Coronary macroangiopathy is preceded by endothelial dysfunction by many years; a reduction in endothelium-dependent vasodilation is a hallmark of nearly all patients with diabetes type 2 and predicts cardiovascular events (Fig. 1) (10, 15). Endothelial-dependent responses become abnormal very early in the course of the disease and therefore they can be substituted as surrogate markers in interventional trials (16). The quality of vascular reactivity is determined by the balance between NO-production and NO inactivation. NO is elaborated from L-arginin by the endothelial NO-synthase (eNOS) and degraded mainly by free oxygen radicals (ROS); it reaches vascular smooth muscle cell by rapid diffusion and causes a fall of intracellular Ca++ concentration resulting in vasodilation. Endothelial dysfunction in diabetes and coronary atherosclerosis can be detected on the basis of paradox vasoconstriction following application of acetylcholine. It is the result of multifactorial process, which eventually leads to reduced concentrations of NO (17). Endothelial NO production is hampered by reduced bioavailability of the precursor L-arginin, by an increased concentration of asymmetric dimethylarginin (ADMA), which inhibits eNOS activity, as well as by alterations of the eNOS protein structure found in patients with polymorphisms (18-23).
Free oxygen radicals that are produced by a number of enzymes particularly in patients with diabetes are capable of destroying NO. Superoxide anions, elaborated by the
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