Acute Kynurenine Exposure of Rat Thoracic Aorta Induces Vascular Dysfunction <i>via</i> Superoxide Anion Production

Abstract

The accumulation of uremic toxins is known to be one of the causes of cardiovascular disorder related to renal disease. Among the many uremic toxins, we focused on kynurenine (kyn), whose levels have been shown to be positively correlated with vascular endothelial dysfunction markers, and directly evaluated the influence of kyn on the rat thoracic aorta. Exposure of the endothelium-intact aorta to kyn markedly attenuated the acetylcholine (ACh)-induced relaxation and significantly increased superoxide anion (O2·-) production. These effects were ameliorated by pretreatment with ascorbic acid, an antioxidant, and CH223191, an aryl hydrocarbon receptor (AhR) inhibitor, but not by apocynin, a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor. In the endothelium-denuded aorta, kyn significantly attenuated the nitric oxide (NO) donor sodium nitroprusside (SNP)-induced vasorelaxation and increased the O2·- production. Ascorbic acid treatment significantly ameliorated these effects, whereas CH223191 and apocynin treatments did not. Kyn had no influence on the vasorelaxant response to BAY 41-2272, a soluble guanylate cyclase stimulator. This suggested that kyn attenuates the NO-mediated vasorelaxation response by promoting O2·- production in thoracic aorta to inactivate NO. O2·- production is likely stimulated in both vascular endothelium and smooth muscle, the former of which may be mediated by AhR activation.