De Carvalho Frimm C, Sun Y, Weber K T
Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia 65212, USA.
J Lab Clin Med. 1997 Apr;129(4):439-46. doi: 10.1016/s0022-2143(97)90077-9.
Tissue angiotensin II (AngII) is increased in the infarcted rat heart, where it may have autocrine or paracrine properties that influence cellular protein synthesis and growth and therefore tissue repair. It was our hypothesis that treatment with an AT1 receptor antagonist would attenuate fibrous tissue formation after myocardial infarction (MI). To investigate a role for local AngII in the regulation of connective tissue formation during early and late wound healing that follows MI, this study was undertaken. Animals were randomized into two groups in which rats were or were not treated with the AT1 receptor antagonist losartan (10 mg x kg(-1) daily gavage). At 1 and 4 weeks after experimental MI was induced by coronary artery ligation, rat hearts were examined. Infarct size, infarct area, and collagen volume fraction at the site of infarction and in noninfarcted myocardium were determined by picrosirius red staining with videodensitometry. Quantitative in vitro autoradiography was used to detect AngII receptor binding density ((125)I-(Sar1,Ile8)AngII). Compared with an untreated MI control group, in losartan-treated rats we found (1) infarct size was comparable in both groups at weeks 1 and 4, (2) infarct area was comparable between groups at week 1 but was significantly reduced (p < 0.05) at week 4 in losartan-treated rats, (3) a detectable reduction in collagen volume fraction at the site of MI was not found at week 1 but was reduced (p < 0.05) at remote sites at week 4, (4) AngII receptor binding density was reduced (p < 0.05) by 50% at the site of MI at both weeks 1 and 4 in keeping with delivery of losartan to this site of injury. Thus AT1 receptor antagonism appears to influence late phase wound healing at and remote to the site of MI and suggests an association between AngII and the fibrogenic response that appears in the injured rat heart. Although still speculative, an attenuation in fibrosis after MI may account for less ventricular dysfunction and geometric remodeling of right and left ventricles and ventricular arrhythmias that have been observed in such rats treated with angiotensin converting enzyme inhibitor or AT1 receptor antagonist.
梗死大鼠心脏中的组织血管紧张素II（AngII）水平升高，在该处它可能具有自分泌或旁分泌特性，影响细胞蛋白质合成和生长，进而影响组织修复。我们的假设是，用AT1受体拮抗剂治疗可减轻心肌梗死（MI）后的纤维组织形成。为了研究局部AngII在MI后早期和晚期伤口愈合过程中对结缔组织形成的调节作用，开展了本研究。将动物随机分为两组，一组大鼠接受AT1受体拮抗剂氯沙坦（每日10 mg·kg⁻¹灌胃）治疗，另一组不接受治疗。在通过冠状动脉结扎诱导实验性MI后1周和4周，检查大鼠心脏。通过苦味酸天狼星红染色和视频密度测定法测定梗死面积、梗死区域以及梗死部位和非梗死心肌中的胶原体积分数。采用定量体外放射自显影法检测AngII受体结合密度（¹²⁵I-（Sar¹，Ile⁸）AngII）。与未治疗的MI对照组相比，在氯沙坦治疗的大鼠中我们发现：（1）在第1周和第4周，两组的梗死面积相当；（2）在第1周时，两组的梗死区域相当，但在第4周时，氯沙坦治疗的大鼠梗死区域显著减小（p < 0.05）；（3）在第1周时，未发现MI部位的胶原体积分数有可检测到的降低，但在第4周时，远处部位的胶原体积分数降低（p < 0.05）；（4）在第1周和第4周时，MI部位的AngII受体结合密度均降低（p < 0.05）50%，这与氯沙坦送达该损伤部位一致。因此，AT1受体拮抗似乎影响MI部位及其远处的晚期伤口愈合，并提示AngII与损伤大鼠心脏中出现的纤维化反应之间存在关联。虽然仍属推测，但MI后纤维化的减轻可能是用血管紧张素转换酶抑制剂或AT1受体拮抗剂治疗的此类大鼠中心室功能障碍、左右心室几何重塑及室性心律失常较少的原因。
