Transient involvement of endothelin in hypertrophic remodeling of small arteries

Objective: This study was designed to evaluate the capacity of norepinephri ne (NE) to induce hypertrophic remodeling of small arteries in rats, and to determine the involvement of endothelin (ET) to initiate and maintain it. Design and results: Treatment with NE (2.5 mug/kg per min) for 14 or 28 day s produced a similar inward hypertrophic remodeling, characterized by a sma ller lumen, but increased media thickness and cross-sectional area. Arteria l stiffness was reduced. Histological evaluation confirmed the hypertrophic nature of remodeling. Concomitant administration of LU135252 (ET-receptor antagonist) for the first 14 days of NE administration prevented the develo pment of hypertrophy, without altering arterial mechanics. Treatment with t he same antagonist from day 14 to day 28 of NE or angiotensin (Ang II) trea tment failed to regress established vascular hypertrophy. In contrast, norm alization of arterial structure was observed with prazosin, an alpha -adren ergic blocker. Endothelin content in small mesenteric arteries showed a tra nsient elevation following chronic NE administration. Conclusions: Increased circulating NE levels are associated with hypertroph ic remodeling of small arteries, in which ET plays an initiating role. Howe ver, the maintenance of vascular hypertrophy is ET-Independent, either in t he presence of augmented circulating levels of NE or Ang II. Thus, early ra ther than late treatment with ET-receptor antagonists may be a preferable a pproach to limit small artery-mediated end-organ damage in cardiovascular d iseases. (C) 2001 Lippincott Williams & Wilkins.