We examined whether endothelial function of the renal microcirculation was impaired in a model of
chronic renal failure (CRF), and further assessed the role of asymmetrical
dimethylarginine (ADMA) and its degrading
enzyme,
dimethylarginine dimethylaminohydrolase (DDAH), in mediating the deranged
nitric oxide (NO) synthesis in CRF. CRF was established in male mongrel dogs by subtotal
nephrectomy, and the animals were used in experiments after a period of 4 weeks. The endothelial function of the renal afferent and efferent arterioles was evaluated according to the response to
acetylcholine, using an intravital needle-lens charge-coupled device camera. Intrarenal arterial infusion of
acetylcholine (0.01 microg/kg/min) elicited 22+/-2% and 20+/-2% dilation of the afferent and efferent arterioles in normal dogs. In dogs with CRF, this vasodilation was attenuated (afferent, 12+/-2%; efferent, 11+/-1%), and the attenuation paralleled the diminished increments in urinary nitrite+nitrate excretion. In the animals with CRF, plasma concentrations of
homocysteine (12.2+/-0.7 vs. 6.8+/-0.4 micromol/l) and ADMA were elevated (2.60+/-0.13 vs. 1.50+/-0.08 micromol/l). The inhibition of
S-adenosylmethionine-dependent
protein arginine N-methyltransferase by
adenosine dialdehyde decreased plasma ADMA levels, and improved the
acetylcholine-induced changes in urinary nitrite+nitrate excretion and arteriolar vasodilation. Acute
methionine loading impaired the
acetylcholine-induced renal arteriolar vasodilation in CRF, but not normal dogs, and the impairment in CRF dogs coincided with the changes in plasma ADMA levels. Real-time polymerase chain reaction revealed downregulation of the
mRNA expression of DDAH-II in the dogs with CRF. Collectively, these results provide direct in vivo evidence of endothelial dysfunction in canine CRF kidneys. The endothelial dysfunction was attributed to the inhibition of the NO production by elevated ADMA, which involved the downregulation of DDAH-II. The deranged NO metabolic pathway including ADMA and DDAH is a novel mechanism for the aggravation of renal function.