Endothelin-1 promotes vascular structural remodeling during the progression of heart failure - Prevention of vascular remodeling using a specific endothelin-converting enzyme inhibitor

To evaluate the effects of endothelin (ET)-converting enzyme (ECE) inhibito r on vascular remodeling in dogs with congestive heart failure (CHF), we ch ronically administered an ECE inhibitor, FR901533 (FR, iv. 0.3mg/kg/hr, n=6 ), to dogs with CHF induced by rapid ventricular pacing. Vehicle CHF dogs w ere given saline (n=7). In the vehicle CHF group after 3 weeks of pacing, t he ET system was activated in the plasma and vasculature (3 and 5 times hig her than normal, respectively). Inward remodeling occurred in the femoral a rtery, medial thickness (MT, 225+/-5 vs 193+/-4 mum, P<0.05) and deposition of collagen (DC, 22+/-2 vs 17+/-1%, P<0.01) significantly increased, while lumen diameter (LD, 1173+/-39 vs 1481+/-44 mum, P<0.05) decreased in the f emoral artery with CHF compared with the normal femoral artery. There were significant correlations between the number of ET-1 positive cells and MT, DC, LD and systemic vascular resistance. FR significantly suppressed the ch anges in these vascular parameters compared with the changes in the vehicle CHF group despite the lack of an effect on blood pressure, and moreover FR caused decreases in ET-1 levels in both the plasma and femoral artery (red uced to 43% and 54%, respectively, of the levels in the vehicle CHF group, P<0.05). In conclusion, ET-1 plays a critical role in the structural deteri oration of the vasculature during the progression of CHF, and ECE inhibitor s can prevent the development of vascular remodeling. (C) 2001 Elsevier Sci ence Inc. All rights reserved.