Prevenção das disfunções vasculares no inicio da aterogenese : efeito da S-Nitroso-N-Acetilcisteina, SNAC, em camundongos knock out para o receptor da LDL

AUTOR(ES)
DATA DE PUBLICAÇÃO

2003

RESUMO

Pathophysiology of the NO/NO synthase system and endothelium dysfunctional changes in early phases of the atherogenic process are incompletely understood. In hypercholesterolemic LDLr-/- mice, we addressed changes in endothelium-dependent relaxations, NO synthase expression and plaque burden in the absence or presence of the nitrosothiol NO donor S-nitroso-N-acetylcysteine (SNAC). Initially, we characterized the hypotensive effect of the S-nitroso-N-acetylcysteine (SNAC) in normotensive and hypertensive conscious rats. The results showed that i) SNAC reduced the medium arterial pressure in a dose-response manner in both normotensive and hypertensive animaIs; ii) At the same doses (ECso of SNAC), SNAC showed a vasodilator effect in normotensive rats more potent and more prolonged than that of sodium nitroprusside (SNP); iii) SNAC acts by both cGMP-dependent and cGMP-independent pathways; iii) It was also shown that the thiol N - acetyl - L - cysteine (NAC) potentiates the action of SNP in hypertensive rats, pointing to the mediation of thiols in the vasodilator action of SNP in this condition. Such mediation may involve the formation of a more potent thiol complex with the nitroprusside anion ar the transfer of.NO to NAC, generating SNAC as a primary vasoactive species. In the second study we characterized the SNAC effect on the endothelial dysfunction in hypercholesterolemic LDLr-/- rnice for two weeks. Increase in plasma cholesterol/triglyceride levels was accompanied by aortic root lesions. Aortic vasorelaxation to acetylcholine was paradoxically increased, while endothelium independent relaxations to sodium nitroprusside were decreased suggesting enhanced basal or stimulated NO release. This dysfunction was associated with enhanced aortic superoxide production and with increased levels of constitutive NOS isoform expression, particularly neuronal NOS. SNAC (O.51Ilmol/Kg i.p., per two weeks) treatment in HC mice (SNAC + HC ) decreased plaque extension by 55%, prevented the alterations in vasorelaxation and brought about a 20% decrease in cholesterol levels. In conc1usion, the present study disc1osed, in early stages of plaque development in LDLr-/- mice, particular changes in NO/NOS pathophysiology, characterized by increased endothelium-dependent vasorelaxation and increased constitutive NOS expression. Such changes were prevented by SNAC, which may therefore constitute a novel strategy to halt early plaque progression

ASSUNTO(S)

oxido nitrico aterosclerose camundongo

ACESSO AO ARTIGO

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