Characterization of a model of an arteriovenous fistula in the rat: the effect of L-NAME.
Vascular access dysfunction contributes to the mortality of patients undergoing chronic hemodialysis. The present study analyzed the changes that evolve in a femoral arteriovenous fistula in the rat. The venous segment of this model exhibited, at 1 week, activation of pro-inflammatory transcription factors and up-regulation of pro-inflammatory, proliferative, procoagulant, and profibrotic genes; and at 4 weeks, the venous segment displayed neointimal hyperplasia, smooth muscle proliferation, and thrombus formation. These changes were accompanied by endothelial (e) nitric oxide synthase (NOS) and inducible (i) NOS up-regulation. The administration of NG-nitro-L-arginine methyl ester, an inhibitor of NOS activity, increased venous neointimal hyperplasia and pro-inflammatory gene expression (monocyte chemoattractant protein-1 and cytokine-induced neutrophil chemoattractant-1), increased systolic blood pressure, and decreased blood flow through the fistula. In another hypertensive model, the rat subtotal nephrectomy model, venous neointimal hyperplasia in the arteriovenous fistula was also exacerbated. We conclude that this arteriovenous fistula model recapitulates the salient features observed in dysfunctional, hemodialysis arteriovenous fistulas, and that venous neointimal hyperplasia is exacerbated when this model is superimposed in two different models of systemic hypertension. Since the uremic milieu contains increased amounts of asymmetric dimethylarginine, we speculate that such accumulation of this endogenous inhibitor of NOS, by virtue of its pressor or nitric oxide-depleting effects, or a combination thereof, may contribute to the limited longevity of arteriovenous fistulas used for hemodialysis.
Croatt
Anthony J
AJ
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA.
Grande
Joseph P
JP
Hernandez
Melissa C
MC
Ackerman
Allan W
AW
Katusic
Zvonimir S
ZS
Nath
Karl A
KA
D000818:Animals; D001164:Arteriovenous Fistula / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D007249:Inflammation; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D006435:Renal Dialysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013927:Thrombosis / Q000473:pathology
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester