Melatonin reference limits at 3:00 AM and 8:00 AM in healthy adults.

We determined melatonin reference limits in blood serum of 129 healthy volunteers, aged 21 to 70 years, using enzyme-linked immunosorbent assay (IBL ELISA kit, Hamburg, Germany). At 3:00 AM, in almost full dark, the reference limits were found to be 18.3-134 pg/ml in males, 19.0-197 pg/ml in females and 18.5-180 pg/ml in the whole group. At 8:00 AM, they were statistically lower (5.63-61.8, 3.30-93.2 and 3.83-80.4 pg/ml respectively) possibly due to the light.

Asymmetric dimethylarginine--mechanisms and targets for therapeutic management.

Evidence has been accrued recently that chronic high levels of asymmetric dimethylarginine (ADMA) can be directly beneficial to the treatment of atherosclerotic vascular disorders thus making the substance a promising new therapeutic target. A therapeutic target can be theoretically each stage in the process of generation and elimination of asymmetric dimethylarginine. The methylation of L-arginine residues is a universal biological process involving hundreds of proteins but still with unknown effects. Interference with these mechanisms can generate ambiguous and speculative discussions. Supplementation with L-arginine seems to be the most natural way to reverse the detrimental effect of ADMA on the endothelium. The enzymatic activity of endogenous nitric oxide synthase is regulated by the ratio between the concentrations of L-arginine (the natural substrate) and that of ADMA (the endogenous inhibitor): in the presence of normal L-arginine levels, any elevation ofADMA levels may cause relative L-arginine deficiency thus attenuating the activity of the endogenous nitric oxide synthase. Target replacement therapy with L-arginine to increase the L-arginine plasma levels results in the normalisation of the L-arginine/ADMA ratio in the presence of higher levels of the latter. There is still some controversy about the effects of the most frequently used drugs on asymmetric dimethylarginine. Most of the relevant studies show that statins do not affect the ADMA levels. On the other hand, patients with high levels of ADMA are resistant to statin therapy--to improve the endothelium-dependent vasodilation they need a combined therapy with L-arginine. The angiotensin-converting enzyme inhibitors and the angiotensin receptor blockers are the most extensively studied substances, the studies predominantly centring on confirming their ADMA reducing effect. Until the specific ADMA-reducing therapy becomes readily available, it is the therapies of modification of the risk factors causing the increase of ADMA or the depletion of L-arginine, and the L-arginine replacement therapy that are the most realistic therapeutic solutions for patients with high plasma levels of ADMA because the synthesis of nitric oxide correlates with the L-arginine/ADMA ratio. A study was conducted in the Surgery of Preventive Cardiology with the Clinic of Cardiology in Plovdiv which included 40 patients with pronounced hypercholesterolemia (HC)--it was found that a one-month therapy with 40 mg simvastatin did not change statistically significantly ADMA plasma levels in spite of the optimal lipid regulation.

Evaluation of the relationship between flow-mediated vasodilation and some atherogenic risk markers in severe hypercholesterolemia.

BACKGROUND: In recent years, there has been a shift of interest in preventive cardiology towards primary prevention in high risk patients such as the patients with severe hypercholesterolemia. There is scanty information available in the respective literature on the levels of asymmetric dimethylarginine in severe hypercholesterolemia and on the correlation of flow-mediated vasodilation with some atherogenic risk biomarkers. AIM: To assess the relationship of flow-mediated vasodilation with lipids, apoproteins and some serum markers of endothelial activation in severe hypercholesterolemia. PATIENTS AND METHODS: The study population consisted of 58 patients with severe hypercholesterolemia (> 7.5 mmol/l) as categorised by Simon-Broome's criteria for clinical definite and probable diagnosis of familial hypercholesterolemia. All patients were asymptomatic. The study included also 50 control subjects that had no evidence of hypercholesterolemia. RESULTS: The analysis of the lipid profile, the atherogenic lipid indices, and the apoproteins of patients and controls supports the alternative hypothesis: there is a statistically significant difference determined by the higher values of these parameters in the patients group (P < 0.0001). The mean values of asymmetric dimethylarginine calculated at baseline in both groups differed significantly (1.64 +/- 0.04 micromol/l vs. 0.47 +/- 0.02 micromol/l for patients and controls, respectively, P < 0.001). There was also a significant difference in the mean values of flow-mediated vasodilation calculated at baseline between the two groups (4.49 +/- 0.62% vs. 8.64 +/- 0.61% for patients and controls, respectively, P < 0.001). We found a very strong negative correlation, which reached statistical significance, between the flow-mediated vasodilation and the asymmetric dimethylarginine, apoprotein B and the apoprotein B/apoprotein A-I ratio (rxy = -0.687 with apoprotein B, p < 0.0001; rxy = -0.518 with apoprotein B/apoprotein A-I ratio, p < 0.0001; and rxy = -0.895 with asymmetric dimethylarginine, p < 0.0001). CONCLUSIONS: Univariate analysis showed that 80% of all variations in the values of flow-mediated vasodilation can be explained by variations in the values of asymmetric dimethylarginine. The significant negative correlation between the flow-mediated vasodilation and apoprotein B, the apoprotein B/apoprotein A-I ratio and the asymmetric dimethylarginine indicates that these biomarkers are more strongly associated with the endothelial dysfunction (the earliest functional abnormality of the vascular wall) than with the lipid profile components that are usually used in clinical practice.