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.