BACKGROUND: Sympathetic hyperactivity is observed in several disease states and may contribute to cardiovascular hypertrophic remodeling. Endothelin has been suggested to be a mediator of hypertrophy. OBJECTIVE: To examine the involvement of endothelin in maintaining the growth response induced by exogenous norepinephrine. DESIGN AND METHODS: Rats were treated with norepinephrine (2.5 microg/Kg per min subcutaneously) for 2 and 4 weeks, alone or in association with the selective 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 elastin characterized norepinephrine-induced aortic remodeling. These effects occurred without marked changes of mean arterial pressure, but may be related to enhanced pressure variability in addition to direct effects of norepinephrine. Inhibition of ETA receptors by darusentan reversed aortic alterations produced by infusion of norepinephrine. Evaluation of medial apoptosis did not reveal any significant change in any group at 4 weeks. CONCLUSIONS: Antagonism of ETA receptors effectively and rapidly reversed norepinephrine-induced aortic structural and compositional changes, suggesting a central role of endothelin in mediating this response. Thus, ETA receptor antagonists may help to regress large artery remodeling in conditions of increased circulating catecholamine concentrations.
BACKGROUND: Sympathetic hyperactivity is observed in several disease states and may contribute to cardiovascular hypertrophic remodeling. Endothelin has been suggested to be a mediator of hypertrophy. OBJECTIVE: To examine the involvement of endothelin in maintaining the growth response induced by exogenous norepinephrine. DESIGN AND METHODS: Rats were treated with norepinephrine (2.5 microg/Kg per min subcutaneously) for 2 and 4 weeks, alone or in association with the selective 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 elastin characterized norepinephrine-induced aortic remodeling. These effects occurred without marked changes of mean arterial pressure, but may be related to enhanced pressure variability in addition to direct effects of norepinephrine. Inhibition of ETA receptors by darusentan reversed aortic alterations produced by infusion of norepinephrine. Evaluation of medial apoptosis did not reveal any significant change in any group at 4 weeks. CONCLUSIONS: Antagonism of ETA receptors effectively and rapidly reversed norepinephrine-induced aortic structural and compositional changes, suggesting a central role of endothelin in mediating this response. Thus, ETA receptor antagonists may help to regress large artery remodeling in conditions of increased circulating catecholamine concentrations.
Authors: C S Ceron; M M Castro; E Rizzi; M F Montenegro; V Fontana; M C O Salgado; R F Gerlach; J E Tanus-Santos Journal: Br J Pharmacol Date: 2010-03-19 Impact factor: 8.739
Authors: S B A Cau; D A Guimaraes; E Rizzi; C S Ceron; L L Souza; C R Tirapelli; R F Gerlach; J E Tanus-Santos Journal: Br J Pharmacol Date: 2011-09 Impact factor: 8.739
Authors: Priscila Portugal Dos Santos; Bruna Paola Murino Rafacho; Andréa de Freitas Gonçalves; Rodrigo Gibin Jaldin; Thiago Bruder do Nascimento; Marcondes Alves Barbosa Silva; Stêfany Bruno Assis Cau; Meliza Goi Roscani; Paula Schimdt Azevedo; Marcos Ferreira Minicucci; Rita de Cássia Tostes; Leonardo Antonio Memede Zornoff; Sergio Alberto Rupp de Paiva Journal: PLoS One Date: 2014-06-12 Impact factor: 3.240
Authors: Chueh-Lung Hwang; James Muchira; Brooks A Hibner; Shane A Phillips; Mariann R Piano Journal: Cardiovasc Toxicol Date: 2022-02-23 Impact factor: 2.755