Uremic levels of urea inhibit L-arginine transport in cultured endothelial cells.
Hypertension in end-stage renal disease (ESRD) may involve lack of endothelial nitric oxide (NO), as suggested by reduced total NO synthase (NOS) in dialysis patients. One reason might be due to substrate deficiency. To test the hypothesis that uremia is a state of intracellular L-arginine deficiency, uremic plasma was obtained from dialysis patients, and its effect was tested on arginine transport in cultured vascular endothelial cells. L-arginine transport (P < 0.01) was reduced in human dermal microvascular endothelial cells (HDMEC) incubated for 6 h with 20% uremic plasma from peritoneal dialysis and hemodialysis patients obtained immediately predialysis. Similar transport inhibition was seen with ESRD plasma in human glomerular capillary and bovine aortic endothelial cells. Hemodialysis partially reversed inhibition of L-arginine transport. HDMECs incubated for 6 h with synthetic media containing high (uremic) urea concentrations showed inhibition of L-arginine 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 inhibition 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 activity and contributing to hypertension in ESRD patients.
Xiao
S
S
Department of Physiology, West Virginia University, Morgantown, West Virginia 26506-9229, USA.
Wagner
L
L
Mahaney
J
J
Baylis
C
C
D000818:Animals; D001011:Aorta / Q000166:cytology; D001120:Arginine / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002196:Capillaries / Q000166:cytology; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006977:Hypertension, Renal / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D014508:Urea / Q000097:blood*; D014511:Uremia / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D014508:Urea; D001120:Arginine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester