期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 283, 期 3, 页码 H1237-H1243出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00680.2001
关键词
risk factor of cardiovascular diseases; endothelium-derived relaxing factor; transnitrosation; reactive oxygen species; renal circulation
资金
- NIDDK NIH HHS [DK-54927] Funding Source: Medline
The present study was designed to test the hypothesis that homocysteine (Hcys) reduces intracellular nitric oxide (NO) concentrations ([NO](i)) and stimulates superoxide (O-2(radical anion)) production in the renal arterial endothelium, thereby resulting in endothelial dysfunction. With the use of fluorescence microscopic imaging analysis, a calcium ionophore, A-23187 (2 muM), and bradykinin (2 muM) were found to increase endothelial [NO](i) in freshly dissected lumen-opened small renal arteries loaded with 4,5-diaminofluorescein diacetate (DAF-2DA; 10 muM). Preincubation of the arteries with L-Hcys (20-40 muM) significantly attenuated the increase in endothelial [NO](i). However, L-Hcys had no effect on NO synthase activity in the renal arteries, as measured by the conversion rate of [H-3] arginine to [H-3] citrulline, but it concentration dependently decreased DAF-2DA-sensitive fluorescence induced by PAPA-NONOate in the solution, suggesting that L-Hcys reduces endothelial [NO](i) by its scavenging action. Because other thiol compounds such as L-cysteine and glutathione were also found to reduce [NO](i), it seems that decreased NO is not the only mechanism resulting in endothelial dysfunction or arteriosclerosis in hyperhomocysteinemia (hHcys). By analysis of intracellular O-2(radical anion) levels using dihydroethidium trapping, we found that only L-Hcys among the thiol compounds studied markedly increased O-2(radical anion) levels in the renal endothelium. These results indicate that L-Hcys inhibits the agonist-induced NO increase but stimulates O-2(radical anion) production within endothelial cells. These effects of L-Hcys on [NO](i) and [O-2(radical anion)] may contribute to endothelial injury associated with hHcys.
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