Homocysteine, a risk factor for atherosclerosis, biphasically changes the endothelial production of kynurenic acid.
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 alpha7-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 microM enhanced, whereas at >or=400 microM 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/microg 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.
Stazka
Janusz
J
Department of Cardiosurgery, Skubiszewski Medical University, Jaczewskiego 8, 20-090 Lublin, Poland.
Luchowski
Piotr
P
Urbanska
Ewa M
EM
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology; D003545:Cysteine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006710:Homocysteine / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007736:Kynurenic Acid / Q000097:blood / Q000378:metabolism*; D007930:Leucine / Q000494:pharmacology; D008297:Male; D008715:Methionine / Q000494:pharmacology; D010649:Phenylalanine / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012307:Risk Factors; D012435:S-Adenosylhomocysteine / Q000008:administration & dosage / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D010875:Pipecolic Acids; D006710:Homocysteine; D010649:Phenylalanine; C053672:selfotel; D012435:S-Adenosylhomocysteine; D008715:Methionine; D007930:Leucine; D007736:Kynurenic Acid; D003545:Cysteine; D005998:Glycine