not yet been investigated.
Using the modified Langendorff model, isolated rat hearts underwent either 90 min of nonischemic perfusion (control group) or 1 h of global cardioplegic ischemia. In both groups, either captopril (360 micromol/liter) or losartan (182.2 micromol/liter) was added before ischemia. The hearts were assayed for messenger ribonucleic acid (mRNA) expression and effluent TNF-alpha levels. In addition, cardiac myocytes were incubated in cell culture with Ang-II.
After ischemia, TNF-alpha mRNA expression intensified from 0.63 +/- 0.06 (control group) to 0.92 +/- 0.12 (p < 0.03), and effluent TNF-alpha levels were 711 +/- 154 pg/ml. The TNF-alpha mRNA expression declined to 0.46 +/- 0.07 (p < 0.01) and 0.65 +/- 0.08 (p < 0.02) in captopril- and losartan-treated hearts, respectively. Effluent TNF-alpha was below detectable levels. Concentrations of TNF-alpha in supernatants of incubated cardiac myocytes treated with 10 and 50 nmol/liter of Ang-II were 206.0 +/- 47.0 pg/ml and 810 +/- 130 pg/ml, respectively (p < 0.004). When pretreated with 700 micromol/liter of losartan, TNF-alpha was below detectable levels.
This study presents an original explanation for previously reported myocardial protection after ischemia, obtained by the use of captopril and losartan. These drugs reduce TNF-alpha synthesis, providing strong evidence of active interactions between paracrine TNF-alpha and Ang-II in the evolution of the ischemic cascade.
本研究旨在探讨心肌缺血期间旁分泌血管紧张素II（Ang-II）与肿瘤坏死因子-α（TNF-α）之间的相互作用。
缺血心肌会释放大量TNF-α。这种旁分泌释放与缺血后心肌损伤相关。其他研究表明，缺血后使用血管紧张素转换酶抑制剂（即卡托普利）和Ang-II 1型受体拮抗剂氯沙坦可获得心肌保护作用。这些药物是否会降低TNF-α合成的可能性尚未得到研究。
使用改良的Langendorff模型，将离体大鼠心脏进行90分钟的非缺血灌注（对照组）或1小时的全心停搏缺血。在两组中，缺血前均加入卡托普利（360微摩尔/升）或氯沙坦（182.2微摩尔/升）。检测心脏的信使核糖核酸（mRNA）表达和流出液中的TNF-α水平。此外，将心肌细胞在细胞培养中与Ang-II一起孵育。
缺血后，TNF-α mRNA表达从0.63±0.06（对照组）增强至0.92±0.12（p<0.03），流出液中TNF-α水平为711±154皮克/毫升。在卡托普利和氯沙坦处理的心脏中，TNF-α mRNA表达分别降至0.46±0.07（p<0.01）和0.65±0.08（p<0.02）。流出液中的TNF-α低于可检测水平。用10和50纳摩尔/升的Ang-II处理的孵育心肌细胞上清液中TNF-α的浓度分别为206.0±47.0皮克/毫升和810±130皮克/毫升（p<0.004）。当用700微摩尔/升的氯沙坦预处理时，TNF-α低于可检测水平。
本研究为先前报道的缺血后使用卡托普利和氯沙坦获得的心肌保护作用提供了一个新的解释。这些药物可减少TNF-α合成，有力证明了旁分泌TNF-α与Ang-II在缺血级联反应演变过程中的积极相互作用。
