| Objective:Endothelial dysfunction is considered to be a widespread phenomenon of cardio-cerebral vascular diseases (CCD). The nitric oxide (NO) produced under the action of endothelial nitric oxide synthase(eNOS) has important antiatherogenic functions. Asymmetric dimethylarginine (ADMA) and homocysteine (Hcy) have metabolic interactions. They can inhibit the generation and bioavailability of NO, resulting in endothelial dysfunction, and may be risk factors for CCD. The study includes 2 parts:(1) A study on the measurement of ADMA, Hcy, eNOS, NO levels in patients with cerebral infarction with or without hypertension, in order to explore the pathogenesis of CCD ADMA and Hcy induced. (2) A clinical trial of the effect of the supplement therapy with folic acid and vitamin B12 on the plasma concentrations of ADMA and Hcy. All of the results from the two parts would be able to provide theoretical guidance and objective basis for early therapeutic approaches of cerebral infarction.Methods:ADMA, Hcy, NO and eNOS concentrations were measured in subjects of cerebral infarction normotensive group, cerebral infarction with hypertension group and health control group, each of which had 60 cases. Patients of acute cerebral infarction normotensive group and hypertension group were randomized to divided into intervention group and nonintervention group respectively. Patients of the intervention group had been treated with folic acid and vitamin B12 for 12 weeks. Then ADMA, Hcy, eNOS, NO were measured after 2 weeks and 12 weeks of supplementation. ADMA and Hcy were measured by high pressure liquid chromatography analysis (HPLC), eNOS and NO were measured by enzyme-linked immunoassay (ELISA) method. Value to mean±standard deviation of that result, all statistical analyses were performed with the statistical software SPSS 18.0.Results:1. There were statistically differences among ADMA concentrations in the three group (P＜0.05). Levels in cerebral infarction with hypertension group (0.74±0.20μmol/L) were higher than those in both cerebral infarction normotensive group (0.59±0.21μmol/L; P＜0.05), and controls (0.39±0.11μmol/L; P＜0.05). Levels of ADMA in cerebral infarction normotensive group was significantly increased compared to controls(P＜0.05).2. There were statistically differences among Hey concentrations in the three group (P＜0.05). Levels in cerebral infarction with hypertension group (33.20±14.60μmol/L) were higher than those in both cerebral infarction normotensive group (24.82±11.34μmol/L; P＜0.05), and controls (13.92±6.24μmol/L; P＜0.05). Levels of Hey in cerebral infarction normotensive group was significantly increased compared to controls (P＜0.05).3. There were statistically differences among eNOS concentrations in the three group (P＜0.05). Levels in cerebral infarction with hypertension group (15.41±4.51ng/ml) were higher than those in both cerebral infarction normotensive group (18.30±4.80ng/ml; P＜0.05), and controls (21.60±4.80 ng/ml; P＜0.05). Levels of eNOS in cerebral infarction normotensive group was significantly decreased compared to controls (P＜0.05).4. There were statistically differences among NO concentrations in the three group (P＜0.05). Levels in cerebral infarction with hypertension group (48.42±13.64μmol/L) were higher than those in both cerebral infarction normotensive group (56.94±14.57μmol/L; P＜0.05), and controls (69.14±14;65μmol/L;P＜0.05). Levels of NO in cerebral infarction normotensive group was significantly decreased compared to controls (P＜0.05).5. According to hypertension classification of cerebral infarction patients with hypertension, compared with patients who suffered from grade 1 and 2 hypertension, the ADMA and Hcy levels of patients with grade 3 hypertension were significantly higher (P＜0.05), while the eNOS and NO levels were lower (P＜0.5). There was not significantly different between the grade 1 and 2 groups(P>0.05).6. Pearson-correlation analysis showed:plasma levels of ADMA were positively correlated with Hcy and age (P＜0.05), and were negatively correlated with levels of eNOS and NO(P＜0.05); plasma levels of Hcy were positively correlated with ADMA, age, TC(infarction patients with normotensive group), SBP, DBP(infarction patients with hypertension group) (P＜0.05), and were negatively correlated with levels of eNOS and NO(P<0.05).7. By the sub-group analysis, compared with the patients with first cerebral infarction, ADM A and Hcy levels of patients with recurrent cerebral infarction were higher (P＜0.05), while the eNOS and NO levels were lower(P<0.05).8.By the OCSP classification, levels of ADMA and Hcy in TACI group were higher than those in POCI group(P＜0.05); eNOS levels in TACI group were lower than those in POCI group(P<0.05); and NO levels in TACI group and LACI group were lower than those in POCI group(P<0.05).9. Compared with baseline levels, folic acid and vitamin B12 supplementation of the subjects in cerebral infarction normotensive intervention group and cerebral infarction with hypertension intervention group for 2 weeks and 12 weeks reduced the plasma levels of ADMA and Hcy significantly(P＜0.05), and increased the levels of eNOS and NO (P<0.05). There was no significant change in the nonintervention group (P>0.05).10. Compared with the control group, the levels of ADMA and Hcy in the cerebral infarction normotensive intervention group remained higher (P＜0.05), while the levels of eNOS and NO remained lower after folic acid and vitamin B12 supplementation for 2 weeks, then there were no significant differences between them for 12 weeks(P>0.05). Compared with the control group, the levels of ADMA and Hcy in the cerebral infarction with hypertension intervention group remained higher, while the levels of eNOS and NO remained lower after folic acid and vitamin B12 supplementation for 2 weeks(P<0.05), then there were no significant differences of Hcy, eNOS, NO levels between them for 12 weeks(P>0.05), but the levels of ADMA in the cerebral infarction with hypertension intervention group remained higher than those in the control group after folic acid and vitamin B12 supplementation for 12 weeks(P<0.05).Conclusion:The levels of ADMA and Hcy in plasma were raised significantly in patients with acute cerebral infarction, as well as the levels of eNOS and NO in serum was reduced obviously, which demonstrated that vascular endothelial dysfunction was prevalence in patients with cerebral infarction. Compared with cerebral infarction normotension group, the ADMA and Hcy levels of cerebral infarction patients with hypertension were higher, while the eNOS and NO levels were lower, and also the ADMA and Hcy levels of patients with grade 3 hypertention were remarkable raised, which suggested that ADMA and Hcy was associated with the morbility and degree of hypertention. On the other hand, based on OCSP classification, ADMA and Hcy levels may be correlated with cerebral infarction recurrence and area. ADMA levels were positively correlated with Hcy levels, and both of them were negatively correlated with eNOS and NO.The present study demonstrated that ADMA which inhibited eNOS, reduced NO production, and interacted with Hcy, leading to endothelial dysfunction and artherosclerosis progressing, was regarded as a novel risk fator of CCD. With supplementation of both folic acid and vitamin B12, the level of ADMA and Hcy were able to be decreased significantly, and sequential improvement of the endothelial function and endothelium dependent vasodilatation, which was propitious to anti-artherosclerosis. These findings provided a novel target for pharmacotherapy of cerebral infarction.
|
PDF Full Text Request