Uremic levels of urea inhibit L-arginine transport in cultured endothelialcells

Hypertension in end-stage renal disease (ESRD) may involve lack of endothel ial nitric oxide (NO), as suggested by reduced total NO synthase (NOS) in d ialysis patients. One reason might be due to substrate deficiency. To test the hypothesis that uremia is a state of intracellular L-arginine deficienc y, uremic plasma was obtained from dialysis patients, and its effect was te sted on arginine transport in cultured vascular endothelial cells. L-argini ne transport (P< 0.01) was reduced in human dermal microvascular endothelia l cells (HDMEC) incubated for 6 h with 20% uremic plasma from peritoneal di alysis and hemodialysis patients obtained immediately predialysis. Similar transport inhibition was seen with ESRD plasma in human glomerular capillar y and bovine aortic endothelial cells. Hemodialysis partially reversed inhi bition of L-arginine transport. HDMECs incubated for 6 h with synthetic med ia containing high (uremic) urea concentrations showed inhibition of L-argi nine transport, but this was not competitive because acute exposure to urea had no impact on L-arginine transport. Over a 6-h period, urea-induced inh ibition of L-arginine transport was not sufficient to inhibit NOS activity, but after 7 days NOS activity was reduced. These cellular findings suggest that substrate delivery may be lowered, thus reducing endothelial NOS acti vity and contributing to hypertension in ESRD patients.