Abstract

Increased serum level of homocysteine is an independent risk factor for vascular disease. The effect of dl-homocysteine on the endothelial production of kynurenic acid, an antagonist of α7-nicotinic and N-methyl- d-aspartate (NMDA) glutamate receptors, has been evaluated in vitro and in vivo. In rat aortic rings, dl-homocysteine at 40–100 μM enhanced, whereas at ≥ 400 μM decreased the synthesis of kynurenic acid. S-adenosylhomocysteine mimicked the biphasic action of dl-homocysteine. On the contrary, thiol-containing compounds, l-cysteine and l-methionine, were only inhibiting kynurenic acid production. l-kynurenine uptake blockers, l-phenylalanine and l-leucine, reversed the stimulatory effect of S-adenosylhomocysteine. l-glycine, co-agonist of NMDA receptor, and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), an antagonist of NMDA receptor, have not influenced kynurenic acid formation. In vivo, dl-homocysteine (1.3 mmol, i.p.) increased the level of kynurenic acid in rat serum from 23.7 ± 7.1 to 60.7 ± 14.2 (15 min, P < 0.01) and 55.7 ± 13.6 (60 min, P < 0.01) pmol/ml, respectively; the endothelial content of kynurenic acid was also increased (51.6 ± 5.8 vs. 73.2 ± 9.4 fmol/μg of protein; 15 min; P < 0.01). dl-homocysteine seems to modulate the production of kynurenic acid both directly and indirectly, possibly following the conversion to S-adenosylhomocysteine. The obtained data suggest a potential contribution of altered formation of kynurenic acid to the endothelial changes induced by hyperhomocysteinemia.

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