Norepinephrine-induced aortic hyperplasia and extracellular matrix deposition are endothelin-dependent

Background Sympathetic hyperactivity is observed in several disease states and may contribute to cardiovascular hypertrophic remodeling. Endothelin ha s been suggested to be a mediator of hypertrophy. Objective To examine the involvement of endothelin in maintaining the growt h response induced by exogenous norepinephrine. Design and methods Rats were treated with norepinephrine (2.5 mug/Kg per mi n subcutaneously) for 2 and 4 weeks, alone or in association with the selec tive endothelin-A (ETA) receptor antagonist, darusentan (LU135252,30 mg/Kg per day orally) for weeks 3 and 4. Results Increases in medial cell number and accumulation of collagen and el astin characterized norepinephrine-induced aortic remodeling. These effects occurred without marked changes of mean arterial pressure, but may be rela ted to enhanced pressure variability in addition to direct effects of norep inephrine. Inhibition of ETA receptors by darusentan reversed aortic altera tions produced by infusion of norepinephrine. Evaluation of medial apoptosi s did not reveal any significant change in any group at 4 weeks. Conclusions Antagonism of ETA receptors effectively and rapidly reversed no repinephrine-induced aortic structural and compositional changes, suggestin g a central role of endothelin in mediating this response. Thus, ETA recept or antagonists may help to regress large artery remodeling in conditions of increased circulating catecholamine concentrations. (C) 2001 Lippincott Wi lliams & Wilkins.