| Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. A number of studies have demonstrated impaired endothelium-dependent vasodilatation in animals and humans with hyperhomocysteinemia. Supplementation of B vitamins and / or folic acid has been shown to reverse hyperhomocysteinemia but is not sufficient to improve vascular endothelial dysfunction or atherosclerotic lesions in hyperhomocysteinemic animals and humans. Therefore, it is important to search for an effective pharmacological approach to the prevention of homocysteine-induced vascular diseases.Angiotensin converting enzyme inhibitors (ACEIs) have achieved widespread usage in the treatment of cardiovascular diseases. Furthermore, ACEIs have been shown to improve endothelial dysfunction in hypertension and atherosclerosis. However, it is unclear whether ACEI can improve the impairment of endothelium-dependent relaxation due to homocysteine. In the present study, we sought to examine whether captopril may exert beneficial effects on homocysteine-induced impairment of endothelium-dependent relaxation in rat aorta.METHODSThe present experiment comprised two parts, in vitro and in vivo In vitro, rat aortic rings were incubated with various concentrations of homocysteine (0.3 ~ 3 mmol/L) for 30 min in organ-bath to induce endothelial damage. In the captopril groups, aortic rings were pre-incubated with captopril (3~30 umol/L) for 15 min and then exposed to homocysteine for another 30 min in the presence of captopril. In order to determine whether scavenging oxygen free radicals and enhancing NO production contribute to the beneficial effect of captopril, we compared effects of superoxide dismutase (200 U/ml) or L-arginine (3 ~ 10 mmol/L) alone or in combination of superoxide dismutase (200 U/ml) and L-arginine (3 mmol/L) on the inhibition of homocysteine in isolated aortic rings with those of captopril. After these incubations, the endothelium-dependent relaxation response to acetylcholine and the endothelium-independent relaxation response to sodium nitroprusside were examined at the plateau phase of phenylephrine-contraction, respectively.In vivo, rats were given tail vein injections with homocysteine (10 mg/kg/d) or with homocysteine plus captopril (3 mg/kg/d, i.v.) for 4 weeks. Isometric tension recordings were used to assess inhibitory effects of homocysteine and protective effects of captopril on endothelium-dependent and -independent relaxation of aortic rings. Inthree groups, serum levels of endogenous inhibitor of nitric oxide synthase asymmetric dimethylarginine (ADMA) and NO2~ were measured. Moreover, serum malondialdehyde, derived from lipid peroxidation, and SOD activity in liver tissue were determined. In addition, serum angiotensin converting enzyme activity and serum creatinine level were assayed.RESULTSExposure of aortic rings to homocysteine (0.3 ~ 3 mmol/L) for 30 min induced a significant concentration-dependent inhibition of endothelium-dependent relaxation response to acetylcholine, but did not affect endothelium-independent relaxation response to sodium nitroprusside. Pre-incubation of aortic rings with captopril (3 ~ 30 umol/L) for 15 min and co-incubation of aortic rings with homocysteine (1 mmol/L) for another 30 min attenuated the inhibition of homocysteine in a dose-dependent manner. Moreover, superoxide dismutase (SOD, 200 U/ml), a scavenger of superoxide anions, reduced homocysteine-induced inhibition. L-arginine (3 mmol/L), a precursor of nitric oxide (NO), also attenuated the impairment of vasorelaxation induced by homocysteine. But in the combined presence of SOD and L-arginine, the inhibitory effect of homocysteine was reversed, which was very similar to the effect of 30 umol/L captopril.Administration of Hey (10 mg/kg/d) to normal male Sprague-Dawleyrats for 4 weeks significantly elevated serum concentration of endogenous ADMA and decreased serum content of NO compared with control group. This elevation of endogenous ADMA in serum of Hcy-... |
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