Hemodynamic Alterations in the Coronary Circulation of Cardiomyopathic Hamsters: Age and Ang II–dependent Mechanisms

Abstract

Background Coronary vasospasms have been reported in the early stages of cardiomyopathy in the Syrian cardiomyopathic hamster (CM; BIO-TO2 strain). It has been proposed these alterations could lead to ischemic heart disease and heart failure. However, the cause of these coronary abnormalities has not been established. In this study, we evaluated coronary hemodynamic to assess the role of Ang-II, reactive oxygen species, and nitric oxide (NO) in the development of these alterations in CM of 1, 2, and 6 months of age. Methods and Results Excised hearts from control (CT) and CM were retroperfused with Krebs-Ringer bicarbonate solution (KRB), and coronary resistance (CR) was determined. The experimental protocol involved sequential infusions of the thromboxane analog U46619 (THX, 0.1 μmol/L), bradykinin (BKN, 10 μmol/L), and sodium nitroprusside (SNP, 10 μmol/L). Similar experiments were conducted after treatment of hearts with N ω -nitro-L-arginine methyl ester (L-NAME, 10 μmol/L). Basal CR increased with age, but no significant differences were observed between CT and CM. Reactivity to THX was increased (69%, P < .05) in 2-month-old CM when compared with CT. This effect was observed concomitantly with a significant reduction (53%, P < .05) in BKN-induced relaxation. The reduction in BKN-dependent relaxation was prevented by treatment for 1 month with the antioxidant N-acetylcysteine (1 g·kg·day), or losartan, an Ang II type 1 receptor blocker (10 mg·kg·day). Losartan also prevented the THX-induced increased reactivity in 2-month-old CM. The BKN-induced relaxation occurred through an L-NAME–sensitive pathway that was impaired with age. SNP dilation was preserved in all animal groups. Conclusions Our results strongly implicate vascular renin-angiotensin-system (RAS) and oxidative stress in endothelial dysfunction and increased reactivity in the early stages of cardiomyopathy in CM. These findings could be relevant to understand the etiology of cardiovascular disorders, in particular, in patients with sarcoglycanopathies.