Jin Denan, Takai Shinji, Sugiyama Tetsuya, Hayashi Tetsuya, Fukumoto Masanori, Oku Hidehiro, Kitaura Yasushi, Ikeda Tsunehiko, Miyazaki Mizuo
Department of Pharmacology, Osaka Medical College, Japan.
J Pharmacol Sci. 2009 Feb;109(2):275-84. doi: 10.1254/jphs.08210fp. Epub 2009 Feb 7.
In the present study, the effects of long-term angiotensin (Ang) II antagonism on the development of cardiac and endothelial disorders were examined in Spontaneously Diabetic Torii (SDT) rats. Blood glucose concentration started to increase markedly in the untreated SDT rats from 20 weeks of age, while the blood glucose concentrations of candesartan cilexetil-treated SDT rats were significantly lower until 30 weeks of age. Cardiac function deteriorated in SDT rats and was accompanied by severe cardiac fibrosis, cardiac hypertrophy, and microstructural pathologic change in cardiomyocytes. Cardiac function was very well preserved in the age-matched Sprague Dawley (SD) rats, but cardiac fibrosis developed with aging. Candesartan cilexetil treatment improved cardiac structural remodeling and cardiac function in SDT rats. Surprisingly, the degree of cardiac fibrosis in candesartan cilexetil-treated SDT rats was less than that of SD rats. Immunohistological staining confirmed that in addition to collagen deposition, fibroblasts and myofibroblasts were the main cellular components in the cardiac fibrotic areas. The diabetic hearts showed positive staining for ACE, Ang II, and AT(1) receptors. SDT rats also showed decreased endothelial function, which was improved with candesartan cilexetil treatment. These findings indicate that Ang II is involved in the development of cardiac dysfunction by accelerating cardiac remodeling and cardiomyocyte damage in the presence of hyperglycemia. On the other hand, although the mechanisms responsible for the cardiac fibrosis that occurs under normal conditions may differ greatly from those responsible for cardiac fibrosis with hyperglycemia, Ang II seems to play an important role in both.
在本研究中，我们检测了长期血管紧张素（Ang）II拮抗作用对自发性糖尿病Torii（SDT）大鼠心脏和血管内皮疾病发展的影响。未经治疗的SDT大鼠从20周龄开始血糖浓度显著升高，而坎地沙坦酯治疗的SDT大鼠在30周龄前血糖浓度显著较低。SDT大鼠心脏功能恶化，并伴有严重的心脏纤维化、心肌肥大和心肌细胞微观结构病理改变。年龄匹配的Sprague Dawley（SD）大鼠心脏功能保存良好，但随着年龄增长会出现心脏纤维化。坎地沙坦酯治疗改善了SDT大鼠的心脏结构重塑和心脏功能。令人惊讶的是，坎地沙坦酯治疗的SDT大鼠心脏纤维化程度低于SD大鼠。免疫组织化学染色证实，除胶原沉积外，成纤维细胞和肌成纤维细胞是心脏纤维化区域的主要细胞成分。糖尿病心脏ACE、Ang II和AT(1)受体呈阳性染色。SDT大鼠还表现出内皮功能下降，坎地沙坦酯治疗可改善这一情况。这些发现表明，在高血糖情况下，Ang II通过加速心脏重塑和心肌细胞损伤参与心脏功能障碍的发展。另一方面，尽管正常情况下发生心脏纤维化的机制可能与高血糖时心脏纤维化的机制有很大不同，但Ang II似乎在两者中都起重要作用。
