Effect of chronic elevated asymmetric dimethylarginine (ADMA) levels on granulopoiesis

The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is elevated in both animal models of chronic inflammatory disorders as well as in patients with chronic inflammatory disease. In vivo data suggest that ADMA can increase the number of circulating monocytes and possibly affect their adhesion potential in vitro. The aim of our study was to evaluate possible effects of chronically elevated levels of ADMA on white blood cell count (WBC), leukocyte subsets, and WBC distribution pattern using a model of chronic exogenous ADMA infusion. Male Sprague-Dawley rats (n = 20, 10 weeks of age) were randomized to receive either (1) isotonic saline or (2) ADMA applied by osmotic mini pumps. After 28 days of infusion, all animals were sacrificed for blood and tissue sampling. WBC count, flow cytometry for subtype assessment, and histological assessment were performed. Over a time period of 28 days, continuous ADMA infusion significantly increased mean plasma levels (1.26 +/- 0.07 mu mol/l) as compared to saline infusion (0.57 +/- 0.02 mu mol/l). Clinical side effects were not observed. Despite a physiologically relevant rise in ADMA plasma levels, measured by decrease of the l-arginine/AMDA ratio-a surrogate parameter of NO production capacity-there was no effect on WBC count or pattern of leukocyte subsets. Numbers and morphology of peripheral blood cells as well as number of NK-cells leveling liver and spleen were not affected by chronic ADMA infusion. Chronically elevated ADMA levels in otherwise healthy rats did not affect WBC counts or leukocyte subsets. Furthermore, anemia frequently found in patients with progressive renal failure and elevated ADMA levels, was not observed. In a chronic inflammatory state, elevated ADMA levels themselves are rather the result than the cause of the underlying inflammatory process.