Long-term treatment with N-omega-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice

Article

关键词: CHRONIC INHIBITION;    ANGIOTENSIN-II;    RECEPTOR ANTAGONISTS;    CHRONIC BLOCKADE;    RAT;    HYPERTENSION;    GENE;   

DOI  :  10.1161/01.CIR.0000029749.16101.44

来源: SCIE

【 摘 要 】

Background-N-omega-nitro-L-arginine methyl ester (L-NAME) is widely used to inhibit endothelial synthesis of NO in vivo. However, it is controversial whether the long-term vascular effects Of L-NAME are mediated primarily by inhibition of endothelial NO synthesis. We addressed this point in mice that are deficient in the endothelial NO synthase gene (eNOS-KO mice). Methods and Results-Wild-type and eNOS-KO mice received L-NAME in drinking water for 8 weeks. In wild-type mice, long-term treatment with L-NAME caused significant medial thickening and perivascular fibrosis in coronary microvessels but not in large coronary arteries. Importantly, in eNOS-KO mice, treatment with L-NAME also caused an extent of medial thickening and perivascular fibrosis in coronary microvessels that was comparable to that in wild-type mice and that was not prevented by supplementation Of L-arginine. Vascular NO and cGMP levels were not significantly reduced by L-NAME treatment, and no expression of inducible or neuronal NO synthase was noted in microvessels of eNOS-KO mice, suggesting an involvement of NO-independent mechanisms. Treatment with L-NAME caused an upregulation of vascular ACE and an increase in cardiac lucigenin chemiluminescence that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or CS866 (angiotensin 11 type I receptor antagonist) along with the suppression of vascular lesion formation. Conclusions-These results provide the first direct evidence that the long-term vascular effects Of L-NAME are not mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of local ACE and increased oxidative stress appear to be involved in the long-term vascular effects Of L-NAME in vivo.

【 授权许可】

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