Circulating endothelial nitric oxide synthase inhibitory factor in some patients with chronic renal disease.
BACKGROUND
Chronic renal disease (CRD) is associated with hypertension and reduced synthesis of nitric oxide (NO). Here, we investigated whether there is a circulating endothelial NO synthase (eNOS) inhibitory factor(s) in some patients with CRD that might directly influence endothelial NOS.


METHODS
Human dermal microvascular endothelial cells (HDMECs) were incubated for six hours with 20% plasma from subjects with normal renal function (PCr = 0.8 +/- 0.2 mg%), and patients with moderate renal insufficiency of various causes (PCr = 4.0 +/- 1.5 mg%) and impact on NOS activity, transport of L-arginine, and abundance of eNOS protein were measured. Plasma concentrations of asymmetric and symmetric dimethyl L-arginine (ADMA and SDMA) were also measured.


RESULTS
There was no effect of any human plasma on L-arginine transport. The NOS activity was variable in CRD patients and fell into two subgroups: CRD I, individual values similar to control, and CRD II, individual values lower than control mean. The effect of CRD plasma on NOS activity in cultured cells was not related to the primary disease, but was predicted by plasma ADMA levels since plasma ADMA was elevated in CRD II versus both control and CRD I. Blood urea nitrogen and creatinine levels were uniformly elevated in CRD plasma. The abundance of eNOS protein was unaffected by plasma.


CONCLUSIONS
High plasma levels of ADMA in CRD patients are independent of reduced renal clearance, suggesting an alteration in ADMA synthesis and/or degradation. High ADMA is a marker and is partly responsible for the inhibition of eNOS activity in cultured cells and may also result in reduced eNOS activity in vivo, with consequent hypertension.
Department of Physiology, West Virginia University, Morgantown, West Virginia 26506-9229, USA.
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Xiao
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Wagner
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RJ
Schmidt
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Baylis
D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D001790:Blood Physiological Phenomena; D001806:Blood Urea Nitrogen; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D012016:Reference Values; D012867:Skin / Q000098:blood supply
C018524:N,N-dimethylarginine; D001120:Arginine; D003404:Creatinine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III