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 so me patients with CRD that might directly influence endothelial NOS. Methods. Human dermal microvascular endothelial cells (HDMECs) were incubat ed for six hours with 20% plasma from subjects with normal renal function ( P-Cr = 0.8 +/- 0.2 mg%), and patients with moderate renal insufficiency of various causes (P-Cr = 4.0 +/- 1.5 mg%) and impact on NOS activity, transpo rt of L-arginine, and abundance of eNOS protein were measured. Plasma conce ntrations of asymmetric and symmetric dimethyl L-arginine (ADMA and SDMA) w ere also measured. Results. There was no effect of any human plasma on L-arginine transport. T he NOS activity was variable in CRD patients and fell into two subgroups: C RD I, individual Values similar to control, and CRD IT, individual Values l ower than control mean. The effect of CRD plasma on NOS activity in culture d 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 a nd CRD I. Blood urea nitrogen and creatinine levels were uniformly elevated in CRD plasma. The abundance of eNOS protein was unaffected by plasma. Conclusion. High plasma levels of ADMA in CRD patients are independent of r educed renal clearance, suggesting an alteration in ADMA synthesis and/or d egradation. High ADMA is a marker and is partly responsible for the inhibit ion of eNOS activity in cultured cells and may also result in reduced eNOS activity in vivo, with consequent hypertension.