Spironolactone Prevents Endothelial Nitric Oxide Synthase Uncoupling and Vascular Dysfunction Induced by beta-Adrenergic Overstimulation Role of Perivascular Adipose Tissue

Autor(es)

Victorio, Jamaira A. ; Clerici, Stefano P. ; Palacios, Roberto ; Alonso, Maria J. ; Vassallo, Dalton V. ; Jaffe, Iris Z. ; Rossoni, Luciana V. ; Davel, Ana P.

• Tipo de documento: Artigo Científico
• Fonte: Hypertension; v. 68, n. 3, p. 726+, SEP 2016.
• Citações Web of Science: 16

Resumo

Sustained stimulation of beta-adrenoceptors (beta-ARs) and activation of renin-angiotensin-aldosterone system are common features of cardiovascular diseases with rising sympathetic activation, including essential hypertension, myocardial infarction, and heart failure. In this study, we investigated the role of AT1 receptor and mineralocorticoid receptor (MR) in the vascular alterations caused by beta-AR overstimulation. beta-AR overstimulation with associated cardiac hypertrophy and increased vasoconstrictor response to phenylephrine in aorta were modeled in rats by 7-day isoproterenol treatment. The increased vasoconstrictor response to phenylephrine in this model was blunted by the MR antagonist spironolactone, but not by the AT1 receptor antagonist losartan, despite the blunting of cardiac hypertrophy with both drugs. Spironolactone, but not losartan, restored NO bioavailability in association with lower endothelial nitric oxide synthase-derived superoxide production, increased endothelial nitric oxide synthase dimerization, and aortic HSP90 upregulation. MR genomic and nongenomic functions were activated in aortas from isoproterenol-treated rats. Isoproterenol did not modify plasma levels of MR ligands aldosterone and corticosterone but rather increased perivascular adipose tissue-derived corticosterone in association with increased expression of 11 beta-hydroxysteroid dehydrogenase type 1. The anticontractile effect of aortic perivascular adipose tissue was impaired by beta-AR overstimulation and restored by MR blockade. These results suggest that activation of vascular MR signaling contributes to the vascular dysfunction induced by beta-AR overstimulation associated with endothelial nitric oxide synthase uncoupling. These findings reveal an additional explanation for the protective effects of MR antagonists in cardiovascular disorders with sympathetic activation. (AU)

• Processo FAPESP: 11/15972-2 - Efeitos vasculares da hiperativação beta-adrenérgica associados à ativação do sistema renina-angiotensina-aldosterona
• Beneficiário: Jamaira Aparecida Victorio
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 14/07947-6 - Possível interação entre estimulação beta-adrenérgica e ativação do receptor de mineralocorticóide em células endoteliais, musculares lisas e do tecido adiposo perivascular
• Beneficiário: Ana Paula Couto Davel
• Modalidade de apoio: Auxílio à Pesquisa - Regular