Arginase Activity Is a Determinant of Nitric Oxide Levels in Adult Vasoocclusive Sickle Cell Crisis.

A number of studies have demonstrated both low nitric oxide (NO) and l-arginine (l-arg, the substrate for NO synthesis) levels during adult sickle cell vasoocclusive crisis (VOC). L-arg levels, while diminished, are 10-fold higher than the k_m (3 mM) of endothelial NO synthase (eNOS) and more than sufficient to saturate this enzyme (a state known as the arginine paradox). Diminished l-arg thus cannot directly explain lower NO levels. Two explanations, enhanced arginase activity (catalyzing the conversion of l-arg to ornithine), and inhibition of NOS by increased levels of asymmetric dimethylarginine (ADMA) have been proposed to explain this arginine paradox in VOC. We sought to investigate these mechanisms during adult VOC in the emergency department (ED). L-arg, ornithine, and citrulline (the end product of ADMA metabolism) were measured via ion exchange chromatography from blood obtained from adult ED VOC patients. Citrulline levels were used as an indirect indicator of ADMA and ornithine levels were used as an indicator of arginase activity. Samples from sickle patients in steady-state and from normal healthy volunteers were obtained for comparison. As expected, VOC subjects had significantly lower median l-arg levels (23.16 μM/l, 18.74–29.81 IQR, p<0.001 vs steady state, 38.56 μM/l, 5.88–20.26 IQR, and control, 73.01 μM/l, 27.42–37.2 IQR). There was no significant difference in citrulline levels. Ornithine, the end product of l-arg metabolism by arginase, was lower in VOC (median: 22.61 μM/l, 17.22–27.3 IQR, p<0.001 vs steady state median of 36.78 μM/l, 30.28–42.26 IQR). It has been suggested that the l-arg:ornithine ratio may be a better reflection of total arginase activity - in this study, the l-arg:ornithine ratio was significantly lower in adult VOC (1.02 vs 2.71) when compared to healthy controls, indicating enhanced total arginase activity. We conclude that the l-arg-arginase-ornithine pathway may play a significant role in the diminished NO seen in adult VOC patients via enhanced arginase activity. This enhanced arginase activity may alter available l-arg, resulting in decreased NO. ADMA does not appear to be an important contributor to the arginine paradox found in adult VOC.